Adult Depression Clinical Practice Guidelines

NATIONAL CLINICAL PRACTICE GUIDELINE

Adult Depression Clinical Practice Guideline

This guideline is informational only. It is not intended or designed as a substitute for the reasonable exercise of independent clinical judgment by practitioners, considering each patient’s needs on an individual basis.

Guideline recommendations apply to populations of patients. Clinical judgment is necessary to design treatment plans for individual patients.

Approved by the National Guideline Directors February 2012

Table of Contents

Introduction...... 1 Guideline Summary...... 5 Rationale Statements ...... 12 1. First-Line Treatment of Major Depressive Disorder (MDD) ...... 12 2. Hypericum (St. John’s Wort) for MDD...... 38 3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, Or Plan...... 44 4. Second-Line Treatment Of MDD ...... 48 5. Length Of Treatment With Antidepressants In Patients With MDD...... 63 6. Follow-Up For Patients In The Acute Phase of Treatment For MDD...... 70 7. Follow-Up For Patients In The Continuation Phase of Treatment of MDD...... 72 8. Follow-Up For Patients In Maintenance Phase of Treatment of MDD...... 74 9. Discontinuation of Antidepressants in Patients with MDD...... 75 10. Treatment Preferences For MDD In Different Ethnic Groups ...... 77 11. Patient Self-Management Strategies for Improving Symptoms of MDD...... 80 12. Behavioral Health Education Classes For Adults With MDD...... 95 13. Antidepressants To Avoid During Pregnancy or Breastfeeding...... 98 Appendix A: Criteria for Grading the Evidence ...... 108 Appendix B: Supporting Documentation ...... 110 1. First-Line Treatment of Major Depressive Disorder (MDD) ...... 110 Problem Formulation 1 ...... 110 Search Strategy ...... 111 Evidence Tables...... 114

2. Hypericum (St. John’s Wort) For Treatment of MDD ...... 196 Problem Formulation 2 ...... 196 Search Strategy ...... 197 Evidence Tables...... 200

3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, or Plan..... 207 Problem Formulation 3 ...... 207 Search Strategy ...... 208 Evidence Tables...... 210

4. Second-Line Treatement of MDD ...... 214 Problem Formulation 4 ...... 214 Search Strategy ...... 215 Evidence Tables...... 218

5. Length of Treatment With Antidepressants In Patients With MDD...... 228 Problem Formulation 5 ...... 228 Search Strategy ...... 229 Evidence Tables...... 232

6. Follow-Up For Patients In The Acute Phase of Treatment For MDD...... 239 Problem Formulation 6 ...... 239 Search Strategy ...... 240 Evidence Table...... 242

7. Follow-Up For Patients In The Continuation Phase of Treatment For MDD ...... 243 Problem Formulation 7 ...... 243 Search Strategy ...... 244 Evidence Table...... 246

8. Follow-Up For Patients In Maintenance Phase Treatment Of MDD ...... 247 Problem Formulation 8 ...... 247 Search Strategy ...... 248 Evidence Table...... 249

9. Discontinuation of Antidepressants In Patients With MDD...... 250 Problem Formulation 9 ...... 250 Search Strategy ...... 251 Evidence Tables...... 253

10. Treatment Preferences For MDD In Different Ethnic Groups ...... 255 Problem Formulation 10 ...... 255 Search Strategy ...... 256 Evidence Table...... 258

11. Patient Self-Management Strategies For Improving Symptoms of MDD...... 259 Problem Formulation 11 ...... 259 Search Strategy ...... 260 Evidence Tables...... 262

12. Behavioral Health Education Classes For Adults With MDD...... 276 Problem Formulation 12 ...... 276 Search Strategy ...... 277 Evidence Tables...... 279

13. Antidepressants To Avoid During Pregnancy or Breastfeeding...... 283 Problem Formulation 13 ...... 283 Search Strategy ...... 284 Evidence Tables...... 285 References...... 298

Introduction

Kaiser Permanente’s National Guideline Program

The National Guideline Program (NGP) supports the development of a core set of explicit, scientifically-based clinical practice guidelines, practice resources, and evidence synopses to assist Kaiser Permanente (KP) physicians, administrators, and other health care professionals in determining the most effective medical practices.

This core set of evidence-based resources will:  Create Programwide economies of scale,  Support ongoing performance improvement activities,  Consistently provide high quality resources for use in care delivery tools and systems, and  Increase KP regions’ abilities to leverage clinical guidelines to improve clinical outcomes.

Clinical practice guidance, based on scientific evidence, is essential for providing high quality care and continuously improving on it. Such guidance needs to be integrated into the electronic medical record and other decision support tools to be accessible to clinicians at the point of care. In addition, engaging our members in collaborative, shared decision-making conversations regarding their personal preferences is an essential component of patient-centered quality care. Furthermore, cost-effectiveness of various evidence-based interventions and resource limitations are important considerations. This involves addressing health problems in ways that maximize the health of the population given the available resources. Who are the National Guideline Directors’? The National Guideline Directors (NGD) are a group of experts and advocates of evidence-based medicine who provide direction and oversight to the National Guideline Program (NGP). In this role, the NGD selects and approves topics for evidence-based knowledge products, owns Kaiser Permanente’s Common Methodology, and is responsible for quality assurance review. This group is composed of representatives from the Care Management Institute (CMI) and all eight regions. What Is the Guideline Quality Committee? The Guideline Quality (GQ) Committee is a subcommittee of the NGD consisting of a group of evidence experts from various KP regions and CMI who review and approve all the National Guidelines. This review ensures that the processes used to develop guideline content have adhered to KP evidence-based methods and that the labels applied to clinical recommendations therein are accurate (e.g., “evidence-based” or “consensus-based”).

How Are Guidelines Developed? Guidelines are developed with the use of an “evidence-based methodology” and involve a systematic literature search, critical appraisal of the research design and statistical results of relevant studies, and grading of the sufficiency (quantity, quality, consistency, and relevancy) of the evidence for drawing conclusions. An evidence search includes literature published in peer- reviewed scientific journals, existing evidence-based guidelines, consensus-based statements from external professional societies and government health organizations, and clinical expert opinion of KP regional specialty groups. For additional information on evidence grading, see Table 1 in Appendix A.

To develop a or revise a guideline, CMI consultants work with a multidisciplinary Guideline Development Team (GDT). Each GDT consists of a core group of physicians, representing primary care and the specialties most affected by the guideline topic, and, as appropriate, other content experts from disciplines such as pharmacy, nursing, and health education. The members of a GDT are nominated by the respective National Guideline Directors to represent their regions. The GDT reviews the appraisal of the evidence and develops or revises clinical recommendations based on the current evidence. Each regional representative then presents the draft guideline recommendations to key experts and champions in their regions for critical review and support to improve the likelihood of implementation once the guideline is published. How Often Are Guidelines Reviewed and Revised? To keep current with changing medical practices, all guidelines are reviewed, and, if appropriate, revised at least every two years. To develop the Adult Depression Guideline, released in February 2010, a multidisciplinary, interregional GDT first met in November 2009 to define the scope of the guideline. The Project Management Team then performed systematic reviews of the medical literature on each of the clinical questions identified by the GDT, assembled the evidence, and developed draft recommendations for review by the GDT. All of the recommendations and supporting evidence were reviewed in depth by the GDT in a series of meetings from November through January 2010. The GQ Committee reviewed and approved the guidelines in February 2010. All recommendations included in the guideline were approved by the NGD. What Does It Mean for a Guideline to Be Evidence-Based? Each clinical recommendation within a guideline is labeled as “evidence-based” or “consensus- based.” A recommendation is considered “evidence-based” if there has been a systematic review of the evidence, the evidence is sufficient, and the recommendation is consistent with the evidence. A recommendation can also be considered “evidence-based” if there is insufficient evidence but either no particular intervention is recommended or options are recommended without favoring one of the options over others. A recommendation is considered “consensus- based” if there has been a systematic review of the evidence, the evidence is insufficient to support an evidence-based recommendation, and the GDT decides to make a consensus recommendation.

What Does It Mean for a Guideline to Be Approved and National? A recommendation that is consistent with the above policies is labeled as “National Guideline Directors Approved.” A recommendation that fails to satisfy those criteria is not approved and will be noted as such. A National Guideline Directors Approved guideline for which at least 90% of the recommendations are approved by at least six of the eight KP regions is a "National Guideline." On the topics for which they exist, National Guidelines are the preferred evidence source for KP HealthConnect content.

Contact information: David Price, MD Devon McCabe, MA Adult Depression Clinical Lead Care Management Consultant Care Management Institute Care Management Institute E-mail: [email protected] E-mail: [email protected]

Acknowledgments

The Kaiser Permanente (KP) Adult Depression Clinical Practice Guideline is the result of the extensive clinical expertise, collaborative efforts, and outstanding personal contributions of the following participants: KP Adult Depression Guideline Project Management Team David Price, MD Clinical Lead Care Management Institute Devon McCabe, MA Project Manager Care Management Institute Christy N. Pham, MPH Lead Analyst KP-Southern California Erin G. Stone, MD, FACP EBM Methodologist Care Management Institute Tabitha Pousson Staff Assistant Care Management Institute

KP Adult Depression Guideline Development Team There were no conflict of interests for any member of the Guideline Development Team (GDT).

Colorado Jean E Milofsky MD – Regional Department Chair, Psychiatry Kerri Gaughan, PharmD, BCPP – Clinical Pharmacy Specialist, Mental Health David Price, MD – Director of Medical Education, CPMG; CMI Depression Guideline & Education Lead; Medical Director, KP National CME Program Georgia Sam W. Moss, MD, MS – Lead Physician, Adult Medicine; Assistant to the Chief of Medicine for Asthma/Depression Hawai’i John Draeger, MD – Chief, Behavioral Health Service Samuel V Gadam – Geriatric psychiatrist Mid-Atlantic States Timothy M Sitts, MD – Psychiatrist Northern California Mason Turner, MD – Chief, Department of Psychiatry; Assistant Director, Regional Mental Health and Chemical Dependency Joyce O. Arango, DrPH – Sr. Managerial Consultant, Northern California Guidelines Director John Guzman, PhD – Subchief, SSF Behavioral Medicine, Regional Chair; Behavioral Medicine Subchiefs Gabrielle Beaubrun, MD – Psychiatrist Assistant Chief of Psychiatry Steve Olson, MD – Family Physician, Depression Champion; Co-Manager Behavior Medicine Services Northwest Jonathan Ebbing, MD – Psychiatrist Ohio William S. Schwab, MD PhD AGSF – Chief of Geriatrics Horia Craciun, MD – Psychiatrist Larissa Elgudin, MD – Regional Chief of Behavioral Health Services, Parma Program Offices Andrew Bertagnolli, PhD – Senior Consultant, Behavioral Medicine & Pain Mgmt Care Management Institute Southern California Christy N. Pham, MPH – Consultant, Technology Assessment & Guidelines Unit Erin G. Stone, MD, FACP – Physician Lead, Clinical Content and Decision Support Debbie R Kubota, PharmD – Pharmacist Evidence Analyst & Strategist Misha Askren, MD – Family Medicine Mark Dreskin, MD – Regional Depression Co-Lead; Physician in Charge; Same Day Acute Medical Services Kerri Gaughan, PharmD, BCPP – Clinical Pharmacy Specialist, Mental Health

Guideline Summary

Guideline recommendations apply to populations of patients. Clinical judgment is necessary to design treatment plans for individual patients.

1. First-Line Treatment of Major Depressive Disorder (MDD) 1A For patients with mild to moderate Major Depressive Disorder (MDD), use either antidepressant medication or psychotherapy* as first-line treatment. Evidence-based: B 1B Given the lack of evidence on a clearly superior approach for mild to moderate MDD, base treatment decisions on patient and clinician preference, potential side effects, and cost. Consensus-based 1C For patients with severe or chronic MDD, combine antidepressant use and psychotherapy* as first-line treatment. Evidence-based: B 1D If antidepressants are used, any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA) may be prescribed as first-line treatment of MDD. Evidence-based: B 1E Given the equivalence of therapeutic effect, base the choice of antidepressant on patient’s prior response, patient and clinician preference, potential side effects, and cost. Consensus-based

* (Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy)

2. Hypericum (St. John’s Wort) For Treatment of MDD 2A The GDT makes no recommendation for or against providing hypericum (St. John’s wort) in patients with mild to moderate Major Depression.

There is fair evidence of effectiveness of hypericum in this population. However, due to lack of consistency of preparation oversight and dosage across trials, and concerns about lack of FDA oversight and consistency of hypericum preparations, the balance of benefits, harms, and costs compared with other treatments cannot be determined. Evidence-based: C* 2B The GDT recommends against providing hypericum (St. John’s wort) to patients with severe Major Depression. Evidence-based

3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, or Plan 3A For patients with Major Depression expressing suicidal intent or plan, the GDT recommends consultation with specialty behavioral health. Consensus-based 3B For patients with suicidal ideation or who have made previous suicide attempts, the GDT recommends consultation or collaboration with a psychiatrist before prescribing TCAs or venlafaxine. Consensus-based

* Please note that only recommendations approved since the adoption in 2006 of evidence grading will use letters (A, B, C, etc.) to specify the grade of the evidence. Recommendations approved prior to 2006 will not include a letter grade following the statement “evidence-based.” For additional information on evidence grading, see Appendix A.

4. Second-Line Treatment of MDD 4A For patients with MDD whose symptoms fail to remit after first-line treatment, the GDT recommends an assessment of the adherence to the initial treatment regimen. Consensus-based 4B For patients with MDD whose symptoms fail to remit after adherence to first-line treatment, the GDT recommends that treatment options include:  Combining antidepressants and psychotherapy. Evidence-based  Increasing the dose of the initial antidepressant. Consensus-based  Switching to a different antidepressant of the same or different class. Consensus-based  Switching from psychotherapy to antidepressants or antidepressants to psychotherapy. Consensus-based  Combined pharmacologic treatment (monitoring for toxicity, side effects and drug interactions) with SSRIs and: . low-dose TCAs, or . bupropion, or . buspirone, or . mirtazepine, or . lithium, or . liothyronine (T3). Consensus-based (all in this list) 4C The GDT makes no recommendation for or against providing folate or inositol to patients whose MDD symptoms fail to remit after adhering to first-line treatment. Evidence-based: I 4D The GDT makes no recommendation for or against providing atypical an antipsychotics to primary care patients with (nonpsychotic, nonbipolar) MDD whose symptoms fail to remit after adherence to first-line treatment.

There is fair evidence of short-term effectiveness for use of atypical antipsychotic agents to augment antidepressants in patients with nonpsychotic, nonbipolar MDD who fail to remit after initial treatment. However, due to lack of longer-term data, known cardiometabolic risks of treatment with these medications, and lack of comparison data against other strategies, the balance of benefits, harms and costs compared with other treatments cannot be determined. Evidence-based: I 4E The GDT recommends against providing augmentation with pindolol for patients with MDD whose symptoms fail to remit after adherence to first-line treatment. Evidence-based

5. Length of Treatment With Antidepressants In Patients With MDD Patients Who Achieve Symptom Remission 5A The GDT recommends that patients with MDD who achieve symptom remission with antidepressants should continue antidepressants at the same dose for at least an additional six to 12 months. Evidence-based Patients With One Lifetime Episode of MDD 5B Based on patient and provider preference, the GDT recommends that a trial of antidepressant discontinuation is optional for patients in their first lifetime episode of MDD, who are being treated with antidepressants, achieve remission, and remain asymptomatic for six to 12 months after acute phase treatment. Consensus-based Patients With Two or More Lifetime Episodes of MDD 5C The GDT recommends that patients with two or more lifetime episodes of MDD, who are being treated with antidepressants and remain asymptomatic after acute phase treatment, should be maintained on the medication and dose with which they achieved remission for at least an additional 15 months to five years after acute phase treatment. Consensus-based Patients With Chronic MDD or MDD With Concurrent Dysthymia 5D The GDT recommends that patients with chronic MDD (continual symptoms for more than two years) or Double Depression (MDD and dysthymia) who improve with antidepressants during acute phase treatment should continue antidepressants for at least an additional 15 to 28 months after acute phase treatment. Evidence-based

6. Follow-Up For Patients In The Acute Phase (First Three Months) of Treatment For MDD 6 For patients who are starting treatment with antidepressants for Major Depression, the GDT recommends that the minimum recommended follow-up frequency is one patient contact* within the first month, and at least one additional patient contact four to eight weeks after the first contact.

Assess for adherence, side effects, suicidal ideation, and patient response during both these visits. Consensus-based

* Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone calls/email between patient and a care manager. The use of email between patients and providers is relatively new, and has not been a widely utilized means of communication to date. However, it is being increasingly advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one member of the GDT uses this modality regularly and deems it effective for follow-up contacts.

7. Follow-Up For Patients In The Continuation Phase (Months Four To 12) of Treatment For MDD 7 After achieving symptom remission, the GDT recommends at least one follow-up contact* during the fifth or sixth month of treatment in patients with Major Depression. Assess for continuing symptom remission and dosage/treatment adjustment during this contact.

The GDT recommends additional patient follow-up to consider either continuing treatment beyond the continuation phase, or attempting a trial of treatment discontinuation. Consensus-based

8. Follow-Up For Patients In The Maintenance Phase (Beyond 12 Months) of Treatment For MDD 8A For asymptomatic patients with Major Depression who are continuing on antidepressants beyond 12 months, the GDT recommends at least one annual follow-up contact* is recommended to assess for continuing symptom remission, the need for ongoing treatment, and dosage/treatment adjustment. Consensus-based 8B The GDT recommends that additional follow-up for asymptomatic patients with Major Depression who are continuing on antidepressants beyond 12 months should be based on patient preference and response. Consensus-based

9. Discontinuation of Antidepressants In Patients With MDD 9A Fluoxetine may be discontinued, without tapering, with a relatively low risk of adverse effects. Evidence-based 9B The GDT recommends tapering other antidepressants (other SSRIs, TCAs, SNRIs, NRIs, and DAs) over a two to four week period. Consensus-based

10. Treatment Preferences For MDD In Different Ethnic Groups 10 Because patient preferences for treatment may vary based on their ethnicity and culture, the GDT recommends asking patients from different ethnic groups about treatment preference when discussing treatment options for MDD. Evidence-based

11. Patient Self-Management Strategies For Improving Symptoms of MDD

Exercise 11A Exercise is an adjunctive strategy (in addition to antidepressants or psychotherapy) for treating MDD. Evidence-based :B Internet Resources 11B Selected internet-based patient self-help materials may be used as an optional adjunct strategy (in addition to antidepressants or psychotherapy) for treating MDD. Consensus-based Bibliotherapy 11C Selected bibliotherapy* may be used as an optional adjunct strategy (in addition to antidepressants or psychotherapy) for treating MDD. Consensus-based Befriending 11D Befriending† is an optional adjunct to antidepressants or psychotherapy for treating MDD. Consensus-based Patient-Initiated Combined Phone/Computer Programs 11E There is insufficient evidence for or against using patient-initiated combined phone/computer programs in the treatment of MDD. Evidence-based: I Light Therapy 11F There is insufficient evidence for or against using light therapy as a primary or adjunctive treatment for nonseasonal forms of MDD. Evidence-based: I Music Therapy 11G There is insufficient evidence for or against using music therapy in the treatment of MDD. Evidence-based: I Life Review Therapy 11H There is insufficient evidence for or against using life review therapy in the treatment of MDD. Evidence-based: I 12. Behavioral Health Education Classes For Adults With MDD (Cognitive Behavioral Skills or Problem-Solving Classes) 12 For patients with mild to moderate MDD, the GDT recommends behavioral health education classes as an adjunctive treatment option. However, these classes should not be used in lieu of either antidepressant medication or psychotherapy. Evidence-based

* Bibliotherapy: Advising people to read specific written material based on cognitive-behavioral approaches to depression treatment.

† Befriending: Consists of a designated befriender who meets the depressed person to talk and socialize with for at least one hour per week.

13. Antidepressants To Avoid During Pregnancy or Breastfeeding

Pregnancy 13A Do not start paroxetine in women who are pregnant. Evidence-based: D 13B Use caution in starting other selective serotonin re-uptake inhibitors (SSRIs) in women who are pregnant. Consensus-based . Discuss risks to the mother and fetus of untreated maternal depression, as well as the risk of fetal adverse effects from antidepressants. 13C If drug therapy is a consideration for treatment of maternal MDD during pregnancy and/or breastfeeding, then: . Individualize according to patient history and need for medication, and . Discuss the benefits and harms of the various treatment options with the patient. Consensus-based 13D If MDD is in remission and a woman becomes pregnant while taking antidepressants during the continuation or maintenance phase of treatment, then: . Discuss the risks to the mother and fetus of untreated maternal depression or depression relapse after antidepressant discontinuation, as well as the risk of fetal adverse effects from continuing antidepressants, and . Monitor for first trimester fetal malformations if taking paroxetine. Consult OB/GYN for considerations on fetal malformation screening. Consensus-based Breastfeeding 13E Do not start fluoxetine and/or citalopram in breastfeeding women in most circumstances. If used, they should be used with caution, and only in patients who had good results with these medications during pregnancy or a previous depression episode. Consensus-based. 13F In women taking antidepressants during pregnancy whose depression is in remission and who desire to breastfeed: . Discuss the risks to the mother and fetus of untreated maternal depression or depression relapse after antidepressant discontinuation and the risk of adverse effects in the nursing newborn of mothers continuing antidepressants, and . Consider changing treatment for depression if the newborn shows potential antidepressant-related adverse effects (withdrawal symptoms) during the first few hours after birth. Consensus-based

Rationale Statements

2010 Update New evidence was found, the recommendation remains unchanged.

* (Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy)

† The criteria for grading the strength of the evidence as either “good,” “fair,” or “insufficient” adheres to the KP National Guideline Program’s “Policies and Procedures” documents entitled “Label and Language of Recommendations” and “KP System for Grading the Strength of a Body of Evidence,” which are located in Appendix A.

Search Strategy Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. Casacalenda(1) study was indexed as a review article in PubMed and did not show up in the search results due to the way PubMed indexing is done. Another information source was the AHRQ Evidence report on the Treatment of Depression- Newer Pharmacotherapies.(2) See Appendix B for more information on the search strategy.

The GDT determined that a limited review of the clinical question focusing on first-line medication treatment for MDD was most appropriate for the current 2010 update. Systematic reviews and meta-analyses were included in the current update. Original studies that demonstrated selective reporting using non-systematic searches or were industry-sponsored were excluded.

Note: There is no universally used definition of mild, moderate, and severe Major Depression. To determine severity, clinicians can use either the depression score from a standardized, validated depression rating scale (such as the PHQ-9, Beck Depression Inventory, Zung Depression Scale, and others that are often used in Major Depression studies) or use the following commonly used clinical consensus rating system as a guide to determining symptom severity. Severity of Major Depression SYMPTOM NUMBER OF MDD SYMPTOMS PATIENT FAMILY, SOCIAL, SEVERITY (DSM-IV CRITERIA) OR OCCUPATIONAL IMPAIRMENT Mild 5 to 6 Minor Moderate 6 to 7 Moderate Severe 8 to 9 Severe; including suicidal intention or plan

After reviewing this new evidence, the overall recommendation for first-line antidepressant treatment remains unchanged. The included studies are summarized below (please refer to Evidence Table 1.1 for study details). A limited review focusing on first-line medication choice for treatment of MDD was conducted. Systematic reviews and meta-analyses were included. Analyses using non-systematic searches and single antidepressant vs. placebo trials of established (previously reviewed) antidepressants were excluded. Eighteen relevant systematic reviews and meta-analyses were identified. Efficacy outcomes were measured by response rates, defined as a reduction of 50% of baseline Hamilton Depression Rating Scale (HAM-D) or the Montgomery-Asberg Depression Rating Scale (MADRS) or a score of ‘much improved’ on the Clinical Global Impression score(CGI); and/or remission, defined frequently in studies by a preset cut-point of ≤ 7 to 9 on the HAM-D score. Tolerability or acceptability was measured by overall dropout rates, discontinuation rates due to adverse events, or rates of adverse events.

Three studies (Mukai 2009,(3) Gartlehner 2008a,(4) Gartlehner 2008b(5)) compared the efficacy and tolerability of different drug classes (e.g., TCA, SSRI, SNRI, other antidepressants) to each other; nine studies (Cipriani 2009b,(6) Cipriani 2009c,(7) Cipriani 2009a,(8) Nakagawa 2009,(9) Omori 2009,(10) Cipriani 2008,(11) Van den Broek 2009,(12) Weinmann 2008,(13) Watanabe 2008(14)) compared individual antidepressants to other antidepressants; and six studies (Arroll 2009,(15) Hansen 2008,(16) Barbui 2009,(17) Barbui 2008,(18) Deshauer 2008,(19) Nelson 2008(20)) evaluated antidepressants, individually or as a class, relative to placebo. The majority of the studies focused on the 12 newer, second-generation antidepressants that included bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine. Head-to-Head Comparisons of Antidepressants*  Mukai et al. (2009)(21) reviewed 18 RCTs examining the efficacy of single- versus dual- action Antidepressants for the treatment of depression among patients ≥ 59 years. In this narrative review, authors conducted a systematic search of published studies; however, data were scarce and insufficient to conduct a meta-analysis of head-to-head comparisons. In addition, publication bias assessment was not reported. Overall, limited data suggest that dual-action agents such as TCAs and SNRIs do not appear to confer any additional efficacy benefits over single-action agents such as SSRIs in the treatment of depression in the elderly. Two trials found no significant difference in efficacy between TCAs vs. SSRIs; three studies found no significant difference between venlafaxine vs. SSRIs; one study of duloxetine vs. placebo (funding source not reported) found significant improvement in depression (p < 0.001), pain (p < 0.001), and cognition (p = 0.013) in favor of duloxetine; and five studies suggested no additional efficacy benefit for the SNRI venlafaxine compared with SSRIs or TCAs.  Gartlehner et al. (2008a)(4) conducted a meta-analysis of 203 studies (including head-to- head RCTs; observational studies; placebo trials; systematic reviews, meta-analyses, and studies with pooled data) on the comparative benefits and harms of second-generation antidepressants. Overall, no substantial differences in comparative efficacy and effectiveness of second-generation antidepressants for treatment of MDD were detected; the evidence did not support the choice of one second-generation antidepressant over another. Nevertheless, authors noted some differences in adverse events. Some statistical differences in onset of action were noted, however these differences may not be clinically significant since most response rates were similar after four weeks of treatment and all seven studies that examined speed of response were funded by manufacturer.

* The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

 In a separate sub-analysis, Gartlehner et al. (2008b)(5) assessed the comparative harms of second-generation Antidepressants for MDD by reviewing 104 studies (83 head-to-head RCTs (N > 17,000) and 21 observational studies (N > 740.000)). Outcome measures were rates of adverse effects, specific adverse effect reported, and overall rate of adverse effect. Adverse effects profiles of second-generation antidepressants were similar; nausea, vomiting, diarrhea, dry mouth, sweating, headache, dizziness, sexual dysfunction and weight gain were commonly reported adverse effect. However, individual drugs differed in frequencies of specific adverse effects, which might be clinically relevant and influence the choice of treatment for individual patients (on a case-by-case basis).  Roughly 63% of patients in efficacy trials experienced at least one adverse effect. No significant difference was detected between second-generation antidepressants and SSRIs, except for venlafaxine, which had higher discontinuation from adverse effects and higher rate of nausea and vomiting than SSRIs [(Relative Risk (RR) discontinuation from adverse effects: 1.42 (95% CI: 1.15 to 1.75); RR = from nausea and vomiting: RR = 1.53 (95% CI: 1.26 to 1.86); NNH = 9 (95% CI: 6 to 23)].  Compared with other second-generation antidepressants, paroxetine frequently was associated with higher rates of sexual dysfunction and bupropion with lower rates of sexual dysfunction; mirtazapine and paroxetine were associated with more weight gain (up to 3 kg, although not always specified); and sertraline was associated with higher rates of diarrhea. However, differences did not lead to significantly different discontinuation rates.  Cipriani et al. (2009a)(8) evaluated the efficacy and acceptability of 12 second-generation antidepressants in a meta-analysis of 117 RCTs (N = 25,928). Only seven of these trials were in primary care settings. Included studies were of short duration. Fifteen unpublished studies from industry were included, it was not specified how many of these favored the funder’s antidepressant (no funnel plots or assessment of publication bias was noted, and it was not clear how many of these studies were also included in the FDA trial database). Authors noted a small number included in each pair-wise comparison. Mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious treatments for depression response (remission was not assessed). Escitalopram, sertraline, bupropion, and citalopram were better tolerated than other antidepressants. Reboxetine, fluvoxamine, paroxetine, and duloxetine tended to have lower efficacy and tolerability than other antidepressants. Numbers needed to treat or harm were not calculated, making it difficult to assess the absolute differences in each analysis. Additionally, statistical significance (defined as p < 0.05 in this analysis) was not adjusted for multiple comparisons, so many differences could have been due to chance.

Escitalopram vs. Other Antidepressants  Cipriani et al. (2009b)(6) examined the efficacy and tolerability of escitalopram compared to other Antidepressants in 22 RCTs. Patients with medical comorbidity were excluded, limiting the potential applicability to primary care settings. In terms of efficacy, escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR = 0.67, 95% CI: 0.50 to 0.87) and remission (OR = 0.53, 95% CI: 0.30 to 0.93). In terms of tolerability, fewer patients allocated to escitalopram withdrew from trials due to any cause compared to duloxetine (OR = 0.62, 95% CI: 0.38 to 0.99). This analysis is limited by potential publication and sponsorship biases and potential selective reporting of results. Milnacipran vs. Other Antidepressants  Nakagawa et al. (2009)(9) examined milnacipran versus other antidepressants in a meta- analysis of 16 RCTs (N = 2777). When compared to TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95% CI: 0.35 to 0.85) and there was a trend that suggested fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation. No other significant differences in efficacy, acceptability and tolerability were detected when comparing milnacipran with other antidepressive agents. However, authors noted that there remained “inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression.” Milnacipran is not currently available in the United States. Fluvoxamine vs. Other Antidepressants  Omori et al. (2009)(10) reviewed the efficacy and tolerability of fluvoxamine and other antidepressants in 53 RCTs (N = 8,244 for efficacy; N = 6,440 for tolerability). In terms of efficacy, no significant differences were detected in response and remission rates between fluvoxamine and other antidepressants as a class (TCAs, heterocyclics, SNRIs, SSRIs) in early or end of acute phase of treatment. In addition, dropouts for any reason or for adverse effects were not significantly different between fluvoxamine and other antidepressants as a class or individually. Nausea or vomiting and weight loss or anorexia were more frequent with fluvoxamine than with TCAs and some other antidepressants (mianserin, milnacipran, and newer antidepressants); constipation and dry mouth were more common with TCAs than with fluvoxamine. The authors concluded that “the initial selection of an antidepressant medication will and should largely be based on the anticipated side effect profile and patient’s preference.”

Sertraline vs. Other Antidepressants  Cipriani et al. (2009c)(22) assessed the efficacy and tolerability of sertraline compared to other antidepressants in 59 RCTs (N = 9,950). Evidence favoring sertraline over some individual antidepressants for the acute phase treatment of major depression was found, either in terms of treatment response (fluoxetine) or acceptability/tolerability (amitriptyline, imipramine, paroxetine, and mirtazapine). No statistically significant difference in remission between fluoxetine and sertraline was noted. However, some differences favoring other antidepressants over sertraline in terms of response (mirtazapine, amitriptyline) and acceptability (bupropion) were also noted. Sertraline was generally associated with a higher rate of participants experiencing diarrhea. Overall, the quality of included studies was low, not all pre-specified outcomes were reported in included studies, and outcomes of clear relevance to patients and clinicians were not reported in any of the included studies. No analysis of publication bias was conducted. Few studies reported remission rates, those that did were underpowered to detect clinical significance. Analysis of sertraline vs. other antidepressants as a class was not conducted.  Cipriani et al. (2008)(11) evaluated sertraline compared to other antidepressants in a meta- analysis of 56 RCTs (N = 8,507 for efficacy; N = 8,387 for tolerability). There was substantial overlap of studies in this analysis and the analysis conducted in Cipriani et al. (2009a)(8), thus many of the same limitations (short duration of included trials, few trials conducted in primary care settings) apply. Trials including patients with medical disorders were excluded from this analysis, also limiting applicability to the primary care setting. FDA trial databases and similar European trial databases were searched for study inclusion in this analysis; most included studies were funded by the maker of sertraline. This analysis also did adjust the level of significance to p < 0.01 to account for multiple comparisons. Included studies used different dosing schedules, making it difficult to determine differences (or lack thereof) between equivalent effective doses of antidepressants. Sertraline was more efficacious than other SSRIs [RR = 0.88 (99% CI: 0.78 to 0.99), p = 0.009; NNT = 17], particularly fluoxetine [RR = 0.85 (99% CI: 0.74 to 0.98); p = 0.004; NNT = 12]. But sertraline’s efficacy was not significantly different from TCAs [RR = 0.95 (99% CI: 0.83 to 1.09)] or any other antidepressants, For acceptability, no significant differences were detected between sertraline and TCAs [RR = 0.83 (99% CI: 0.66 to 1.04)], SSRI [RR = 0.9 (99% CI: 0.68 to 1.18)], or any other antidepressants. In the conclusions section, the authors site “cardiovascular physicians’ belief and clinical care practices” in treating depression in patients with cardiovascular disease as observational evidence supporting their conclusion of sertraline “as a candidate for initial choice of antidepressant.” Venlafaxine vs. Other Antidepressants  Van den Broek et al. (2009)(12) compared the effectiveness of venlafaxine to TCAs in seven RCTs (N = 947). There were no significant differences for response [OR = 0.88 (95% CI: 0.66-1.16)] or withdrawal [OR = 1.21 (95% CI: 0.89-1.64)] of TCA vs. venlafaxine. However, authors noted that “because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.”

 Weinmann et al. (2008)(13) evaluated the efficacy and tolerability of venlafaxine compared with SSRI in 17 RCTs (N = 3,523 for response analysis; N = 3,142 for remission analysis). There were no statistically significant differences between venlafaxine and the SSRI group with respect to response [random-effect RR = 1.05, (95% CI: 1.00 to 1.10); NNT = 27] and remission [random-effect RR = 1.04, (95% CI: 0.96 to 1.13); NNT = 34]. Total rate of treatment discontinuation did not differ between venlafaxine and SSRIs (RR = 1.05, 95% CI: 0.93 to 1.2, NNH = 100), but there were significantly more dropouts due to adverse effects in the venlafaxine vs. SSRIs group [RR = 1.38, 95% CI: 1.08 to 1.77, NNH = 32]. Mirtazapine vs. Other Antidepressants  Watanabe et al. (2008)(14) conducted a systematic review on 25 RCTs (N = 4,842) on the effectiveness and tolerability of mirtazapine compared with other antidepressants (TCAs, SSRIs, SNRIs, and other). Results were stratified according to treatment duration, including early phase (2 weeks), end of acute-phase (6 to 12 weeks), and end of continuation phase (4 to 6 months).  Analysis of efficacy at early phase of treatment found no significant differences between mirtazapine and TCAs in response [RR = 0.9 (99% CI: 0.69 to 1.18)] and remission [RR = 0.87 (99% CI: 0.52 to1.47)]; mirtazpine was superior to SSRIs in both response [RR = 1.36 (99% CI: 1.13 to 1.64); NNT = 11] and remission [RR = 1.68 (99% CI: 1.2 to 2.36); NNT = 25], particularly, significantly better than paroxetine in response [RR = 2.02 (99% CI: 1.09 to 3.75); NNT = 8] and sertraline in remission [RR = 1.73 (99% CI: 1.01 to 2.98); NNT = 12]; and mirtazapine was significantly superior to SNRI in terms of response [RR = 1.77 (99% CI: 1.08 to 2.89); NNT = 6] but not in remission [RR = 2.21(99% CI: 0.93 to5.26)].  At the end of the acute phase (6 weeks), no statistical significant differences were detected, except for superior remission outcome in comparison of mirtazapine with paroxetine [RR = 1.34 (99% CI: 1.04 to 1.73); NNT = 10)].  At the end of the continuation phase (24 weeks), one study examined mirtazapine with paroxetine and no significant differences were detected.  No significant differences in tolerability were identified between patients treated with mirtazapine and TCAs (RR = 0.87 (95% CI: 0.7 to 1.08)], SSRIs (RR = 1.07 (95% CI: 0.92 to 1.26)], SNRI (venlafaxine) [RR = 0.82 (95% CI: 0.58 to 1.16)], or other antidepressants (trazodone) [RR = 0.93 (95% CI: 0.58 to 1.5)].  Mirtazapine dropouts due to adverse effects were similar to SSRI [RR = 1.22 (95% CI: 0.87 to 1.73)], SNRI [RR = 0.59 (95% CI: 0.27 to 1.29)], and trazodone [RR = 0.66 (95% CI: 0.3 to 1.46)]. Subgroup analysis found mirtazapine had lower withdrawals due to adverse effects compared with sertraline [RR = 2.58 (95% CI: 1.28-5.24); NNH = 11].  Based on findings authors concluded that “although mirtazapine is highly likely to have better efficacy profile than paroxetine or venlafaxine in terms of early response, in view of similar efficacy of mirtazapine and other antidepressants, results suggest that clinicians should also focus on other practically or clinically relevant considerations such as differences in the side effect profiles, to tailor treatment to best fit an individual patient’s needs.”

Antidepressants vs. Placebo*  Arroll et al. (2009)(15) reviewed 14 RCTs examining the effectiveness of TCAs and/or SSRIs compared to placebo. Both TCAs and SSRIs were significantly more effective than placebo for depression reduction and symptoms [RR = 1.24 (95% CI: 1.11 to 1.38) and NNT = 7 to 16; and RR = 1.28 (95% CI: 1.15 to 1.43) and NNT = 7 to 8, respectively]. More adverse effects were associated with TCAs than with SSRIs [NNH = 4 to 30 vs. 20 to 90, respectively].  Hansen et al. (2008)(16) compared MDD relapse and recurrence rates during continuation and maintenance phase treatment with second-generation antidepressant compared with placebo in 27 RCTs. Results were stratified by duration (those <1 year were categorized as relapse prevention and trials ≥ 1 year were categorized as recurrence prevention). NNTs for relapse prevention over a (mean of eight months) and recurrence (mean of 16 months) were each five [RR = of relapse: 0.54 (95% CI: 0.46 to 0.62), RR = of recurrence: 0.56 (95% CI: 0.48 to 0.66)]. In addition, loss to follow-up because of adverse events was not significantly different between active treatment and placebo (RR = 1.42, 95% CI: 0.92 to 2.20).  Nelson et al. (2008)(20) reviewed 10 RCTs (N = 2377) on the efficacy of second-generation antidepressants for depression in late-life (> 60 years) with respect to treatment response, remission, and tolerability. Those assigned to active drug treatment had significantly greater response [OR = 1.4 (95% CI: 1.24 to 1.57); NNT = 13] and remission [OR = 1.27 (95% CI: 1.12-1.44); NNT = 20] compared with placebo. Response rates were higher in the longer trials compared to the shorter trials [10 to 12 weeks OR = 1.73 (95% CI: 1.42 to 2.09) vs. 6 to 8 weeks OR = 1.22 (95% CI: 1.05 to 1.42)]. However, compared with placebo, there were increased odds of overall medication discontinuation [OR = 1.22 (95% CI: 1.06 to 1.4); I2 = 48.2%] and discontinuation due to medication adverse effects [OR = 1.84 (95% CI: 1.51 to 2.24)]. Evidence did not suggest superiority of one class of medication over another. Authors concluded that “for every 100 patients treated, eight would show a response and five a remission in excess of placebo and for every two patients who responded, one discontinued prematurely because of adverse effects.”  Deshauer et al. (2008)(23) pooled 6 RCTs (N = 1299) to evaluate SSRIs versus placebo for MDD. Treatment response at sic to eight months showed SSRIs to be superior to placebo [OR = 1.66 (95% CI: 1.12 to 2.48)], particularly in depressed patients without other comorbidities [OR = 2.13 (95% CI: 1.11 to 4.08)]. There were no statistically significant differences in remission [OR = 1.46 (95% CI: 0.92 to 2.32)] or drop-out rates [OR = 0.87 (95% CI: 0.67 to 1.14)] between SSRI and placebo.

* The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

Paroxetine vs. Placebo  Barbui et al. (2008)(18) compared paroxetine with placebo in a meta-analysis of 40 RCTs (N = 6391). The primary outcome was discontinuation and the secondary outcome was response. Significantly more patients assigned to receive paroxetine left the study because of side effects [random effect RR = 1.77 (95% CI: 1.44 to2.18); NNH = 17], reported any adverse effects [OR = 1.27, 95% CI: 0.88 to 1.83, NNH = 9], and experienced suicidal tendencies compared with patients given placebo OR = 2.55 (95% CI: 1.17 to 5.54); NNH = 142]. Patients who received paroxetine were more likely to experience an improvement in depressive symptoms compared to patients receiving placebo [random effect RR = 0.83 (99% CI: 0.77 to 0.90); NNT = 9]. Suicide Risk – Antidepresants vs. Placebo  Barbui et al. (2009)(17) conducted a meta-analysis of eight observational studies (> 200,000 patients) to assess the risk of suicide based on SSRI exposure. Overall, there was an increased risk of attempted or completed suicide among adolescents exposed to SSRIs [random-effect OR = 1.92 (95% CI: 1.51 to 2.44)]. In subgroup analysis, paroxetine and venlafaxine were associated with increased risk. However there was a decreased risk of attempted or completed suicide among adults and elderly individuals exposed to SSRIs (≥ 65 years) [OR = 0.57 (95% CI: 0.47 to 0.70); OR = 0.46 (95% CI: 0.27 to 0.79)]. No individual antidepressant was significantly associated with completed or attempted suicide in adults. Patients may have had additional comorbidities that may have influenced selection of treatment and have unaccounted for effects on suicide risk. Funnel plot suggested that small negative studies may not have been published and included in the analysis. Discussion: In aggregate, updated evidence suggests no significant differences in efficacy among the different classes of antidepressants (TCAs, SSRIs, SNRIs; N = 4 new studies(21), (4), (5), (24)). Five newly identified meta-analyses/systematic reviews ((20), (16), (17), (25), (23)) support the proposition that antidepressant treatment for MDD is more efficacious than placebo, especially among patients without other comorbidities.(23) One study (Nelson 2008(20)) found that response to treatment is greater in longer trials (10 to 12 weeks) compared with shorter trials (6 to 8 weeks), supporting findings of the STAR*D trial (reviewed previously). Three studies ((21), (4), (5)) did not detect significant differences among antidepressant drug classes in discontinuation for any reason and/or from side effects. However, one study (Arroll 2009(15)) suggested that more adverse events were associated with TCAs than SSRIs and another study (Nelson 2008(20)) noted increased odds for discontinuation of medication treatment compared to placebo. One study (Barbui 2009(17)) reported a decreased risk of suicide attempts or completion in depressed adults treated with SSRIs, but supported previously found associations between antidepressant exposure and suicide risk in adolescents. Although significant differences in tolerability were not detected in several studies, there was some evidence that showed marginal differences in the adverse event profiles among individual antidpressants ((4), (5), (13)).

A variety of results were reported among studies that assessed the effectiveness and tolerability of individual antidepressants relative to other antidepressants or placebo. In a head-to-head comparison study of 12 new second-generation antidepressants, Cipriani et al. (2009a)(8) reported that mirtazapine, escitalopram, venlafaxine and sertraline were among the most efficacious while reboxetine, fluvoxamine, and duloxetine were the least efficacious. One study (Watanabe 2008(14)) found that mirtazapine was equivalent to TCAs and more efficacious than SSRIs, (particularly paroxetine); no significant differences in tolerability were detected between mirtazapine and other antidepressants. Cipriani 2009b(6) showed statistically better response for escitalopram compared with citalopram and better escitalopram tolerability compared with duloxetine. Two studies demonstrated no significant differences in efficacy between venlafaxine and SSRI(13) or TCAs,(12) although one study found more dropouts due to adverse events in venlafaxine treated patients compared with SSRI patients(13). Cipriani (2009c(7)) found better response for sertraline compared with fluoxetine, and a trend in favor of mirtazapine for efficacy and bupropion for tolerability over sertraline. Another Cipriani analysis (2008(11)) reported no differences in efficacy and tolerability between sertraline, TCAs, and other antidepressants while sertraline was superior to SSRI, especially fluoxetine, in efficacy. There were significant overlaps in the studies included in these two Ciprani analyses. One study(9) found better tolerability of milnacipran compared with TCAs; however, the authors noted that there was insufficient evidence to establish the overall effectiveness and acceptability of milnacipran compared to other antidepressants (milnacipran is not available in the United States). One study(10) reported no significant differences in tolerability between fluvoxamine and other classes of antidepressants. Finally, one study (18) concluded that paroxetine was superior to placebo in response, but more withdrawals due to adverse events were observed in patients allocated to paraoxetine than placebo.

Altogether, the NNT for antidepressant treatment, either as a class or individually, ranged from 4 to 34 and the NNH ranged from 9 to 90. As a result, the benefits of antidepressant treatment for MDD appear to outweigh the identified harms.

Several important limitations were present in most of the included systematic review and meta- analyses that warrant cautious interpretation of the reported results. The majority of included studies were funded by the pharmaceutical industry, which tends to favor the funded medication. Unpublished results were likely missing from many of the analyses. The same small group of researchers published many of the studies included, and in some cases, separate analyses were presented that included several common trials, making it appear that there is stronger evidence to support a conclusion than really exists. Only a minority of studies in some analyses was conducted in primary care settings, and several studies excluded patients with comorbidities, making generalization to primary care difficult. Data was unavailable for many head-to-head comparison studies of individual antidepressants, and selective reporting of results may have occurred in several of the included trials. Selective participation of symptomatic volunteers was observed in most included trials, which may potentially overstate the true effectiveness in real world settings. Most studies reported on symptom response rather than symptom remission.

Many trials included multiple comparisons, increasing the risk of finding a statistically significant result that is truly a chance finding. Data on tolerability based on dropout rates due to adverse events were also difficult to interpret due to the variability among individual drug adverse effects profiles. Methodological concerns such as inadequate blinding and analytical methods (e.g., completer analyses and last observation carried forward methods of imputing missing data) may bias studies in favor of active treatment). Variability in dosing strategies can lead to higher effective doses of one medication being compared with lower effective doses of another. Although some studies found statistically significant results, whether these findings translate to significant clinical relevance is questionable. Conclusion: New evidence from systematic reviews of mostly lower quality studies did not suggest the need to change the previous guideline recommendation regarding antidepressants for treatment of severe MDD. Although individual studies suggest marginal benefit for specific antidepressants, in aggregate there is no consistent “directionality” amongst the studies. Furthermore, the absolute clinically important difference between antidepressants is uncertain, due to the limited quantity of the comparison studies.

Therefore, the GDT continues to find that the balance of evidence supports the use of antidepressant medication as a first-line treatment for MDD. The GDT continues to recommend, consistent with the previous guideline recommendations, that any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA) may be prescribed as first-line treatment of MDD. Similarly, the GDT maintains that clinicians base the choice of antidepressant on a patient’s prior response, patient and clinician preference, potential side effects, and cost. 2008 Guideline No new evidence was found, the recommendation remains unchanged.

2006 Guideline New evidence was found that did not change the existing recommendation. Antidepressants Alone or vs. Placebo*  Montgomery, et al. (2003)(26) reviewed four RCTs examining the effectiveness of reboxetine in the treatment of severe depression. In three of the four trials, the reboxetine group had a significantly greater decrease in Hamilton Depression Scale (HAMD) score when compared with placebo. In three of the four trials, antidepressant efficacy occurred significantly faster (at two weeks) in the reboxetine group when compared with the placebo group. In three of the four trials, the responder rate (50% improvement from baseline HAM-D score) was significantly higher in the reboxetine group (56 to 74%) compared with placebo (20 to 52%). Patients unresponsive to previous antidepressant treatment were excluded. Remission rates were not reported. Limitations of this analysis include: small number of studies, all studies included were funded by Pharmacia, the manufacturer of reboxetine, and a systematic review was not performed (unpublished studies may not have been included), the four studies were not similar in terms of duration or number of subjects, and one of the four studies had a higher baseline mean HAMD score than the rest (35.4 vs. 26.4, 27.0, and 27.2).  One systematic review(27) found in the Cochrane Database found that TCAs, SSRIs, and MAOIs are all effective in treating older adult patients with depression and a severe medical illness. The results, using a fixed effects model, for the three groups respectively were: TCAs: OR = 0.32 (95% CI: 0.21 to 0.47); SSRIs: OR = 0.51 (95% CI: 0.36 to 0.72); MAOIs: OR = 0.17 (95% CI: 0.07 to 0.39).  Another Cochrane review(28) analyzed the effectiveness of antidepressants compared with “active placebos”, based on growing concerns that differential rates of side effects between active antidepressant drugs and inactive (inert) placebos in RCTs may lead to “unblinding” of patients and clinicians to their treatment group and may potentially bias results in favor of active medication.  All the studies in the review produced a pooled estimate of effect of 0.39 standard deviations (95% CI: 0.24 to 0.54) in favor of antidepressants. When one strongly positive trial was omitted, sensitivity analysis reduced the pooled effect size to 0.17 (95% CI: 0.00 to 0.34). The review concludes that differences between antidepressants and active placebos are small.  In their analysis of five systematic reviews and seven subsequent RCTs, Clinical Evidence (Issue 14, January 2006) found a positive treatment effect of antidepressants over placebo for adults in primary and secondary care with MDD. They note, however, that there is relatively little information given about severe side effects when compared with placebo, and that publication bias has been found in RCTs of selective serotonin reuptake inhibitors.  On average, 69% of people taking placebo had worse outcomes over a mean of six weeks than the average person taking antidepressant drugs (mean effect size = 0.5 for change in score with antidepressant drugs versus placebo).(29)

* The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

 Low-dose TCAs significantly increased the proportion of people who responded at four weeks and at three to 12 months (RR = 1.65, 95% CI: 1.36 to 2.00) compared with placebo (RR = 2.14, 95% CI: 1.41 to 3.26).(30)  Newer antidepressants significantly increased the proportion of people who responded compared with placebo (51% vs. 31% respectively; RR = 1.6, 95% CI: 1.5 to 1.7).(31)  Antidepressants significantly increased the proportion of people who responded to treatment over four to 12 weeks compared with placebo (RR = 1.9, 95% CI: 1.6 to 2.3).(32)  Reboxetine significantly increased the proportion of people who responded at six weeks compared with placebo (74% vs. 20% respectively, p < 0.001).(33)  Reboxetine at any dose significantly increased the proportion of people who responded over four weeks compared with placebo (60% vs. 35% respectively; p < 0.05).(34)  Reboxetine significantly improved mean Social Adaptation Self-Evaluation Scale score at eight weeks compared with placebo (35.3 vs. 27.2 respectively, p < 0.05).(35)  Escitalopram significantly improved depressive symptoms compared with placebo at eight weeks (change in MARDS score: -15 with escitalopram, -12 with placebo, p = 0.002).(36)  Escitalopram 10 mg daily, escitalopram 20 mg daily, and citalopram 40 mg daily all significantly improved depressive symptoms compared with placebo at eight weeks (change in MADRS score from baseline: -12.8, -13.9, -12.0, -9.4 respectively; p ≤ 0.05 for all treatments versus placebo).(37)  Duloxetine significantly improved depressive symptoms compared with placebo (change in HAM-D score from baseline: -10.9 vs. -6.1 respectively, p < 0.001).(38)  In a meta-analysis (nonindustry funded) examining the efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo in primary care, Arroll, et al. (2005)(39) extracted pooled data showing that both classes of antidepressant were significantly more effective than placebo. Most studies were of short duration (less than eight weeks) and of lower methodologic quality. For TCAs, the pooled NNT for improvement was about four; the NNH for withdrawal due to side effects was 5 to 11. Low doses of tricyclic antidepressants (75 to 100 mg of amitriptyline or equivalent) were as effective as higher doses. For SSRIs, the NNT for improvement was six, the NNH for withdrawal due to side effects ranged from 21 to 94. This meta-analysis included many more studies comparing TCAs with placebo than those comparing SSRIs with placebo, and patients’ severity of depression was heterogeneous across studies. The authors conclude that “prescribing antidepressants in primary care is a more effective clinical strategy than prescribing placebo.”

Head-to-Head Comparisons of Antidepressants*  At the end of an eight week randomized trial with no placebo control subjects, Moore, et al. (2005)(40) found that patients treated with escitalopram had significantly greater adjusted (2.1 points, p < 0.05) decrease in MADRS (Montgomery-Asberg Depression Rating Scale) scores from baseline and higher responder (76.1% vs. 61.3%, p < 0.01) and remitter rates (56.1% vs. 46.3%, p < 0.05) compared with patients treated with citalopram. Adverse effects and treatment withdrawals were not significantly different between groups. Both the difference in mean score changes from baseline, and the calculated difference between mean MADRS scores at endpoint (13.9 vs. 15.4 points) are of marginal clinical significance.  In a small Japanese study examining the efficacy and safety of fluvoxamine and nortriptyline, Otsubo, et al. (2005)(41) found no significant differences in total HAMD score change (-9 vs. -12, p = 0.14), CGI (Clinician rating of Global Improvement) scores (figures not reported, p = 0.055), responder rates (55.6% vs. 57.9% on HAMD, 52.8% vs. 44.7% on CGI) or HAMD remission rates (38.9% vs. 26.3%). The authors state that the incidence of adverse events was generally higher in nortriptyline-treated patients, but no statistical analysis of significance was reported.  In a six week study with small sample sizes (n = 41 patients), Wehmeier, et al. (2005)(42) found that geriatric patients taking fluoxetine had the same HAMD treatment response (57.1% vs. 60.0%) and improvement in HAMD scores (11.9 vs. 15.8 points) as those taking trimipramine. The fluoxetine group reported fewer adverse events than the trimipramine group (54.5% vs. 66.7%) but no statistical analysis of significance was performed. The authors conclude that the two drugs are similar in terms of effectiveness and tolerability.  In a two-phase study (eight week acute phase and six month continuation phase) Detke, et al. (2004)(43) tested the effectiveness of duloxetine (both 80 mg and 120 mg doses) and paroxetine against a placebo control. In the acute phase, the authors found both doses of duloxetine and paroxetine to be statistically significantly different from placebo on all of the following outcomes: HAMD score reduction (range -11 to -12.1 points), response rates (70 to 82%), and remission rates (47 to 58%). In the continuation phase, of all the treatment groups, the higher dose of duloxetine had the longest time to loss of response when compared with placebo (p = 0.023). The adverse events ranged from 4 to 11.4%, statistical significance was not reported). Despite the implication of superiority of duloxetine, it should be noted that there was no statistical analysis comparing duloxetine with paroxetine, and duloxetine was used at doses higher than currently recommended by the manufacturer.  Sechter, et al. (2004)(44) compared milnacipran and paroxetine and found no significant differences between the two drugs on any of the following measures: HAMD score reduction from baseline (-11.8 vs. -12 points), MADRS score reduction (-16.2 vs. -16.8 points), response rate (58.1 vs. 60.3%), and remission rate (33.1% vs. 35.1%). The paroxetine group had significantly greater post-treatment discontinuation symptoms (31.8% vs. 13.0%) (p = 0.032). The study was funded by the manufacturer of milnacipran.

* The great majority of antidepressant studies included here were funded by pharmaceutical companies. In almost all cases, at least some results favored the drug manufactured by the funder.

 In a multicenter, 22 week study of 151 geriatric outpatients, Allard, et al. (2004)(45) examined the efficacy and tolerability of venlafaxine compared with citalopram, and found that both treatment groups showed comparable improvements in MADRS score (-18 vs. -17.4 points) over time. The incidence of spontaneously reported side effects/adverse effects was higher in the venlafaxine group than in the citalopram group (62% vs. 43% respectively), but no statistical analysis was performed to evaluate this difference. Treatment discontinuation due to side effects was rare (less than 10% in each group).  In an eight week trial, Montgomery, Huusom, & Bothmer (2004)(46) compared escitalopram and venlafaxine and found no significant differences between groups on MADRS (-20.7 vs. -20.4 points) or HAMD (-14.4 vs. -14 points) scores. The escitalopram group achieved response and remission significantly faster than the venlafaxine group (4.6 days p < 0.05 and 6.6 days p < 0.001 respectively). These authors found greater incidences of side effects in the venlafaxine group, specifically nausea, constipation and sweating (p < 0.05), but overall treatment discontinuation rates were similar (14.4% vs. 13.3%).  Rapaport (2003)(47) studied the efficacy of paroxetine controlled release (CR) compared with paroxetine immediate release (IR) and placebo. A statistically significant adjusted difference compared with placebo was found for both active treatments in HAMD total score change (-12.1 and -12.3 points vs. -9.5 points), CGI response rate (43% and 44% vs. 26%) and HAMD remission rate (72% and 65% vs. 52%) at 12 weeks. Post-hoc analysis noted that patients with chronic depression (duration of more than two years) responded as well as those with short-term depression. Statistical comparisons between active treatments were not reported. Withdrawal due to adverse events was highest in the paroxetine IR group, (16% vs. 12.5% vs. 8.3% for placebo) but statistical significance was not evaluated. Two authors were either employees or major stockholders of the company funding the study.  Sauer, Uppertz-Helmhold & Dierkes (2003)(48) found noninferiority of venlafaxine ER compared with amitriptyline ER, based on equivalent changes in HAMD total scores (-10.5 vs. -10.4 points). Adverse effects (70.9% vs. 81.8%, p = NS) and adverse drug reactions (55.7% vs. 71.4%, p = 0.04) were high in both groups.  In a 2003 study, Wade, et al.(49) found no significant difference between mirtazapine and paroxetine in HAMD score changes (-18.2 vs. -16.6 points), response (87% vs. 78%, p = 0.28) and remission rates (61% vs. 42%, p = 0.075) at 24 weeks. However, there were statistically significant two point differences in HAMD scores in favor of mirtazapine at two and four weeks (p = 0.012, and p = 0.030 respectively). Overall adverse effects were high and similar in each group 79% vs. 85%); the mirtazapine group had higher incidences of fatigue while the paroxetine group had significantly more sweating, headache and nausea. More than fifty percent of patients in each group discontinued treatment.  In a comparison of venlafaxine and nortriptyline in older adult patients, Gasto, et al. (2003)(50) found no significant differences in remission rates (approximately 70% overall for each drug), regardless of the severity of the depressive episode. Both drugs were similarly well tolerated; side effects were frequent (73.5% vs. 82.3%) but generally mild. Venlafaxine scored lower on the autonomic side effects subscale.

 Hansen, et al. (2005)(51) conducted a systematic review of RCTs, meta-analyses, and observational studies examining the efficacy and safety of second-generation antidepressants, and found similar outcomes among different SSRIs, and comparing SSRIs with other second generation antidepressants on all of the following outcome measures: efficacy, speed of response, quality of life, and tolerability/adverse effects. The authors concluded that “overall, second generation antidepressants probably to not differ substantially for treatment of Major Depressive Disorder.” The majority of systematic reviews and RCTs reported in Clinical Evidence (Issue 14, January 2006) found no significant differences in outcomes among different classes of antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors). The two most relevant reviews are reported here.  One review suggested that TCAs were more effective than MAO inhibitors, but may be less effective in depression with atypical biological features (increased sleep, increased appetite). Specific data were not cited.(52)  Another review cited in Clinical Evidence found that about twice as many people taking TCAs compared with SSRIs had dry mouth, constipation, and dizziness; but that slightly more people taking SSRIs had nausea, diarrhea, anxiety, agitation, insomnia, nervous-ness, and headache. It concluded differences in overall side effects were small, but didn’t quantify the magnitude of difference.(53)  One Cochrane systematic review(54) found that SSRIs show only a modest advantage in tolerability over TCAs. Specifically, in 136 trials, participants taking SSRIs had significantly lower drop-out rates than those taking tricyclic/heterocyclic antidepressants (OR = 1.21, 95% CI: 1.12 to 1.30). The authors note that this difference from short duration, RCTs may not have clinical significance over the longer term.  Another Cochrane review(55) found no clinically significant differences in effectiveness between SSRIs and TCAs: the standardized effect size was 0.030 (95% CI: -0.018 to 0.09). Given the apparent equal efficacy, the authors advise that treatment decisions should be based on “patient acceptability, toxicity, and cost.”  Another Cochrane review(56) found amitriptyline as effective as other TCAs or newer compounds. Compared with SSRIs, however, amitriptyline was not as well-tolerated: OR = 0.84 (95% CI: 0.75 to 0.95).  The evidence-based NICE (National Institute for Clinical Excellence)(57) guideline found strong evidence showing a statistically significant difference favoring SSRIs over TCAs on reducing the likelihood of patients leaving treatment early due to side effects (RR = 0.69, 95% CI: 0.62 to 0.67). However, other reviews, such as the Cochrane review cited above, show that all cause discontinuation rates do not vary significantly among antidepressant classes.

Psychotherapy vs. Antidepressants  In a study comparing cognitive therapy with antidepressants for treatment of moderate to severe depression, DeRubeis, et al. (2005)(58) found both active treatments were significantly more effective than placebo at eight weeks in improving depression symptoms (50% antidepressants, 43% cognitive therapy, 25% placebo), with no significant difference between active treatments. At 16 weeks the response rate was still similar for both active treatments (58%), although the remitter rate was significantly different, in favor of anti-depressant medication (46% vs. 40%, p = 0.04). These results should be interpreted with caution, since the antidepressant group had twice as many subjects as the cognitive therapy group (120 vs. 60 respectively) and a significant interaction effect was noted for site of intervention (p = 0.02), suggesting that therapists experience levels were not equal between the two sites used in the study. Combination Therapy  In a complex study with multiple outcome measures and several limitations de Jonghe (2004)(59) found that patients with mild to moderate MDD initially treated with psychotherapy alone and patients treated with combination psychotherapy and antidepressants each experienced improvement over six months (primary outcome change in HAMD score: -6.79 points in psychotherapy group vs. -8.46 points in combined therapy group, p = 0.083). Combination therapy did not lead to significantly greater improvements in depressive symptoms in the intent to treat sample compared with psychotherapy alone. In the per-protocol sample, there were minor differences favoring combined therapy on some measures, but not others. The authors conclude that the benefits of combination therapy in this population are “equivocal.”  In a study of specialty mental health outpatients, Kool, et al. (2003)(60) found that antidepressant treatment (initially fluoxetine, changed to amitriptyline if initially intolerant, then moclobemide [a MAOI] if still intolerant) combined with 16 sessions of short psychodynamic supportive psychotherapy (SPSP), starting two weeks after the initiation of medication, was more effective than pharmacotherapy alone for depressed patients with personality disorders (change in HAMD scores -9.02 vs. -5.86, p = 0.04), but not in depressed patients without personality disorders (change in HAMD scores -8.61 vs. -9.1, p = 0.74). The generalizability of this study to primary care is uncertain; most patients with depression and personality disorders are referred to specialty mental health for treatment.

A search of Clinical Evidence (Issue 14, January 2006) yielded two systematic reviews and two subsequent RCTs:  The first review found that combination therapy significantly improved depressive symptoms compared with drug treatment alone (OR = 1.86, 95% CI: 1.38 to 2.52). A greater effect was found in longer duration (12-week) studies with shorter treatment times (OR = 2.20, 95% CI: 1.22 to 4.03).(61)  The second review found a small yet significant effect of combination pharmacotherapy and psychotherapy over either intervention alone (effect size: Cohen’s d = 0.34 with BDI and 0.18 with HRSD; further details not reported).(62)

Clinical Evidence also cited the studies by de Jonghe (2004)(59) and Kool (2003)(60) which were reviewed by the GDT and discussed above.  Another RCT(63) of 102 older patients (older than 60 years) with MDD compared desipramine plus cognitive behavioral therapy, desipramine alone, and/or cognitive behavioral therapy alone. All three groups showed a significant reduction in symptoms from baseline as assessed using the HAM-D after 16 to 20 weeks of treatment. It found that combined treatment significantly improved symptoms compared with desipramine alone (p < 0.05), but there was no significant difference between combined treatment and cognitive behavioral therapy alone. Other Interventions  Proudfoot, et al. (2004)(64) found that, compared with usual care (with or without antidepressants), a computerized CBT intervention yielded a significantly greater improvement in depressive symptoms, assessed primarily by BDI scores at three months (6.5 point difference favoring intervention group); differences continued to be present at eight months (5.8 point difference favoring the intervention group). Slightly over half of each patient group received pharmacotherapy. It is unclear how many patients in the usual care group received pharmacotherapy – if many usual care patients received no treatment, it would bias results in favor of the intervention group. Both authors have commercial interests in the computerized CBT intervention.  In a poorly reported study, Sirey, Bruce, and Alexopoulous (2005)(65) examined the effectiveness of The Treatment Initiation Program (TIP), an individualized, early intervention to address older adults’ attitudes about depression and barriers to care. The control group was given pharmacotherapy as usual; the intervention group was given both pharmacotherapy and TIP. The intervention group showed greater (71% vs. 42%) remission (defined with a low threshold as HAMD scores < 10) after 24 weeks. The intervention group had significantly lower HAMD scores at baseline, suggesting poor randomization; and overall changes in HAMD scores were not reported (lower pretreatment scores in the intervention group might bias remission results in favor of the intervention group, when in fact both groups could have equal changes in HAMD scores). The authors claim, but do not quantify, that patients in the intervention group were more likely to remain in treatment. Discussion: There has been increasing discussion about the “true efficacy” of antidepressants compared with placebo. Concerns have been raised about publication bias, especially since analyses show that published studies funded by the pharmaceutical industry overwhelmingly tend to favor the funder’s medication. Some studies have found statistically significant differences on some outcomes (differences between changes in scores on depression rating scales) whose clinical relevance is debatable. The methodological quality of studies, especially as it relates to blinding and analytic methods (completer analyses and last observation carried forward methods of imputing missing data may bias studies in favor of active treatment). Interestingly, a recent analysis(66) notes that over the past 20 years, overall antidepressant response and placebo responses have both increased This suggests that study design factors and other external factors (patient awareness, direct to consumer and other antidepressant marketing) might be influencing trial results.

Almost all clinical trials include some degree of “attention” for patients receiving placebo, and patients who enroll in clinical trials may be more “responsive” to placebo than patients at large; therefore, the placebo response in trials may be higher than the placebo response that would be found in the ‘real world’, that is, uncontrolled clinical conditions with a wider range of patients. While trials may overstate the magnitude of benefit of antidepressants, the NNT for antidepressant treatment still would likely remain more favorable than the NNH in most analyses.

Considering all this information, the GDT concludes that the balance of evidence supports the use of antidepressant medication for treatment of MDD, but also underscores the need (given studies showing it’s effectiveness) to consider structured psychotherapeutic treatment options (Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy) and the use of shared decision-making with patients.

New evidence did not surface to suggest the need to change the previous guideline recommendation regarding combined antidepressant and psychotherapy for treatment of severe MDD. Although this combination may provide marginal benefit in patients with milder forms of depression, the benefit is small in light of the additional resources required, so the GDT recommends, consistent with the previous guideline recommendation, limiting combination therapy in this group of patients to patients who fail to respond to initial treatment, which by definition includes patients with chronic depression (see the recommendations for second-line treatment). Patients with personality disorders and depression are usually treated in specialty behavioral health settings.

After review of the new evidence summarized here, the GDT believes that the previous recommendations are still valid. 2004 Guideline

Supporting Evidence for Antidepressants versus Placebo Since the previous revision of the Depression Guidelines, three RCTs and one systematic review were found which looked at the efficacy of antidepressants versus placebo.  Detke(38) included adult patients with MDD that had a baseline score of ≥ 15 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17). The study was a randomized, double- blind, placebo controlled trial. The study compared a SNRI (duloxetine), 60 mg /day (n = 121) and inert placebo (n = 115) for efficacy. This study also compared duloxetine (n = 123) and inert placebo (n = 122) for safety analysis. The duration of study was nine weeks. Duloxetine was significantly superior to placebo (4.8 point difference on the HAM- D-17 scale (p < 0.001), NNT to achieve one additional remission = 4). Significant side effects associated with duloxetine versus placebo included: nausea (p < 0.001), dry mouth (p < 0.001), somnolence (p < 0.001). Other statistically significant side effects of duloxetine were dizziness (p = 0.010), diarrhea (p = 0.006), insomnia (p = 0.021), and constipation (p = 0.001).

 Goldstein(67) included adult patients with MDD that had a baseline score of at least 15 on the HAM-D-17 scale for depression. The study was a randomized, double-blind, placebo controlled trial comparing a SNRI (duloxetine), 40 mg/day to 120 mg/day (n = 70) and inert placebo (n = 70) for a period of eight weeks. An SSRI (fluoxetine), 20 mg/day (n = 33) was included as an internal control to be sure patients were antidepressant responsive. Duloxetine was statistically superior to placebo in reducing the symptoms of MDD, with a 3.1 point difference between treatments on the HAM-D-17 scale (p = 0.009), and a NNT = 4 to achieve one additional remission compared with placebo. Insomnia was significantly more common with SNRI treated patients (p = 0.046, NNH = 13 to 14). There was a mean increase in standing diastolic blood pressure for SNRI treated patients of 2.8 mm Hg (p = 0.041). The study also showed a small but statistically significant (p = 0.005) reduction in body weight (0.59 kg) in SNRI treated patients. The clinical significance of the latter two findings is questionable.  Wade(68) included adult patients between ages of 18 and 65. There was a 3:1 ratio of women to men, with more than 97% being Caucasian. All patients met the DSM-IV criteria for MDD and had a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score between 22 and 40. The study was a randomized, double-blind, placebo controlled trial comparing a SSRI (escitalopram) (n = 191) and inert placebo (n = 189) for a period of eight weeks. Escitalopram (10 mg/day) was statistically superior to placebo, with a 2.7 point greater adjusted mean change in MADRS total score from baseline to week eight (p = 0.002) (NNT not given). Headache and nausea were the most frequent adverse events, but nausea was the only adverse effect that was statistically significant in SSRI treated patients (p ≤ 0.05, NNH = 20).  Moncrieff(69) reviewed six randomized and quasi-randomized, double-blinded studies of men and women of all age groups with a primary diagnosis of depressive disorder. These studies compared TCA drugs and an active placebo containing atropine. The duration of studies varied from three to 12 weeks. Change in mood at the end of treatment was the outcome of interest in these studies. The majority of trials found only small differences (p not stated) between TCA antidepressants and active placebos.  The Cochrane systematic review, Wilson,(27) included 17 trials that assessed the efficacy of different antidepressants in older adult patients (over 60 years) with MDD. All trials compared SSRIs, TCAs, or MAOIs (monoamine oxidase inhibitors) with placebo, no head- to-head active drug comparisons were reported. The authors concluded that TCAs, SSRIs, and MAOIs were effective in the treatment of older community patients and they recommended that at least six weeks of antidepressant treatment to achieve optimal therapeutic response.

Clinical Evidence, Vol. 9, was also searched and our recommendations are in line with their conclusions.  They note that systematic reviews in people aged 16 years or greater have found that antidepressant drugs (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, or tricyclic antidepressants) versus placebo improve symptoms in acute treatment of all grades of depressive disorder. One systematic review in people aged 55 years or greater with all grades of depressive disorder has found that tricyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors versus placebo significantly reduce the proportion of people who fail to recover over 26 to 49 days. They found no specific evidence on adverse effects in older adults.(70) Overall Conclusion: Since the previous revision of these guidelines, three RCTs and one meta-analysis were found that supported the use of antidepressants compared with inert placebo. One systematic review found only a small difference between treatment and active placebo. Although antidepressants have side effects, they are superior to placebo in treating MDD. Supporting Evidence for Psychotherapy vs. Placebo Volume 9 of Clinical Evidence,(70) most recent search date November 2003, was searched and one systematic review was found showing benefit of cognitive therapy vs. placebo in younger and older adults with mild to moderate depression.  RCTs in younger and older adults with mild to moderate depression found that problem- solving treatment or interpersonal psychotherapy versus placebo significantly improved depressive symptoms in the short term. One systematic review in people aged ≥ 55 years with mild to moderate depression found five of six comparisons of cognitive or cognitive- behavioral therapy vs. no treatment lead to significant mean changes of -7.3 points on the HAM-D rating scale (95% CI: -10.1 to -4.4); however, there were no significant differences found between active treatments and “nonspecific attention” control groups. This review was based on a small number of studies, the populations varied (although most were community samples), and many of the studies were short term. RCTs found limited evidence about the effects of psychological treatments in severe depression. This evidence of the efficacy of psychotherapy versus placebo is summarized in Table 1.26, Effects of Specific Psychological Treatments for Depressive Disorders, in Appendix B.

No additional systematic reviews or RCTs since the Clinical Evidence review were found that addressed this question. Other Considerations: There is insufficient evidence across trials to determine the optimal number of sessions for each type of psychotherapy, and some concern that rigorous study protocols may not be delivered in “real world” settings, potentially affecting the achieved effectiveness of psychotherapy in different settings. Overall Conclusion: The evidence supports the efficacy of structured forms of psychotherapy (cognitive, cognitive- behavioral, interpersonal, or problem-solving therapy) delivered by behavioral health professionals as a first-line treatment option for patients with Major Depression.

Supporting Evidence for Antidepressants versus Psychotherapy or Combination of Antidepressants and Psychotherapy One systematic review that addressed this issue was found.  Six multiple-cell, randomized, controlled, double-blind trials were included in the Casacalenda(1) systematic review. The studies included adults with nonpsychotic Major Depression. These studies compared medication (five studies used tricyclics and one used phenelzine, a MAOI) (n = 261) and psychotherapy (three studies used cognitive behavior therapy, three used interpersonal therapy, one used problem-solving) (n = 352) and placebo (n = 270). Intention-to-treat analyses indicated that pharmacotherapy and psychotherapy were significantly more efficacious than control conditions (p < 0.0001) but were not significantly different from each other when treating mildly to moderately depressed patients.  Structured forms of psychotherapy have established efficacy in treating the symptoms of Major Depression. Mynors-Wallis(1, 71) compared the following:  Problem-solving therapy delivered by a general practitioner  Problem-solving therapy delivered by a nurse  Antidepressant medication (either fluvoxamine or paroxetine)  Combination of psychotherapy and medication. . Patients receiving psychotherapy met with the doctor or nurse for one hour on the first visit and for 30 minutes on subsequent visits. . All patients received 12 weeks of treatment and at 52 weeks had follow-up interviews. . A total of 151 patients participated in the study. All patients had "probable" or "definite" acute Major Depression according to Diagnostic Research Criteria. . Patients receiving psychotherapy had lower completion rates (completed all 52 weeks of treatment) at the end of the study (64% and 68% respectively) as compared with medication alone or combination therapy (83% and 86% respectively). . At 52 weeks, there were no statistically significant differences between patients who received problem-solving therapy, medication, or combination therapy (as determined by a 50% reduction in depression symptom score on the Hamilton Depression Rating Scale and the Beck Depression Inventory). Therefore, the authors concluded that problem-solving therapy and medication were effective treatments for Major Depression. However, patients receiving problem-solving therapy had higher dropout rates than those in the medication or combination group. . The Mynors-Wallis study showed that patients assigned to medication experienced higher rates of symptom resolution at 12 weeks (67% versus 54%, ARR = 13, NNT = 8), therefore psychotherapy had slower onset of therapeutic effect.

 Schulberg(72) compared usual care, nortriptyline, and Interpersonal Therapy (IPT) in 276 primary care patients.  Patients were aged 18 to 64 years and had to meet DSM-III-R(73) criteria for MDD.  Patients were followed for eight months.  The authors concluded that the severity of depressive symptoms was reduced more rapidly and more effectively among patients randomized to pharmacotherapy or psychotherapy than among patients assigned to a physician's usual care.  Among treatment completers, approximately 70% of patients participating in the full pharmacotherapy or psychotherapy protocol achieved resolution of symptoms but only 20% of usual care patients were judged as recovered at eight months. However, this intervention is very resource intensive. Clinical Evidence(70) was also searched and our recommendations are in line with their conclusions. The following are their findings:  One systematic review in people aged over 18 years with recent onset psychological problems, including depression, found that brief, nondirective counseling versus usual care by a physician significantly reduced symptom scores in the short term (less than six months), but found no significant difference in scores in the long term (more than six months).  They found one nonsystematic review showing that the combination of psychotherapy and antidepressant medication in patients age 18 to 80 with severe MDD is more beneficial than either treatment alone.  One RCT was also found showing that combination antidepressant treatment is more effective than either treatment alone for patients with mild to moderate Major Depression. Overall Conclusion: New evidence since the previous Depression Guideline revision shows that combining antidepressant medication and psychotherapy may be more beneficial than either treatment alone for patients with severe, and perhaps even mild to moderate, Major Depression. However, many patients with mild to moderate depression will respond to monotherapy (either antidepressants or psycho-therapy used alone), and extra resources are required to provide combined treatment to all depressed patients. Therefore, the GDT recommends that combining antidepressants and psychotherapy be reserved as an option for those patients with mild to moderate depression who do not initially respond to either treatment alone.

However, for patients with severe MDD, who are most adversely affected, most significantly impaired, and are at higher risk for suicide, the added cost of initially starting with both antidepressant medication and psychotherapy in combination may be worth the incremental cost (in time and resources). Therefore, the GDT believes that combined antidepressant- psychotherapy is appropriate first-line treatment for patients with severe MDD.

Supporting Evidence For Head-To-Head Comparison of Antidepressants Since the previous revision of the Depression Guidelines, one RCT and one nonsystematic review were found that compared the efficacy of antidepressant against each other.  Thase,(74) a nonsystematic review, included eight randomized, double-blinds studies comparing a SNRI (venlafaxine) and SSRIs (fluoxetine, paroxetine, and fluvoxamine) and placebo for six to eight weeks (only four of eight trials were placebo controlled). Studies included adults (18 and older) who met the DSM-III-R or DSM-IV criteria for MDD for at least one month. All studies were funded by the SNRI manufacturer. Remission rates (using Hamilton Rating Scale for Depression, HRSD) were significantly higher (10%) with SNRI (venlafaxine) than with an SSRI (fluoxetine, paroxetine, and fluvoxamine). Odds ratio indicated that venlafaxine-treated patients had a 50% greater chance of attaining remission than patients treated with an SSRI (NNT = 10). However, the reported SSRI remission rates in this analysis (35%) are noticeably lower than the SSRI remission rates seen in other trials, raising the possibility of publication bias.  Mulsant(75) included outpatients and inpatients age 60 and older with MDD and a HAM-D-17 score of 15 or above. The population was 71.6% female and 86.2% white. The study was a 12 week randomized double-blind trial comparing a TCA (nortriptyline, 25 to 50 mg) and a SSRI (paroxetine, dose range of 10 to 20 mg). There was no statistical difference in efficacy based on HAM-D-17 scores (p = 0.16). Patients were twice as likely to discontinue TCA (33%) as SSRI (16%) due to a significant side effect (p = 0.04), but the overall discontinuation rates did not differ significantly, p = 0.30.  AHRQ’s systematic review, Mulrow(76) included 81 trials that addressed efficacy of antidepressant medications. The majority of trials were conducted in outpatient setting. All trials were in patients with MDD. All trials were double-blind and were six to eight weeks in duration. All studies were sponsored by pharmaceutical companies. The review included 80 studies that demonstrated that multiple newer antidepressants (SSRIs, SNRIs, and NRIs) were equally as effective as older tricyclic antidepressants. In 55 studies reporting response rates, SSRIs were compared with TCA1 (n = 38), TCA2 (n = 5), triazolopyridine (trazodone) (n = 4), tetracyclic antidepressants (n = 7), and MAOI (n = 1). SSRIs were equally effective compared with TCA1 (RR = 1.0, 95% CI: 0.9 to 1.1), TCA2 (RR = 1.1, 95% CI: 0.9 to 1.3), triazolopyridine (RR = 1.1, 95% CI: 0.7 to 1.6), tetracyclic (RR = 1.1, 95% CI: 0.9 to 1.3), and MAOI antidepressants (RR = 0.9, 95% CI: 0.7 to 1.3). There is no evidence that any one medication is more efficacious than any other. SSRIs have a small, short-term advantage in six week continuation rates over TCAs and heterocyclic medications (NNT = 20 to 33).

The two subsequent systematic reviews in the Cochrane database included Geddes and Barbui.  Geddes(77) compared SSRIs with a variety of antidepressants, including TCAs and heterocyclics. This systematic review included 98 studies conducted in primary and secondary care in 13,336 inpatients and outpatients with MDD.  All the trials were double-blind and were six weeks in duration.  The analysis of efficacy was based on 5,044 patients treated with an SSRI or related drug and 4,510 treated with an alternative antidepressant. The standardized effect size for SSRIs and related drugs together versus alternative drugs using a fixed effects model was 0.035. (95% CI: -0.006 to 0.076; Q = 149.25, df = 97, p < 0.001).  The standardized effect size for SSRIs alone versus TCAs was 0.044 (95% CI: -0.020 to 0.107). There was no evidence of statistically or clinically significant differences between the drugs.  In AHRQ’s systematic review(76) less than 10% of the trials addressed adherence. These trials demonstrated that overall dropouts did not differ significantly between active treatments.  In the Geddes(77) review, 27.7% of patients treated with SSRIs dropped out, compared with 32.7% of patients treated with TCAs (ARR = 5%, NNT = 20).  Barbui’s systematic review(78) focused on adherence and included 136 trials, 58% of which were conducted in the primary care setting, the total N was not reported. The majority of trials were six weeks in duration (84%) and nearly all studies were in patients with Major Depression.  The estimate of overall dropout rates showed significantly fewer dropouts in the SSRI group compared with TCAs. (OR = 1.21, 95% CI: 1.12 to 1.30)  On average, 27 out of every 100 patients taking SSRIs will dropout compared with 30 of every 100 taking TCAs. (ARR = 3%, NNT = 33)  The authors concluded that there was a small difference in dropout rates between SSRIs and TCAs (amitriptyline, imipramine, clomipramine, desipramine, dothiepin, doxepin, lofepramine, and nortriptyline).

Eight studies were found since the Cochrane systematic review that addressed treatment of MDD in older patients.  Of these, Finkel(79) and Newhouse(80) compared sertraline with fluoxetine in 75 (university center) and 236 (outpatients) respectively. The trials were 12 weeks in duration. Finkel reported results that favored sertraline; however, this study was sponsored by Pfizer and there was evidence of selection bias. Newhouse concluded that both drugs were equally efficacious in this population; however, the authors didn't report any head-to-head comparisons and not all comparisons were reported. In addition, Newhouse used a one week placebo run-in, which doesn't control for the difference in half-life between sertraline and fluoxetine.

 Bondareff(81) and Oslin(82) compared sertraline with nortriptyline in specialty care (n = 210 and 76) and nursing home patients (n = 97). Trials ranged from 10 to 12 weeks in duration. The studies report conflicting results; Bondareff and Finkel favor sertraline while Oslin favors nortriptyline. Oslin compared sertraline open-label patients with double-blind treated nortriptyline (regular and low-dose) patients. Bondareff also reported that nortriptyline patients over 70 had poorer prognosis. Bondareff excluded placebo responders.  Schweizer(83) compared imipramine and buspirone with placebo in 177 primary care outpatients. Results indicated that imipramine was superior to placebo but no head-to-head comparisons were reported. More patients taking imipramine also used over the counter medications (such as painkillers, etc.).  Mulsant(84) compared nortriptyline with paroxetine in 80 mixed setting patients (inpatients and outpatients). The trial was six weeks in duration. The authors concluded that both drugs were equally efficacious.  Forlenza(85) compared sertraline with imipramine in 55 specialty care outpatients. The trial was six weeks in duration. The authors concluded that both drugs were equally efficacious; while there was no significant difference in overall dropout rates, the majority of patients taking imipramine dropped out in the first two weeks. The trials were short in duration; had selection and publication bias; and small N’s. Clinical Evidence, Vol. 9,(70) was searched and it was found that our recommendations are in line with their conclusions. The followings are their findings:  Two systematic reviews have found no clinically significant difference in outcomes with different kinds of antidepressant drug, although one systematic review found that monoamine oxidase inhibitors were less effective than tricyclic antidepressants in people with severe depressive disorders, but may be more effective in atypical depressive disorders, for example increased sleep, increased appetite, mood reactivity, and rejection sensitivity. Systematic reviews have found that antidepressant drugs differ in their adverse event profiles. One systematic review has found that, on average, people seem to tolerate selective serotonin reuptake inhibitors a little better than tricyclic antidepressants, but the difference was small. Another systematic review and one retrospective cohort study found no strong evidence that fluoxetine was associated with increased risk of suicide. One RCT and observational data suggest that abrupt withdrawal of selective serotonin reuptake inhibitors is associated with symptoms including dizziness and rhinitis, and that these symptoms are more likely with drugs with a short half-life, such as paroxetine.

Other Considerations Group Health Cooperative’s 2003 Adult Major Depression Guideline included one additional study on venlafaxine vs. SSRIs identified from a Medline search using similar mesh terms that did not appear in our PubMed search (Smith(86)).

Group Health concluded:  “This study (Smith) found that venlafaxine was more effective than other antidepressants at treating depression. The difference in effect size was equal to about 1.2 points on the HAM- D which, although statistically significant, may not be a clinically significant difference. The meta-analysis was funded by Wyeth Laboratories, the manufacturer of venlafaxine, and this may have introduced bias in the study design, analysis, or reporting. The existing evidence is not sufficient to recommend the use of venlafaxine as first-line medication rather than well-established antidepressants such as SSRIs.” Overall Conclusion The preponderance of evidence suggests that generally, all antidepressants are equally effective. While some evidence suggests that venlafaxine may be more effective that SSRIs in achieving remission in the first few weeks of treatment, due to concerns about publication bias and the lack of longer-term outcomes data, the GDT believes that currently there is insufficient evidence to preferentially recommend venlafaxine over other antidepressants for first-line treatment of MDD in the primary care setting. 2. Hypericum (St. John’s Wort) for MDD 2A The GDT makes no recommendation for or against providing hypericum (St. John’s wort) in patients with mild-to-moderate Major Depression. There is fair evidence of effectiveness of hypericum in this population. However, due to lack of consistency of preparation and dosage across trials, and concerns about lack of FDA oversight and consistency of hypericum preparations, the balance of benefits, harms, and costs compared with other treatments cannot be determined. Evidence-based: C 2B The GDT recommends against providing hypericum (St. John’s wort) to patients with severe Major Depression. Evidence-based Evidence Grade Evidence for Recommendation 2A: Fair Evidence for Recommendation 2B: Evidence-based

Rationale:

2008 Guideline New evidence was found that did not change the existing recommendations. Search Strategy We found four RCTs comparing hypericum with placebo and/or standard antidepressants:  Kasper et al. (2006)(87) found that hypericum decreased depressive symptoms significantly more than placebo in patients with mild-to-moderate Major Depressive Disorder. The percentages of responders (NNT = 3) and remitters (NNT = 5) were higher in patients receiving hypericum than in patients receiving placebo as well.  Gastpar et al. (2005)(88) found that hypericum was not inferior to sertraline in reducing depressive symptoms in moderately depressed patients (score 20 to 24 on the Hamilton Depression Scale) meeting the ICD-10 diagnosis for moderate depression, with at least four or more DSM-IV typical depression symptoms. Although no placebo group was studied, the percentage of responders did not differ between treatment groups either. Due to the inclusion criteria, it is possible that not all patients would meet the DSM-IV classification for Major Depressive Disorder.  Gastpar et al. (2006)(89) found that hypericum was not inferior to citalopram in reducing depressive symptoms in moderately depressed patients (score 20 to 24 on the Hamilton Depression Scale and diagnosis of Major Depressive Disorder), whereas both hypericum and citalopram were superior to placebo. The percentage of responders was higher in both treatment groups than in the placebo group as well.  Fava et al. (2005)(90) found that patients with mild-to-moderate Major Depressive Disorder diagnosed by Structured Clinical Interview for DSM-IV who were taking hypericum showed a significant improvement in depressive symptoms over patients taking fluoxetine (NNT = 12), and reported a trend toward superiority for hypericum over placebo (NNT = 6). Overall Conclusion We found no new evidence on the use of hypericum for patients with severe Major Depressive Disorder. Therefore, there is no change in the recommendation on use of hypericum in these patients.

Three of the four studies we reviewed studied patients with Major Depressive Disorder, addressing one of the GDT’s concerns about the heterogeneity of study populations in previous studies. However, the GDT has persistent concerns regarding the lack of standardization of dose and preparation of hypericum across trials. Given the lack of FDA oversight, it is uncertain whether trial preparations and doses of hypericum would be consistently available to patients for routine use. The GDT is, therefore, unable to determine the balance of benefit and risk of hypericum for mild-to-moderate Major Depression compared with other existing evidence-based therapies.

For the 2008 Guideline, the health outcome of “change in symptoms” was the only relevant outcome for which evidence was found. In addition, all three health interventions – prescription antidepressants, hypericum, and no treatment - were addressed in this 2008 Guideline. 2006 Guideline We found four RCTs comparing hypericum with placebo and/or standard antidepressants, with mixed results:  Gelenberg, et al. (2004)(91) found that the lack of hypericum efficacy in previous studies was unlikely to be attributable to treatment-resistant subjects.  Uebelhack, et al. (2004)(92) found that moderately depressed patients taking hypericum showed a significant improvement in depressive symptoms over placebo control subjects.  Szegedi, et al. (2005)(93) showed decreases in depressive symptoms in both patients taking hypericum and patients taking paroxetine, and concluded that hypericum is not inferior to paroxetine.  Bjerkenstedt, et al. (2004)(94) found a significantly higher remission rate among mild to moderately depressed subjects who had taken hypericum versus those who had taken placebo, but study duration was short (four weeks) and there was no comparison of remission rates between hypericum and fluoxetine subjects.  The Cochrane systematic review(95) included 37 trials comparing hypericum with placebo or antidepressant. Larger placebo-controlled trials restricted to patients with Major Depression showed only minor effects of hypericum (RR = 1.15, 95% CI: 1.02 to 1.29); older, smaller trials including patients with minor depression showed more marked effects (RR = 2.06, 95% CI: 1.65 to 2.59).  Trials comparing hypericum extracts and standard antidepressants were heterogeneous. Patients given hypericum extracts had fewer adverse effects than those given SSRIs specifically, but the difference was not statistically significant (OR = 0.60, 95% CI: 0.31 to 1.15). The authors conclude that current evidence regarding hypericum is “inconsistent and confusing.”  Some trials involving patients with Major Depression suggest hypericum has a minimal beneficial effect, while others suggest the effect is comparable with standard antidepressants.  Furthermore, the pharmaceutical quality of hypericum preparations varies considerably, and trial results are limited and specific to preparations used in the study.

Clinical Evidence (Issue 14, January 2006) also cited the Linde & Mulrow systematic review and the authors made similar conclusions about the quality of the trials and the concerns about pharmaceutical quality of hypericum. They emphasize the need to interpret RCTs on the efficacy of hypericum cautiously due to the lack of standardization of preparations used across trials and the varying doses of comparator standard antidepressants.

We found no trials comparing hypericum with psychotherapy.

Overall Conclusion The statement that the evidence is "insufficient and confusing" is an appropriate summary of the studies we reviewed. Based on this finding and other concerns expressed in previous reviews (varying definitions and inclusion criteria for depression, concerns over adequacy of blinding in the studies, and short trial duration), the GDT believes that there is insufficiently consistent evidence to recommend hypericum instead of prescription antidepressants for the treatment of MDD. 2004 Guideline

Supporting Evidence for Hypericum (St. John’s Wort) versus Placebo Two RCTs examining the efficacy of hypericum versus placebo for treatment of MDD were found.  The hypericum Depression Trial Study Group(96) was a randomized, double-blind, controlled trial including adults (at least 18 years old) with MDD and a minimum score of 20 on the HAM-D scale for depression. The study compared hypericum (900 to 1,500 mg/dl) (n = 113) and placebo (n = 116) for eight weeks, with sertraline (50 to 100 mg/day) (n = 111) as an active comparator to evaluate the study’s sensitivity. The study found no evidence that hypericum is more effective than placebo in treating moderately severe Major Depression (p = 0.59). The only significant adverse event with hypericum was anorgasmia (p = 0.04).  Kalb(97) included adult outpatients between 18 and 65 years old with mild to moderate single episode or recurrent MDD and a total score of greater than 16 on HAMD-17 scale. The study was a randomized, double-blind, controlled trial comparing hypericum extract WS 5572 (3 x 300 mg/day) (n = 37) and placebo (n = 35) for six weeks.  The study concluded that the standardized hypericum extract WS 5572 has superior efficacy compared with placebo and very good tolerability in the acute treatment of mildly to moderately depressed patients.  There was a significant decrease in HAM-D scores (p < 0.001) in hypericum (54.8%, or 10.8 points) compared with placebo (29.2%, or 5.7 points).  There was no significant difference in the percentage of patients with at least a 50% improvement in HAM-D scores (a commonly used measure of antidepressant response) 62.2% for hypericum vs. 42.9% for placebo, p = 0.10, but the study may have been underpowered to detect this difference.  There was, however, a significant difference in percentage of patients with at least a 60% improvement in HAM-D scores (51.4% vs. 17.1%, p = 0.002); however, this measure is not commonly used in other antidepressant efficacy trials.

Clinical Evidence(70) was also searched and our recommendations are in line with their conclusions. They concluded:  Two systematic reviews in people with mild to moderate depressive disorders have found that St. John's wort (Hypericum perforatum) versus placebo significantly improves depressive symptoms over four to 12 weeks, and have found no significant difference in symptoms with St. John's wort versus prescription antidepressant drugs. However, these findings have not yet been repeated in people with all grades of depression using standardized preparations of St. John's wort.  The evidence cited must be interpreted cautiously because it is unclear how closely people in these trials match people in clinical practice, and the preparations and doses of H. perforatum and types and doses of standard antidepressants varied. More studies are needed on clearly defined, clinically representative people using standardized preparations. Interactions with other drugs are possible and should be considered.  Shelton(98) compared St. John's wort with placebo in 167 outpatients attending academic medical centers for the treatment of severe Major Depression. The authors concluded that St. John's wort was no more effective than placebo in treating severe Major Depression.

Since severe Major Depression is associated with morbidity and an increased risk for suicide, also since there are other effective available treatments, and the only study of St. John's wort in severely depressed patients showed no efficacy, the GDT recommends that St. John's wort not be used in patients with severe Major Depression. Supporting Evidence for Hypericum (St. John’s Wort) Versus Antidepressants One RCT examining the efficacy of hypericum versus antidepressants for treatment of MDD was found since the previous revision of the Depression Guidelines.  Behnke(99) included adult patients (18 to 73 years old) with mild to moderate Major Depression and HAM-D scores between 16 and 24. The study was a randomized, double- blind, controlled trial comparing hypericum (150 mg twice daily) (n = 35) and SSRI (fluoxetine, 20 mg twice daily) (n = 35) for six weeks. There was no placebo control group. The study concluded that Hypericum perforatum is therapeutically equivalent to fluoxetine and therefore a rational alternative to synthetic antidepressants. There was a significant decrease in HAM-D score (p < 0.001) in both hypericum (50%) and fluoxetine (58%), but it was not significantly different (p = 0.23) between the two groups.  Five RCTs of patients with milder forms of depression were reviewed. All were six to eight weeks in duration. Harrer,(100) Philipp,(101) Schrader,(102) and Woelk(103) studied patients with mild to moderate depression, while Brenner(104) looked at 30 patients with MDD (number of patients with severe MDD not specified), dysthymia, adjustment disorder, and depression - not otherwise specified.  Harrer(100) and Schrader(102) compared St. John's wort with fluoxetine in 161 older adult and 238 outpatients with mild to moderate depression. The authors concluded that both medications are equally efficacious in treating mild to moderate depression. However, the Harrier study used low doses of fluoxetine (11 mg/day) that in many instances may be insufficient to achieve symptom remission. Comparisons with higher yet commonly used fluoxetine dosage regimens were not included in the Harrier study, and no placebo group was included to control for possible no effect of low-dose fluoxetine in this setting.

 Both Philipp(101) and Woelk(103) compared St. John's wort with imipramine in 263 and 288 outpatients with mild to moderate depression. The authors concluded that both medications are equally efficacious but patients tend to tolerate St. John's wort better than imipramine.(103) Philipp's study used low doses of imipramine that are often not sufficient to induce remission of depressive symptoms. Woelk's study was conducted in primary and specialty care patients.  Brenner's(104) study compared St. John's wort with sertraline in 30 patients with Major Depression (number of patients with severe MDD not specified), dysthymia, adjustment disorder, and depression - not otherwise specified. The authors concluded that both medications were equally efficacious in treating mild to moderate depression. This study may be underpowered to detect significant differences, and no placebo control group was included. The GDT expressed several concerns about St. John's wort including:  Wide range of dosages and different preparations of St. John's wort used across trials (some preparations may have other, undetermined active ingredients).  Short duration of the trials (longer-term results are not clear).  The definitions and classification of depression varied in trials, making it difficult to translate the results consistently into practice.  Many of the patients in the reviewed trials with mild depression had adjustment disorders or minor/subsyndromal depression. There is no current evidence that suggests these types of depression need treatment with medication. Therefore, without a placebo control group in these trials, it is possible that while St. John's wort was equal to a comparator medication, neither medication may have been superior to placebo.  Potential for bias due to difficulty in patient blinding (due to the characteristic taste and smell of St. John's wort).  The products used in trials may not be widely available commercially.  Dietary supplements are not subject to evaluation for safety and efficacy by the US Food and Drug Administration (FDA) nor is their manufacture held to compliance with the FDA’s Good Manufacturing Practices. As a result of the lack of standardization and quality control, herbal content and efficacy vary, and contamination and misidentification of plant species may occur.  St. John's wort is not approved by the FDA for treatment of depression.  Traditional treatment alternatives (regulated antidepressant medication, structured psychotherapy) are readily available, well-tested, known to be effective, and subject to oversight.  St. John's wort can cause potentially serious drug interactions, which were not adequately addressed in the reviewed studies.

Overall Conclusion There is no evidence that St. John’s wort is effective for severe MDD. There is lower quality evidence of short-term effectiveness in milder forms of depression. These trials often lacked placebo controls and included patients with subsyndromal forms of depression, who often remit spontaneously and therefore, it is unclear that any medication is indicated. Due to concerns about the quality of the evidence, absence of data on longer-term outcomes, and reports of adverse drug-hypericum interactions that are not yet routinely documented in prescribing decision-support software, the GDT believes there is insufficient evidence for or against St. John's wort as an alternative to other effective, regulated treatments for mild to moderate Major Depression.

The GDT recognizes that some patients may initiate discussions about St. John's wort, or may already be taking St. John's wort at the time they consult a clinician. In these instances, the GDT suggests that clinicians discuss the evidence and concerns with patients, using a shared decision- making approach. 3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, Or Plan 3A For patients with Major Depression expressing suicidal intent or plan, the GDT recommends consultation with specialty behavioral health. Consensus-based 3B For patients with suicidal ideation or who have made previous suicide attempts, the GDT recommends consultation or collaboration with a psychiatrist before prescribing TCAs or venlafaxine. Consensus-based Rationale:

2008 Guideline No new evidence was found, the recommendations remain unchanged. 2006 Guideline We found four studies that examined the association of antidepressants with suicidal intent or behavior.  Yerevanian, et al. (2004)(105) found no difference in rate of suicidal behavior between patients taking tricyclic antidepressants (TCAs) versus those taking selective serotonin reuptake inhibitors (SSRIs). They did, however, find a significant increase in suicidal behavior in the discontinuation period of both classes of antidepressant.  Martinez, et al. (2005)(106) showed no difference in rate of suicidal behavior in patients prescribed SSRIs versus those prescribed TCAs. There was a similar risk for different SSRIs, as well as for different TCAs.  Fergusson, et al. (2005)(107) found no difference in odds of suicide attempts in patients receiving SSRIs versus those receiving TCAs.

 Gibbons, et al. (2005)(108) did not find a significant association between all prescribed antidepressants and suicide rate. The authors did find a significant positive association between TCAs specifically and suicide rate, but since this was an ecological study and individual patient data was not collected, it cannot be concluded that a causal relationship exists. A Clinical Evidence (Issue 14, January 2006) systematic review, one retrospective cohort study, and two case control studies specifically examined the risk of suicide between different classes of antidepressants.  The systematic review found no difference in risk of suicide between SSRIs and TCAs (OR = 0.88, 95% CI: 0.54 to 1.42). It should be noted that RCTs were included in this review regardless of treatment condition and 59% of the RCTs used were in people who had a diagnosis other than MDD.(109)  The retrospective cohort study found that the risk of suicide was higher in people who received fluoxetine (19/10,000 person years, 95% CI: 9/10,000 person years to 34/10,000 person years) than in those receiving dosulepin (dothiepin; RR = of suicide vs. dosulepin 2.1, 95% CI: 1.1 to 4.1). However, a subgroup analysis of people with no history of suicidal behavior or previous antidepressant prescription broadened the confidence interval to make the result nonsignificant (RR = 2.1, 95% CI: 0.6 to 7.9).(110, 111)  One case control study reported no significant increase in suicide risk in people prescribed SSRIs compared with TCAs (OR = for suicide 0.57, 95% CI: 0.26 to 1.25).(106)  Another case control study found no significant increase in suicide risk with individual SSRIs (amitriptyline, fluoxetine, paroxetine) compared with dothiepin (amitriptyline: OR = 0.83, 95% CI: 0.61 to 1.13; fluoxetine: OR = 1.16, 95% CI: 0.90 to 1.50; paroxetine: OR = 1.29, 95% CI: 0.97 to 1.70).(110) Overall Conclusion There is little consistent evidence of differences in all-cause suicide between classes of antidepressants. However, the consensus of the GDT remains that due to potential toxicity in overdose, TCAs and venlafaxine should be prescribed to suicidal patients only after consultation or collaboration with a psychiatrist. 2004 Guideline No studies were found with a design that directly addressed our question. However, we did find two studies on safety of antidepressants in overdose situations.  Buckley(112) calculated the fatal toxicity index expressed as death per million prescriptions for antidepressants. The serotoninergic drug class overall had a much lower index (1.6) than the tricyclic antidepressants (34.8) and monoamine oxidase inhibitors (20.0). Venlafaxine had a higher index (13.2) than the individual and combined results of other serotoninergic drugs.  Shah(113) examined trends in suicide from drug overdose in older adults (65 years old and older) between 1993 to 1999. Antidepressants were the third (15%) most commonly used drugs in overdose leading to suicide. Of these deaths, 95% were due to tricyclic antidepressants. Death rates increased with age, with highest rates in men over 75.

Volume 9 of Clinical Evidence,(70) most recent search date November 2003, was also searched, and our recommendations are in line with their conclusions. They found:  One systematic review (search date not stated, which included RCTs completed by December 1989) pooled data from 17 double-blind RCTs in people with depressive disorders aged 12 to 90 years comparing a TCA (731 people) versus fluoxetine (1,765 people) or versus placebo (569 people). It found no significant difference in the rate of suicidal acts [attempts] between the groups (TCAs 0.4%, fluoxetine 0.3%, and placebo 0.2%), but development of suicidal ideation was less frequent in the fluoxetine group (1% fluoxetine vs. 3% placebo, p = 0.04; and vs. 4% TCAs, p = 0.001).  One historical cohort study followed 172,598 people who had at least one prescription for one out of ten antidepressants during the study period in general practice in the UK. The risk of suicide was higher in people who received fluoxetine (19/10,000 person years, 95% CI: 9 to 34) than those receiving the TCA dosulepin (RR = of suicide vs. dosulepin 2.1, 95% CI: 1.1 to 4.1).  In a nested case controlled, subanalysis in people with no history of suicidal behavior or previous antidepressant prescription, the risk remained the same, although the confidence interval broadened to make the result nonsignificant (RR = 2.1, 95% CI: 0.6 to 7.9). Although the apparent association may be because of residual confounding, there remains uncertainty about the possible association between fluoxetine and suicide. However, any absolute increase in risk is unlikely to be large.

One systematic review was found that addressed suicide attempts or completions.  AHRQ's review(2) included 15 studies, two cohort studies, and 13 meta-analyses. Only one of these studies was conducted in primary care. Nine trials compared fluoxetine with placebo or TCA, two trials compared fluvoxamine with placebo or TCA, three trials compared paroxetine with placebo, and one trial compared fluoxetine with placebo or a TCA.  There is no evidence that any one medication is associated with higher rates of attempted or completed suicides, when all methods of suicide are considered in the primary care setting.  Evidence suggests that there is a higher rate of completed suicide by overdose with TCA.  Evidence also suggests that there is a lower rate of suicide by overdose with SSRIs than expected. On closer examination of the studies, Henry(114) looked at the relative mortality of antidepressants in the UK.  The authors calculated the number of deaths per million prescriptions during the six years for all drugs taken together, for each of the four groups of antidepress-ants, and for each drug individually. The chi-square test was applied to the groups of antidepressants. The expected numbers of deaths were given for the individual drugs, with the Fisher’s exact probability applied to the data. The authors concluded that TCAs had a higher ratio of observed to expected rates of suicide by overdose as compared with all antidepressants taken together.  SSRIs has a lower ratio of observed to expected rates of suicide by overdose.  A head-to-head TCA to SSRI comparison was not done.

 The Jick(111) study had small N’s underscoring the low frequency of suicide in primary care settings, and was probably not sufficient to draw conclusions.  Studies or reviews might not have large enough N's to account for differences in rare events. There may be unreported differences in trials because patients with suicidal ideation or severe forms of depression are often excluded from studies.  These trials include not only patients with suicidal ideation, intent, or plan; but also patients without these characteristics. However, the GDT believes that the evidence above could be extrapolated to patients with suicide ideation, intent, or plan. Other Considerations and Overall Conclusion There is no evidence to support referring patients with suicidal intent or plan to specialty behavioral health. However, retrospective studies and expert opinion note that patients who express intent to commit suicide or have a specific plan to commit suicide are at higher risk for completed suicide. Therefore, consistent with current practice and common sense, and for clarity, the GDT recommends patients who endorse suicidal intent or plan be referred to specialty behavioral health.

In contrast, many patients with depression will endorse occasional thoughts of suicide but deny intent or plan, and will agree not to commit suicide. These patients can be and often are managed successfully in primary care. However, observational evidence suggests that certain classes of antidepressants (TCAs and venlafaxine) are associated with higher incidences of death by overdose than other anti-depressants. But there are some patients who might benefit from receiving these antidepressants instead of other available alternatives. For example, patients may have other medical comorbidities where TCAs are useful in treatment (for example, chronic pain). In other instances, patients may have responded to these antidepressants in the past, and are an established patient well known to their provider. In these instances, the GDT would not automatically exclude these patients from receiving these medications, but recommends that the provider discuss the potential risks and benefits with a psychiatrist.

(Note: MAOIs are excluded from this guideline, as this class of antidepressants is not recommended for use by primary care clinicians in treating depression).

4. Second-Line Treatment Of MDD 4A For patients with MDD whose symptoms fail to remit after first-line treatment, the GDT recommends an assessment of the adherence to the initial treatment regimen. Consensus-based 4B For patients with MDD whose symptoms fail to remit after adherence to first-line treatment, the GDT recommends that treatment options include:  Combining antidepressants and psychotherapy. Evidence-based  Increasing the dose of the initial antidepressant. Consensus-based  Switching to a different antidepressant of the same or different class. Consensus-based  Switching from psychotherapy to antidepressants or from antidepressants to psychotherapy. Consensus-based  Combined pharmacologic treatment (monitoring for toxicity, side effects, and drug interactions) with SSRIs and . low-dose TCAs, or . mirtazepine, or . bupropion, or . lithium, or . buspirone, or . liothyronine (T3). Consensus-based (all in this list) 4C The GDT makes no recommendation for or against providing folate or inositol to patients whose MDD symptoms fail to remit after adhering to first-line treatment. Evidence-based: I 4D The GDT makes no recommendation for or against providing atypical antipsychotics to primary care patients with (nonpsychotic, nonbipolar) MDD whose symptoms fail to remit after adherence to first-line treatment. Evidence-based: I 4E The GDT recommends against providing augmentation with pinodol for patients with MDD whose symptoms fail to remit after adherence to first-line treatment. Evidence-based Rationale: Evidence for Recommendation 4C: Insufficient Evidence for Recommendation 4D: Insufficient Evidence for Recommendation 4E: Evidence-based

Note: It is the expert opinion of the GDT, based on criteria used in trials of Major Depression treatment, that partial response is usually seen within four weeks of initiating treatment for MDD, and that remission, if it is going to occur, usually occurs within six to 12 weeks of initiation of treatment. For purposes of this guideline, patients whose symptoms have not improved by four weeks or resolved by six to 12 weeks after initiation of treatment are candidates for second-line treatment.

2008 Guideline New evidence was found that did change the existing recommendations.

Five RCTs and one new meta-analysis were identified that address a second line of treatment for patients whose symptoms did not resolve after initial treatment.  Mahmoud et al. conducted a six-week, multicenter, double-blind, placebo-controlled trial of augmentation of antidepressant therapy with risperidone (Risperdal) (up to 2 mg per day) in patients with Major Depressive Disorder whose symptoms had not resolved after a minimum of four weeks.(115) In the intention-to-treat analysis, remission of depression was seen in significantly more patients in the active treatment group than in the placebo group (24.5% vs 10.7%, p = 0.004, NNT = 7). The intervention group also had a higher percentage of patients with response (50% improvement in HAM-D scores; 46.2% vs. 29.5%, p = 0.004, NNT = 6). The 2.8 point mean change in HAM-D scores between groups, although statistically significant, is of marginal clinical significance. Patients who received risperidone gained an average of 2.8 lb in six weeks vs. an average of 0.3 lb in the placebo group (p < 0.001).  One meta-analysis and one RCT were identified that addressed the efficacy of augmentation of antidepressant therapy with atypical antipsychotic agents.  Papakostos et al. (2007)(116) published a meta-analysis that pooled the results of ten randomized placebo-controlled trials of augmentation with three atypical antipsychotic agents, olanzapine, quetiapine, and risperidone. Of these trials, four were published in the peer-reviewed literature and six were data from unpublished scientific reports (the quality of the latter studies cannot be explicitly determined). Data from a total of 1500 patients were pooled. These authors found that remission rate and symptom scores were significantly improved in the actively treated population (NNT for response and remission, ~ 4). There was no difference in overall discontinuation rates, but more patients in active treatment discontinued medication due to side effects (NNH not determined).  In a randomized, double-blind, placebo-controlled trial (Berman et al., 2007)(117) the efficacy and safety of apiprazole as augmentation therapy for patients with treatment-resistant depression. Both remission rates and improvement in depression scores were reported to be improved in actively treated patients. While the overall rate of adverse effects was high, the discontinuation rate due to adverse effects was only 2.2% in the apiprazole group.  The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial reported the results of comparing treatment modalities as second-step therapy after initial treatment failure with citalopram monotherapy. Both augmentation and substitution strategies were examined. Comparable outcomes were seen with cognitive therapy and pharmacotherapy with several different medications, although fewer than one-third of participants consented to randomization strata that permitted comparison of pharmacotherapy with cognitive therapy. Switch to cognitive therapy seemed to be associated with fewer side effects than switch to medication, but because of the small sample size, the differences were not statistically significant (NNT undetermined). When it was used as augmentation of citalopram, the effect of pharmacotherapy was seen more rapidly than that of cognitive therapy, with mean time to first remission (for those who did remit) 40 days in the pharmacotherapy group compared with 55 days in the cognitive therapy group.(118)

 In a comparison of sustained-release bupropion, sertraline, and extended-release venflaxine, Rush et al. studied the substitution of these drugs as monotherapy for patients whose depression had not responded adequately to SSRIs.(119) All three strategies resulted in the same degree of improvement; no significant difference in side effects was seen among the three treatment groups.  Trivedi et al. compared augmentation of monotherapy with bupropion or buspirone. Both groups had similar rates of remission, but a greater reduction in the severity of symptoms and fewer side effects (NNT = 8 for discontinuation due to side effects) were seen with bupropion treatment.(120)

Two RCTs were identified that compared third-line treatment for patients who had not achieved remission in two separate therapeutic trials.  Fava et al.(121) compared mirtazapine and nortriptyline as sole medications for patients who had not achieved remission with, or had been unable to tolerate, two previous therapies in the STAR*D trial. Both groups achieved similar results, with remission rates lower than 20%.  In another study in the third level of the STAR*D trial, Nierenberg et al.(122) compared lithium with triiodothyronine as augmentation therapy for patients who did not have remission of symptoms after two previous trials. Outcomes were similar in the two groups, but triiodothyronine use was associated with fewer side effects (NNT = 14). Overall Conclusion:  The STAR*D trial is a national, multicenter, academic and community, private and public sector equipoise RCT. Patients not responding to initial treatment with citalopram (an SSRI) at mean doses of 41 mg were randomized to different, multiple follow-up treatment options, but patients could be excluded from consideration of randomization to treatments they found unacceptable. (This design mimics real-world discussion of shared decision making.) Patients who failed to adequately respond to second-phase treatment proceeded to third-stage treatment with similar patient “opt out” possibilities; continued refractory patients proceeded to stage 4 treatment. The STAR*D and other trials reinforce, or in some cases add, options for primary care clinicians treating patients with Major Depression who fail to remit with initial treatment. Because of the lack of placebo in these trials, the GDT did not feel these recommendations deserved an “evidence-based” rating, unless previous placebo RCTs supported specific recommendations. (It is possible that some patients would have responded to placebo in these trials as a result of the nonspecific “attention” effect of being in a clinical trial.) Also of note, the STAR*D population might not exactly reflect the Kaiser Permanente population (STAR*D patients tended to be more socioeconomically disadvantaged, a high percentage were uninsured, and 15% to 18% expressed suicidal ideation).

 Contrary to previously reviewed evidence on atypical antipsychotic augmentation for Major Depression, the Mahmoud and Berman studies and the Papakostis meta-analysis suggest that short-term augmentation with risperidone may be beneficial. All of these trials were drug company sponsored and of short duration. Some of the findings (i.e., the Mahmoud study) were of questionable clinical significance, whereas the Papakostis meta-analysis suggests some potentially clinically significant findings. All of these studies compared atypical antipsychotic augmentation with placebo, not with other proven or established augmentation or second-line strategies.  Additionally, concerns have been raised about cardiometabolic side effects and safety of atypical antipsychotics. Patients taking these medications require laboratory, as well as mood, monitoring (consensus statement: Diabetes Care 2004: 27:596-601). Finally, atypical antipsychotics are currently significantly more costly than other available strategies.  There is fair evidence of short-term effectiveness for use of atypical antipsychotic agents to augment antidepressants in patients with nonpsychotic, nonbipolar MDD who fail to remit with initial treatment. However, due to the lack of longer-term data, the known cardiometabolic risks of treatment with these medications, and the lack of comparison data against other strategies, the balance of benefits, harms, and costs compared with other treatments cannot be determined.

The GDT sought evidence of both health outcomes and health interventions for the clinical question listed above. The only relevant health outcome found in the previous guideline pertains to change in depression symptoms among participants in the various trials listed above.

Health interventions were sought in: changing antidepressant medication, increasing existing antidepressant dose, switching to psychotherapy, adding psychotherapy, adding another antidepressant to existing antidepressant, augmentation to existing antidepressant, rTMS, and vagus nerve stimulation. Relevant information on all listed health interventions were found in the studies listed above. However, to avoid duplication of efforts, the GDT has decided to defer the recommendations for vagus nerve stimulation and rTMS to those made by KP’s Interregional New Technology Committee (INTC).

Excerpts from Kaiser Permanente’s INTC recommendations on vagus nerve stimulation and repetitive transcranial magnetic stimulation (rTMS) are summarized below: Vagus Nerve Stimulation The INTC maintains its prior recommendation: There is insufficient evidence to determine whether vagus nerve stimulation is a medically appropriate treatment for any patient with treatment-resistant depression. The existing evidence is of insufficient quantity and quality.

Repetitive Transcranial Nerve Stimulation Based upon a review conducted by the INCT in Oct. 2003, there is insufficient evidence to determine whether repetitive transcranial magnetic stimulation (rTMS) is a medically appropriate treatment for any patient.

For more information on vagus nerve stimulation and Repetitive Transcranial Magnetic Stimulation (rTMS) for the treatment of Depression, please refer to the following, updated statements made by (INTC):  Vagus Nerve Stimulation: http://cl.kp.org/pkc/national/cpg/intc/topics/01_31_080.html  rTMS: http://cl.kp.org/pkc/national/cpg/intc/topics/10_20_032.html 2006 Guideline We found several studies that address a second-line of treatment for patients whose symptoms did not resolve after initial treatment.  Schatzberg (2005)(123) found that patients with Major Depression who failed to respond to initial treatment with nefazodone or CBASP (cognitive behavioral therapy) both showed statistically significant improvement when switched to the alternate therapy. Patients who switched from nefazodone to CBASP showed a significantly greater improvement in depressive symptoms than those who switched from CBASP to nefazodone, possibly due to a decrease in medication-related side effects when switching to CBASP. There was no nonresponder control group continuing in the initial treatment.  Parker, Brotchie & Parker (2005)(124) found that the addition of olanzapine to antidepressants did not significantly improve symptoms in patients with nonpsychotic Major Depression when compared with control subjects who were treated with antidepressants exclusively.  Perry, et al. (2004)(125) found that, when compared with control, pindolol augmentation did not have a significant effect on depressive symptoms of patients who previously did not respond to SSRIs.  Kauffmann (2004)(126) found a significantly positive effect of right prefrontal transcranial magnetic stimulation (rTMS) over ten days in a small group of patients who failed to respond to at least two standard antidepressants given at adequate doses for at least eight weeks.  Rumi (2005)(127) studied the effect of rTMS on patients with severe nonpsychotic Major Depression and found that rTMS had a significantly better impact on depressive symptoms and remission rates when compared with control.

Clinical Evidence reports several RCTs within systematic reviews that found positive improvement in depressive symptoms after the addition of an antidepressant to psychotherapy, or the addition of psychotherapy to an antidepressant. These findings are consistent across all severities of depression – mild, moderate, and severe. For more details, see the rationale statements under “First-line treatment” recommendations.

Clinical Evidence found one systematic review and one subsequent RCT examining augmentation of prescription antidepressant drug treatment with lithium or pindolol versus placebo in adults with treatment-resistant depression.

 One systematic review found no significant difference in the proportion of people who responded over one to eight weeks between pindolol augmentation and placebo; responders: 10/53 [19%] with pindolol augmentation vs. 6/53 [11%] with placebo; absolute risk difference +8%, 95% CI: -6 to +21%; RR = not reported). The same review found that lithium augmentation significantly increased the proportion of people who responded over two weeks compared with placebo; 11/26 [42%] with lithium vs. 4/24 [17%] with placebo; absolute risk difference 25%, 95% CI: 2% to 49%; RR = not reported.(128)  The subsequent RCT found no significant difference between lithium augmentation and placebo in the proportion of people who responded over six weeks was 2/18 [11%] with lithium vs. 3/17 [18%] with placebo; reported as nonsignificant, CI not reported.(129)  A Cochrane review(130) yielded two RCTs (151 patients) that examined the use of folate in addition to other treatments for Major Depression. It found that patients treated with folate in addition to other treatments had an additional average decrease in Hamilton Depression Scale ratings of 2.65 points (95% CI: 0.38 to 4.93); fewer folate patients experienced an inadequate response to treatment (less than 50% decrease in depression scores from baseline) with a NNT of 5. The trials did not reveal any problems with the safety or acceptability of folate. The Cochrane review suggests that limited evidence to suggest folate may be of benefit as a supplement to other treatments for depression, but it is unclear if this benefit depends on baseline serum folate levels (or presence of baseline folate deficiency).  Another Cochrane systematic review(131) examined the effectiveness of inositol as an adjunct to antidepressants. Combining continuous measures using Standardized Weighted Mean Difference (SMD), no statistically significant overall heterogeneity of effect between trials was observed (Chi-square = 3.57, df = 3, p = 0.31). The authors concluded that there was no clear therapeutic benefit and that further research would be needed before a recommendation for this intervention could be made.  Cochrane also examined the therapeutic efficacy and safety of rTMS for depression.(132) Five studies compared rTMS with a sham rTMS intervention and showed statistical homogeneity. The relative risk, using a fixed effects model was 0.81 (95% CI: 0.36 to 1.83; p = 0.6). The authors concluded that there is “no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit.”  In their systematic review of the literature, the National Institute for Clinical Excellence (NICE)(57) found strong evidence suggesting there is a clinically significant difference favoring combined CBT and antidepressants over antidepressants alone on increasing the likelihood of remission in people with chronic depression (which, by definition, is refractory to initial treatment). (N = 1, n = 454, RR = 0.73, 95% CI: 0.62 to 0.84). Overall Conclusion The evidence continues to support our previous recommendations for treatment of patients with MDD whose symptoms do not resolve after the initial treatment. Additional wording was included to clarify that these recommendations assume that patients were adherent to the initial treatment but resistant to it (differentiating lack of adherence from true treatment nonresponse).

Psychotherapy We found one new study that supports changing from antidepressants to psychotherapy or vice versa in patients who fail to respond to initial treatment for Major Depression after 12 weeks.  There was no control group (continuing on previous therapy) in this study, therefore it is unclear how many patients would have responded to the initial therapy given more time. However, clinically, a change in therapy for nonresponse is usually initiated before 12 weeks. Given that this is the only study we identified that suggests that switching is effective for nonresponse to initial treatment for Major Depression, and the presence of more evidence for other treatment options, the GDT does not believe that it can make an evidence-based recommendation for this strategy at this time. However, structured psychotherapy (CBT, IPT, and PST, as outlined in the problem formulation) and antidepressants have been shown to be equivalent treatment options for initial treatment for many patients with Major Depression. Extrapolating from this, the GDT believes that offering the alternative treatment as one of several strategies (albeit a strategy without as much direct evidence as others) for patients who fail to respond to initial MDD treatment to consider is reasonable, and includes this as a consensus option. Lithium Augmentation Evidence remains mixed on lithium augmentation. The Fava RCT(133) reviewed by the GDT in 2004 was not included in the systematic reviews covered above. We therefore have one systematic review and one RCT (although the latter has some limitations as discussed in the 2004 review) favoring lithium augmentation, and one RCT finding no significant difference. The weight of the evidence seems to favor use of lithium as a potential augmentation strategy, with a consensus-based (rather than evidence-based) recommendation. Primary care clinicians (the main audience for this guideline) seldom initiate lithium therapy, although they commonly see patients taking lithium prescribed by a psychiatrist. Therefore, the GDT recommends consultation with psychiatry for patients in whom this option is being considered. Transcranial Magnetic Stimulation Since our previous iteration of the guideline, we found two studies on transcranial magnetic stimulation. Although these studies showed benefit, the studies were small and of short duration, the technology is not readily available, no comparisons have been made with other augmentation strategies, and the added value has not been quantified. Therefore, the GDT agrees with the Cochrane review that there is insufficient evidence at this time to recommend this intervention for the treatment of MDD. Folate The GDT discussed the Cochrane reviews on folate in combination with antidepressants for treatment of Major Depression. The GDT believes that more studies are needed, particularly examining differences in patients with normal vs. below-normal serum folate levels, before this strategy can be recommended. Inositol The GDT concurs with the Cochrane review on inositol. The authors concluded that there was no clear therapeutic benefit and that further research would be needed before a recommendation for this intervention could be made.

Vagus Nerve Stimulation The following rationale statement on Vagus Nerve Stimulation for depression comes from the Kaiser Permanente Interregional New Technologies Committee (INTC) meeting of November 14, 2005: “The INTC reviewed this topic in July of 2004 and had an update March 2005. At that time, the INTC found there is insufficient evidence to determine whether vagus nerve stimulation (VNS) is a medically appropriate treatment option for any patient with Major Depressive Disorder. The existing evidence regarding how VNS effectively treats Major Depressive Disorder (MDD) is of insufficient quantity and quality. The published studies are not blinded, report incomplete data sets of short-term results, and fail to follow intent-to-treat principles, which can cause results to be overestimated. Recent publications and requests from TPMG, NWPMG, and TSPMG are bringing this topic back to the INTC. Marc Meisner, MD, TPMG Chief of Psychiatry, presented this topic to the committee. Recent publications, an ECRI Target 10/05, Hayes 10/05, and BCBSA TEC 08/05 assessment served as the basis for the discussion.

“The vagus nerve stimulation (VNS) Therapy System, developed by Cyberonics, Inc., Houston, TX, consists of an implanted pacemaker-like pulse generator and nerve stimulation and delivers intermittent stimulation to the patient's left vagus nerve. The device costs $15,500.

“In 1997, the FDA approved this Cyberonics technology for treatment-resistant seizures in epilepsy patients. The mechanism of action of VNS for treatment- resistant depression (TRD) remains unknown. However, the vagus nerve projects into areas of the brain associated with neuropsychiatric disorders, neuroimaging studies have shown changes in areas of the brain linked to mood regulation with VNS, and evidence of mood improvement was seen in VNS for epilepsy studies irrespective of seizure control.

“In July 2005, the FDA approved Cyberonics' VNS pre-market approval application for "the adjunctive long-term treatment of long term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments." With its approval, the FDA required two post-approval studies to examine optimal stimulation dosing with one-year follow-up for 450 patients in a randomized double-blind study and five-year patient outcomes in 1,000 implanted patients.

“Of the 18 million people in the United States who experience a major depressive episode in one year, four million suffer chronic or recurrent pharmacoresistant depression. Some of these latter patients have TRD per the July 2005 FDA- labeled indication for VNS.

“Four published studies, all sponsored by Cyberonics, compose the scientific evidence for VNS for TRD. They involved a total of 422 patients with TRD. Dr. Meisner provided an overview on the pilot study (D-01), the Acute and Long-Term Pivotal Study (D-02), and the Comparative Study (D-04). Recent publications from Rush and George 2005, focused on D-02 and D-04.

“An open label study of 60 patients (pilot study D-01) who received VNS implant showed a response, defined as greater or equal to a 50% reduction on the Hamilton Rating Scale for Depression (HRSD), of 31% at 12 weeks, 44% at one year, and 42% at two years. Remission, defined as less than ten on the HRSD, was 15%, 27% and 22% for the same periods, respectively. However, differences in response rates between periods were not statistically significant.

“Rush, 2005, reported that in the D-02 12-week, pivotal double-blind, randomized controlled trial, active VNS therapy (n = 112) was no more effective than sham VNS (n = 110) in alleviating symptoms of depression among a population of adults diagnosed with Major Depressive Disorder or bipolar disorder. Active and sham treatment groups were well balanced with respect to baseline characteristics. At week 12, there was no significant difference between active and sham VNS in treatment response rates (15.2% versus 10.0%, respectively), nor were there significant differences between active and sham VNS groups for 4 of 5 scales used as secondary measures of efficacy. The only endpoint to show a significant difference between the two study arms was the self-administered Inventory of Depressive Symptomatology-Self-Report (IDS-SR) (17% vs. 7%).

“A two-year follow-up active treatment study (long-term pivotal study D-02, Rush 2005) consisted of patients from both active and sham arms of the acute pivotal study. This open label study demonstrated statistically significant improvement in depression scores measured by the 24-item HRSD and the 30- item IDS-SR. The study found an HRSD response of 27% at one year and 21% at two years as well as HRSD remission in 16% of patients at one year follow-up. Dr. Meisner discussed various study limitations. Comparisons of long-term outcomes must also be interpreted with caution, as patients were not randomized or blinded to treatment in longer-term trials. Patients treated with long-term VNS in clinical trials were allowed to receive additional concomitant treatments, raising the possibility that the observed response was not a result of VNS. Stimulation parameters varied among patients, which may have affected treatment outcomes. The manufacturer supported these studies, and a number of investigators listed as authors in these studies have disclosed individual financial relationships with the manufacturer, therefore, the potential for bias cannot be excluded.

“A fourth study (comparative study D-04) examined outcomes for the more than 200 patients in the long term pivotal study relative to those of more than 120 patients with TRD from a separately recruited control group who had not received VNS implants and were being treated with standard of care therapies. This trial resulted in a statistically significant HRSD response rate at one year of 27% for the VNS group, which could also use standard of care remedies, versus 13% HRSD response for the group only allowed standard of care treatment. Study limitations were also noted with the D-04 comparative study. The patients from the comparison control group were recruited separately, after results from D-02 were known, so do not represent adequate controls for the long-term effect of VNS.

“These studies, together with prior experience with VNS therapy in seizures, confirmed that surgical complications for VNS implant, including infection and vagus nerve damage, are low. More than half of implanted patients report stimulation-related voice alteration; much smaller percentages note increased cough, dyspnea, neck pain and other VNS-induced discomforts which tended to lessen with time. Further, VNS therapy does not appear to pose a greater risk for mania, suicide, and worsening depression.

“Overall, the evidence is limited by the studies' designs and the data quality suffers from inadequate controls and blinding, placebo effect, research site differences, heterogeneous stimulation parameters, various concomitant treatments allowed, and possible investigator bias.

“The updated Hayes Assessment from 10/05 concluded that the currently available evidence is insufficient to permit conclusions regarding the efficacy and safety of VNS as an adjunct therapy in treatment-resistant Major Depression and bipolar disorder. A Hayes Rating of C is assigned for VNS as an adjunctive therapy in adults with severe Major Depression or bipolar disorder when symptoms associated with a major depressive episode are refractory to multiple regimens of standard medication and other therapies, including electroconvulsive therapy (ECT) and psychotherapy; D is assigned for VNS in patients with other types of depression and in patients with Major Depression or bipolar disorder who respond to medical treatment, psychotherapy, and/or ECT; and D is assigned for VNS in patients with contraindications to VNS. These Ratings reflect the paucity or lack of evidence regarding the safety and/or efficacy of VNS in these patient populations.

“The updated ECRI Assessment also concludes there is limited ability to draw strong conclusions about the efficacy of VNS to treat treatment-resistant depression (TRD) using the available evidence. "All studies thus far have been manufacturer-sponsored with notable design weaknesses. The largest study fails to follow intent-to-treat principles, potentially overestimating results by not reporting outcomes of all patients entered in the study. Although VNS therapy lacks the severe side effects (e.g., long-lasting cognitive impairments, renal and thyroid toxicity, hypertensive crises, anticholinergic effects) of the treatments typically offered to patients with TRD, conclusions cannot be drawn regarding adverse events associated with long-term use of VNS therapy for depression due to incomplete adverse event reporting in the larger of the two trials used to write this report."

Apart from the KP Northwest, which intends to use VNS for highly select patients with TRD, no other region expressed support for its use at this time as no definitive benefit of VNS for TRD has been yet shown in a large, prospective, randomized trial with adequate follow-up. There is insufficient evidence to determine whether vagus nerve stimulation is a medically appropriate treatment for any patient with treatment-resistant depression. The existing evidence is of insufficient quantity and quality. Pindolol Augmentation We found one additional negative study on pindolol augmentation. Combining this with our previous findings on pindolol, the GDT recommends against the use of pindolol as an augmenting agent for Major Depression at this time. Assessing Adherence Finally, we found no evidence examining the benefit of assessing adherence to initial treatment before attempting other treatment alternatives. However, the studies on alternative treatments we reviewed included patients who were adherent to initial treatment regimens. Furthermore, assessing patient adherence is consistent with patient-centered practices designed to promote self-care, and is a generally accepted tenant of practice. Therefore, the GDT elected to include this consensus recommendation in order to be thorough.

2004 Guideline

Supporting Evidence For Antidepressant or Psychotherapy Alone Versus Combined Treatment of Antidepressant and Psychotherapy One RCT looked at efficacy of combined psychotherapy and antidepressant treatments versus psychotherapy or antidepressant medication alone in patients with chronic MDD.  Hirschfeld(134) (n = 681) included adult patients with chronic Major Depression (who by definition have failed initial treatment) between the ages of 18 and 75. The population was 65% female, 91% white. The study was a randomized, open-label, controlled trial comparing a SNRI (nefazodone 200 to 600 mg/day) and Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and the combined nefazodone/CBASP treatment for 12 weeks. There was no placebo control group. HAM-D score analysis (taken from the original publication of the study by Keller(135)) indicated that that the combined treatment was statistically superior to either treatment alone; p ≤ 0.001 for nefazodone vs. combined treatment, p ≤ 0.001 for CBASP vs. combined treatment. SF-36 general health indicated the same results, p = 0.0003 and p = 0.02 respectively. There was also greater improvement in psychosocial functioning when combined treatment was used (p = 0.02 and p = 0.02).

We also searched Volume 9 of Clinical Evidence,(70) most recent search date November 2003, and found that our recommendations are in line with their conclusions. They found:  One nonsystematic review showing that the combination of psychotherapy and antidepressant medication in patients age 18 to 80 with severe MDD is more beneficial than either treatment alone.  Two RCTs showing that combination antidepressant-psychotherapy treatment is more effective than either treatment alone for patients with mild to moderate Major Depression. One of these studies specifically examined patients with chronic, refractory, or depression recurring on treatment (who by definition have failed first-line treatments). Overall Conclusion Combining antidepressant treatment with psychotherapy is more effective than either treatment alone for patients who have failed first-line treatment or for patients with severe MDD. See discussion in the rationale for first-line treatment of MDD for discussion of the role of initially combining antidepressant-psychotherapy for patients with mild to moderate MDD.

Supporting Evidence For Increasing Existing Antidepressant Dose, Switching Antidepressants, Adding Another Antidepressant to Existing Antidepressant or Adding An Augmenting Agent to The Existing Antidepressant Four RCTs looked at second-line treatment strategies for the treatment of MDD in adults whose symptoms did not resolve after the first treatment.  Fava (n = 101) included outpatients with MDD (initial HAM-D-17 score of ≥ 16) between ages of 18 and 65 who were either partial responders or nonresponders to (133)eight weeks of treatment with SSRI (fluoxetine, 20 mg/day). The study was a randomized, double-blind, controlled trial comparing increasing the SSRI (fluoxetine) dose (40 to 60 mg/day), adding low dose desipramine (25 to 50 mg/day) to existing 20 mg/day fluoxetine, and adding an augmenting agent (lithium, 300 to 600 mg/day) to existing 20 mg/day fluoxetine for a period of four weeks.  Mean change in HAM-D-17 score (from visit one to endpoint) showed no statistically significant differences among these patients (p = 0.4, for all comparisons). The difference in response rates (patients who showed at least a 50% reduction in HAM-D scores) across these three treatment groups was also not significantly significant (p = 0.5, for all comparisons). There was also no significant differences in dropout rates across the three groups (p = not stated).  The study did not include a placebo group, so placebo response to augmentation or an eventual response to continued treatment at the same does cannot be excluded, and the study may not have had sufficient power to detect true differences between groups.  Peet(136) included patients aged 18 to 70 with HAM-D-17 score of 15 or more despite ongoing treatment with a standard antidepressant at an adequate dose. The study was a small (n = 70), randomized, double-blind, controlled study comparing augmenting with ethyl- eicosapentaenoate (E-EPA) at 1 g/dl, 2 g/dl, 3 g/dl; liquid paraffin placebo for a period of 12 weeks.  Change in 17-item Hamilton Depression Rating Scale (HDRS) score (p = 0.02), Montgomery-Asberg Depression Rating Scale (MADRS) score (p = 0.006) and Beck Depression Inventory (BDI) score (p = 0.007) for the intention-to-treat population showed that augmentation with ethyl-eicosapentaenoate at a dosage of 1 g/dl was statistically significant in treatment of Major Depression in patients who remain depressed despite adequate standard therapy.  Nemets(137) included adults 18 to 75 years old with a current diagnosis of MDD (24-item Hamilton Depression rating Scale of 18 or higher).  The study was an extremely small (n = 20), randomized, double-blind, controlled study comparing ethyl-eicosapentaenoate (E-EPA at 2 g/day) and placebo for a period of four weeks. The author concluded that the study showed significant benefits in adding E-EPA to the existing treatment (p = not stated).

 Perez(138) included adults 18 to 65 years old with single or recurrent MDD, with the current episode resistant to pharmacological treatment. The study was a small (n = 80), randomized, double-blind, controlled study comparing augmenting with pindolol and placebo for a period of ten days. There was no significant difference in the change in HAM-D score from day 0 to day 10 between pindolol and the placebo groups (p not given). The study does not support the hypothesis that the addition of pindolol results in a rapid augmentation of the effects of SSRIs in depressed patients resistant to treatment.

Other pindolol studies (of mixed results) were found, but those studies addressed the effect of adding pindolol to antidepressants at the onset of treatment for Major Depression, rather than augmenting antidepressants with pindolol after initial nonresponse to antidepressants. As these studies examine a different clinical question (improving speed of initial response to antidepressants rather than augmentation in cases of nonresponse), these studies were excluded from formal review. Other Considerations  E-EPA may not be widely available in a standardized preparation, and the two E-EPA trials were small. Therefore, the GDT considers the E-EPA findings preliminary, and pending further study, does not currently recommend E-EPA be used regularly by primary care physicians as an augmentation strategy.  No evidence was found on the efficacy or safety of combining antidepressants from the same class in the treatment of MDD that has failed to respond to initial treatment.  There are theoretic safety concerns about the increased risk of serotonin syndrome when combining SSRIs or using SSRIs with other highly serotonergic antidepressants (SNRIs).  MAOIs are generally not recommended for use by primary care, given their potential toxicity and drug interactions, and have been excluded from this guideline. Combining MAOIs and SSRIs have been associated with adverse patient outcomes and are contraindicated.  Only one RCT was found on combining low-dose TCAs and SSRIs for MDD that failed to respond to initial treatment and it used desipramine, a “later generation” TCA with fewer side effects and more noradrenergic action than most other TCAs. There are theoretic reasons that augmenting serotonergic agents with norepinephrinergic agents would lead to improved outcomes (by affecting two different neurotransmitter systems). However, we did not find good evidence that so-called dual action antidepressants (enhancing both serotonin and norepinephrine) are superior to either SSRIs or TCAs in the treatment of depression.

There was also no consensus among the GDT that the TCA augmentation effect seen in this study can be extended to other TCAs as a class-effect. Therefore, the GDT elected to limit the recommendation to desipramine because it had been specifically studied. The recommendation is labeled “consensus” because of the limitations in the Fava study discussed above.  Combined use of SSRIs and higher doses of TCAs increases the risk of TCA toxicity, primarily manifested as cardiac arrhythmia. Therefore, only low doses (< 50 mg) of TCAs should be used, and the GDT recommends careful monitoring for symptoms of TCA toxicity. Most primary care physicians do not prescribe lithium, due to complexities in dosage and laboratory monitoring. Some primary care physicians may be comfortable prescribing lithium, but in general the GDT believes that consultation with psychiatry should occur when this treatment option is being considered.  Group Health Cooperative’s 2003 Adult Major Depression Guidelines included three additional studies from a Medline search using similar mesh terms that did not appear in our PubMed search: Bauer,(139) Appelberg,(140) and Thase.(141)  Group Health concluded: “Bauer found that lithium augmentation was superior to placebo for nonresponders to antidepressants. The majority of the studies included initial treatment with TCAs and findings may be less applicable to SSRI treatment.”  Appelberg did not find a significant difference between augmentation with buspirone or placebo among patients initially treated with SSRIs. In the Appelberg study, “33% of patients responded to buspirone augmentation and 31% responded to placebo augmentation…the Appelberg RCT may have been underpowered…a substantial proportion of patients responded to placebo augmentation, so it is difficult to draw conclusions from studies that do not include a placebo group.”  “Thase conducted an RCT in which patients who did not respond to initial treatment with SSRIs or TCAs switched to the other class of medication. There was no significant difference in outcomes between groups after switching. A substantial proportion of patients in each group experienced a remission after switching, 32% in the imipramine to sertraline group and 55% in the sertraline to imipramine group.”  Despite the presence of observational studies and case reports, we did not find any RCTs or quasi-experimental trials evaluating the use of Cytomel, carbamazepine, valproic acid, or methylphenidate for augmentation of antidepressants. Clinical Evidence did not examine this question. Overall Conclusion Increasing the dose of the initial antidepressant; adding low-dose desipramine to an SSRI; switching antidepressants; or adding lithium 300 to 600 mg/day are potential treatment options for patients with MDD whose symptoms do not remit after initial treatment. Due to complexities in management, most primary care clinicians will not prescribe lithium without psychiatric consultation or assistance, so the GDT added consultation with psychiatry to this consensus option to reflect real world practice.

Due to methodological limitations, including lack of control groups simultaneously maintained on pre-existing treatment, the evidence is not as strong as the evidence for combining psychotherapy and antidepressants, so the GDT has labeled these recommendations “consensus- based.”

5. Length Of Treatment With Antidepressants In Patients With MDD

Patients Who Achieve Symptom Remission 5A The GDT recommends that patients with MDD who achieve symptom remission with antidepressants should continue antidepressants at the same dose for at least an additional six to 12 months. Evidence-based Patients With One Lifetime Episode of MDD 5B Based on patient and provider preference, the GDT recommends that a trial of antidepressant discontinuation is optional for patients in their first lifetime episode of MDD, who are being treated with antidepressants, achieve remission, and remain asymptomatic for six to 12 months after acute phase treatment. Consensus-based Patients with Two or More Lifetime Episodes of MDD 5C The GDT recommends that patients with two or more lifetime episodes of MDD, who are being treated with antidepressants and remain asymptomatic after acute phase treatment should be maintained on the medication and dose with which they achieved remission for at least an additional 15 months to five years after acute phase treatment. Consensus-based Patients with Chronic MDD or MDD with Concurrent Dysthymia* 5D The GDT recommends that patients with chronic MDD (continual symptoms for more than two years) or Double Depression (MDD and dysthymia) who improve with antidepressants during acute phase treatment should continue antidepressants for at least an additional 15 to 28 months after acute phase treatment. Evidence-based Rationale:

2008 Guideline No new evidence was found, the recommendations remain unchanged. 2006 Guideline Our search yielded three RCTs that examined depression relapse or recurrence rates in an extended continuation phase with antidepressants:  Keller, et al. (2005)(143) found that over a 44 week continuation phase, there was a significantly lower percentage of relapse in gepirone ER treated patients compared with those treated with placebo.  Montgomery, et al. (2004)(144) found that over a 52 week continuation phase, the cumulative probability of recurrence was significantly lower in patients treated with venlafaxine versus those treated with placebo.

* Dysthymia = Depressed mood plus at least two additional DSM-IV(142) symptoms present more days than not for at least two years.

 Rapaport, Bose & Zheng (2004)(145) found that over a 36 week continuation phase, the cumulative rate of relapse was significantly lower in patients treated with escitalopram versus those treated with placebo.

Clinical Evidence found one systematic review that underscored the importance of the continuation phase. Patients continuing on a course of antidepressants after recovery had a reduced risk of relapse over one to three years. This effect was independent of duration of initial treatment, duration of previous antidepressant treatment, or underlying risk of relapse.  The review found that, overall, continuing antidepressant drugs in people who had responded to them significantly reduced the proportion of people who relapsed compared with placebo (31 RCTs, 4,410 people with first episode or recurrent depression; numbers relapsing: 465/2,527 [18%] with continuing antidepressants vs. 1,031/2,505 [41%] with placebo; OR = 0.30, 95% CI: 0.22 to 0.38).(146)  In their systematic review of RCTs, the National Institute for Clinical Excellence (NICE)(57) depression guideline makes an evidence-based recommendation that patients with moderate to severe depression should continue antidepressants for at least six months after remission. This conclusion is based primarily on the findings of two studies in which a greater percentage of patients on SSRIs were able to complete six months of treatment than those taking TCAs.  An RCT conducted in the USA randomized 536 adults to receive desipramine, imipramine, or fluoxetine (Simon, et al., 1996).(147) Sixty percent of the fluoxetine patients completed six months of treatment compared with less than 40% of the TCA patients. Those who discontinued one antidepressant were offered another. There were no differences in overall completers or response rates at endpoint suggesting that initial drug choice did not affect outcome. However, outside of clinical trials, patients may not return to their general practitioner to have their treatment changed and outcome may be less positive.

For example, a Swedish study of 949 patients found that 35% only ever received one prescription irrespective of whether it was for a TCA or a SSRI (Isacsson, et al., 1999).(148) After six months, 42% of SSRI patients were still receiving prescriptions compared with 27% of TCA patients. There is some evidence from this study that the relapse rate may have been higher in the TCA group: 28% of TCA treated patients received a subsequent prescription for an antidepressant after a nine-month treatment-free gap compared with 10% of SSRI patients. Overall Conclusion Evidence consistently shows that continuing antidepressants after remission of symptoms of MDD reduces the risk of relapse. This new evidence, in combination with some of the evidence reviewed previously, suggests that a minimum of six months of antidepressant continuation after acute phase treatment and symptom remission may be more appropriate than the previously recommended four month minimum continuation phase. Consistent with all the previously reviewed evidence, these new studies support continuation at the same antidepressant dose that was used to achieve remission. Therefore, the GDT recommends continuation phase treatment should last at least six to 12 months following acute phase antidepressant treatment of MDD.

2004 Guideline

How Long Should Patients With MDD Who Have Responded To Antidepressant Medication Continue Taking Medications Beyond The Acute Phase Of Treatment? Acute Phase: Up to three months after starting treatment (period to assess for response to treatment/remission.) Continuation Phase: Next four to 12 months. Maintenance Phase: Treatment beyond continuation phase. Supporting Evidence for Minimal Length of Treatment With Antidepressants in Patients With MDD after Acute Phase Symptom Remission Two new RCTs were found that addressed this issue.  Weihs(149) studied men and women at least 18 years old with moderate to severe, recurrent Major Depression based on Diagnostic and Statistical Manual-IV (DSM-IV) criteria who had a minimum score of 18 on the 21-item Hamilton Depression Scale (HAMD). The current depressive episode must have been preceded by at least one other episode within the last 60 months. All patients (n = 816) were received open label treatment for eight weeks (acute phase), with bupropion SR (150 to 300 mg/day). Patients who responded to the treatment and continued to meet the selection criteria entered a 44-week (11 months) randomized, double-blinded, placebo controlled continuation phase with bupropion SR, 300 mg/day (n = 207) or placebo (n = 210). The study showed that treatment with bupropion SR for up to 44 weeks decreases the risk of depression relapse. Time to depression relapse (time from randomization to intervention) was 44 weeks for bupropion SR treated patients and 24 weeks for the placebo group (p = 0.003, favoring continuation treatment). Survival estimates indicated 52% of placebo treated patients and 37% of bupropion patients would have become depressed by the end of the study (p = 0.004 favoring bupropion). By the end of one year treatment, the odds of placebo-treated patients requiring treatment intervention for a relapse of depression were 1.83 times greater that those of bupropion SR-treated patients (confidence interval not specified).

 Reimherr(150) studied male and female outpatients 18 to 65 years of age that met DSM-III-R criteria for Major Depression with a duration of at least one month and had a modified 17-item Hamilton Depression Rating Scale score of at least 16. After a five to nine day medication-free baseline phase, all patients (n = 839), received 12 to 14 weeks of open-label acute therapy phase with fluoxetine, 20 mg/day. The 395 remaining patients were then randomized into one of four double-blind continuation treatment groups: 14 weeks of continuation therapy with fluoxetine followed by 38 weeks of placebo (n = 97), 38 weeks of continuation therapy with fluoxetine followed by 14 weeks of placebo (n = 100), 50 weeks of continuation therapy with fluoxetine (n = 102), or 50 weeks of placebo (n = 96). Relapse rates were calculated during 12 week periods after each double-blind transfer from fluoxetine to placebo (weeks 12, 26, and 50). Relapse rate (Kaplan-Meier estimates) were 26.4% for the fluoxetine-treated group and 48.6 for the placebo group after 12 weeks of continuation treatment (p < 0.001, favoring continuation treatment), and 9.0% for the fluoxetine-treated group and 23.2% for the placebo group after 26 weeks of continuation treatment (p < 0.001, favoring continuation treatment). There was no statistical difference (p = 0.54) in the relapse rate between the fluoxetine group (10.7%) and placebo (16.2%) after 50 weeks of continuation treatment (possibly due to lack of statistical power due to patient attrition).  The British Medical Journal(151) review consisted of six RCTs with a total sample size of 312 patients on current treatment with antidepressant medication. Findings indicated that continuation of antidepressant medication four to six months after acute phase treatment reduced the relapse rate by nearly half. The authors also pointed out that several more RCTs confirm the reduction in risk of early relapse with continuing medication for six to 12 months after acute phase treatment. Based on this evidence, the GDT recommends that depressed patients treated with antidepressants who are asymptomatic at the end of the acute phase (three months) of MDD treatment be maintained on antidepressants for an additional four to 12 months, to decrease the risk of early symptom relapse.

Clinical Evidence,(70) Volume 9, included the above studies in their review. Their conclusions are consistent with ours.

Supporting Evidence For A Trial Discontinuation For Patients With One Lifetime Episode of MDD No new evidence was found.  A published review(152) notes that patients in their first episode of MDD have a lifetime risk of relapse of approximately 50%.  Viguera(153) examined data from 27 randomized trials to determine the effects of discontinuation on relapse rates. Of these, two trials included only patients in their first episode of depression. In both of these trials, amitriptyline was the anti-depressant used, one trial included combination amitriptyline and lithium. Both trials were published before 1984. This review did not separately analyze the data in these two trials from five other trials whose inclusion criteria included “one or more” lifetime episodes of depression.  Among patients with one or more past episodes, the corresponding two year survival rates (symptom-free at two years) were not statistically different: 64.1% with treatment (95% CI: 58.7% to 69.4%) versus 52.7% without (95% CI: 42.9% to 62.6%). The relative weighting of patients with only one lifetime episode vs. one or more lifetime episodes in this data is unknown.

No additional trials were identified that specifically examined the risk of relapse in patients with one lifetime episode of MDD. Based on the paucity of data, and recognizing that some patients might choose, based upon their individual circumstances, to continue antidepressant treatment if made aware of the 50% lifetime risk of recurrence, the GDT has labeled this an “option” for patients. Because the GDT was unable to identify “clean” data in the systematic review that adequately addresses this question, this recommendation has been labeled as “consensus-based.” Supporting Evidence For Maintenance of Medication For Patients With Two or More Lifetime Episodes of MDD Two new RCTs were found that addressed this issue.  Hochstrasser(154) studied mental health in- and out-patients 18 to 65 years of age with recurrent unipolar Major Depression (DSM-IV), a Montgomery – Asberg Depression Rating Scale (MADRS) score of ≥ 22 and two or more previous depressive episodes, one within the past five years.  Four hundred, twenty-seven patients entered acute phase treatment with citalopram, 20 to 60 mg/day. Patients who responded after six to nine weeks (n = 327) continued citalopram for an additional 16 weeks (continuation phase). Patients whose depressive symptoms remained in remission (MADRS score < 11, n = 269) were then randomized in a double-blind fashion to maintenance treatment with citalopram (n = 132) versus placebo (n = 132) for an additional 48 to 77 weeks. Data from five patients initially assigned to the placebo group was excluded due to “major protocol violations.” Time to recurrence was longer in patients taking citalopram than in patients taking placebo (p < 0.001), with crude rates of recurrence of 0.22 recurrences /person-year at risk in the citalopram vs. 0.76 recurrences/person-year at risk in the placebo group.

 Gilaberte(155) studied male and female outpatients, 18 to 65 years of age, who met DSM-III-R criteria for unipolar Major Depression, had at least one previous major depressive episode in the last five years, a score of at least 18 on the 17-item Hamilton Rating Scale for depression (HAM-D-17) and at least four on the Clinical Global Impression (CGI) severity scale. All patients (n = 253) completed 32 weeks of open-label treatment phase consisting of both an acute (eight weeks) and a continuation period (six months) before being randomized to a double-blind maintenance phase with fluoxetine, 20 mg/day (n = 70) or placebo (n = 70) for 48 weeks. The recurrence rate was 20% for the fluoxetine-treated group compared with 40% for placebo (p = 0.010, favoring maintenance fluoxetine treatment). The symptom-free period was significantly longer for patients treated with fluoxetine vs. placebo (295 days vs. 192 days; Kaplan-Meier estimates, log-rank test, p = 0.002).  In the Viguera(153) analysis, a total of 3,037 depressed patients were treated for 5.78 (0 to 48) months and then followed for a mean of 16.6 (5 to 66) months with antidepressants either continued or discontinued. Compared with patients whose antidepressants were discontinued, those with continued treatment showed much lower relapse rates (1.85 versus 6.24% per month), longer time to 50% relapse (48.0 vs. 14.2 months), and lower 12 month relapse risk (19.5 versus 44.8%) (all p < 0.001). A survival analysis presented in the Viguera article shows a statistically significant difference in symptom remission between patients continuing medication and patients not continuing medication, which persisted through 54 months of follow-up.  Among patients with more than two or more past episodes, the corresponding one year survival rates (symptom-free at one year) were: 79.5% with treatment (95% CI: 73.2% to 85.8%) versus 56.5% without treatment (95% CI: 48.9% to 64.2%). Viguera did not differentiate between patients in their second lifetime episode of MDD and those with more than two lifetime episodes.  In patients with at least three past episodes or a chronic course, the two year survival rate (no recurrence of depressive symptoms) was 71.7% (95% CI: 64.6% to 78.9%) with antidepressant versus 14.7% (95% CI: 7.10% to 22.2%) without antidepressant - a highly significant 4.88 fold difference.  Viguera did not differentiate between patients with and without psychiatric comorbidities or history of suicide attempt.  Frank(156) found that active imipramine at a dose of 200 mg per day is effective at maintaining remission for three years in patients with three or more lifetime episodes of MDD.  Kupfer(157) followed a smaller subset of patients from the Frank study for an additional two years and found that imipramine 200 mg per day continued to effectively prevent recurrence of symptoms for up to five years. There is no patient outcomes data available to demonstrate the effect on patients maintained on medications for more than five years.

The studies examined all include maintenance therapy with antidepressants at the same or higher dose that achieved symptom remission or resolution. No evidence was found examining the effect of different dosage strategies, or changing medication, on disease-free interval.

A recently published review(152) notes that patients with three or more episodes of MDD have a lifetime risk of relapse of approximately 90%. Patients with two prior lifetime episodes of depression have a lifetime risk of relapse of 70%, intermediate to those with one prior episode and those with three or more prior episodes. No additional studies were found that examined outcomes of maintenance therapy specifically for patients with two past episodes of Major Depression. Conclusion Our systematic review did not identify any RCTs or meta-analyses on length of antidepressant treatment that clearly distinguished between patients with a history of two lifetime episodes vs. three or more lifetime episodes of MDD. There is insufficient “clean” evidence to make different recommendations for patients with two lifetime episodes of MDD and patients with three or more lifetime episodes of MDD. The data, in aggregate, suggest benefit to long-term continuation of antidepressants in patients with at least two lifetime episodes of MDD who respond to antidepressant treatment. The optimal duration of treatment is not clear from available data, but it appears that a minimum of 15 months and in some cases as long as five years of treatment after the acute phase response demonstrates benefit. It is possible that longer- term treatment (beyond five years) also provides continued benefit, but studies have not been conducted to examine the benefits of longer-term antidepressant treatment compared with discontinuation after five years. Because of these limitations, the GDT has labeled this recommendation “consensus-based.” Supporting Evidence For Patients With Chronic MDD or Double Depression to Continue Medication Two new RCTs were found that this addressed this issue.  Kocsis(158) studied out patients who met DSM-III diagnostic criteria for “pure” dysthymia (40%), chronic Major Depression (10%), and dysthymia with current Major Depression (“double depression”) (50%). All patients were treated with desipramine 50 to 325 mg/d during the acute phase (ten weeks) and continuation phase (16 weeks = four months). Patients who responded to treatment were then randomized to double-blind maintenance treatment with desipramine (n = 28) or placebo (n = 25) for 24 months. 15% of patients receiving long-term maintenance treatment with desipramine experienced a relapse, compared with 52% of patients receiving placebo (ARR = 37%, NNT = 3, p = 0.01). Fourty percent of patients studied did not have MDD (they had dysthymia only), although response in each patient subgroup did not differ in either the acute, continuation, or maintenance phases.  Keller(159) studied outpatients meeting a DSM-III-R structured clinical interview diagnosis of chronic Major Depression (symptoms for at least two years) or dysthymic disorder with Major Depression (double depression) and a minimum baseline severity of 18 on the 24-item Hamilton Depression Scale (HAM-D). All patients (n = 253) completed 12 weeks of treatment (acute phase) and four months of continuation phase treatment with sertraline 50 to 200 mg/day. Responders were then randomized to 48 weeks of double-blind maintenance phase with sertraline (n = 77) or placebo (n = 84). Sertraline treated patients had significantly fewer recurrences than placebo treated patients (6% vs. 23%), p = 0.002 for the log-rank test of time-to-recurrence distributions. Clinically significant depressive symptoms reemerged in 26% of patients treated with sertraline versus 50% in the placebo group (p = 0.001).

 The available evidence suggests benefit to long-term continuation of antidepressants in patients with chronic MDD or double depression (MDD with concurrent dysthymia) who respond to initial acute phase antidepressant treatment. The optimal duration of treatment is not clear from available data, but it appears that a minimum of 15 to 28 months of treatment after acute phase response demonstrates benefit. It is possible that longer-term treatment also provides continued benefit, but studies have not been conducted to examine the benefits of longer-term antidepressant treatment compared with discontinuation after 28 months. 6. Follow-Up For Patients In The Acute Phase (First Three Months) of Treatment For MDD 6 For patients who are starting treatment with antidepressants for Major Depression, the GDT recommends that the minimum recommended follow-up frequency be one patient contact within the first month, and at least one additional patient contact four to eight weeks after the first contact. Assess for adherence, side effects, suicidal ideation, and patient response during both these visits. Consensus-based Rationale: Note: HEDIS requires three follow-up contacts in the first 12 weeks of treatment with antidepressants, one of which must be with a prescribing clinician. HEDIS allows one of the three follow-up contacts to be by telephone; currently the other two contacts must be in-person visits. The HEDIS requirements are not evidence-based. 2008 Guideline No new evidence was found, the recommendation remains unchanged. 2006 Guideline We found one RCT examining an intervention for patients in the first three months (acute phase) of treatment for MDD:  Swindle, et al. (2003)(160) tested whether the services of a Clinical Nurse Specialist (CNS) would improve symptoms of primary care patients receiving treatment for depression or dysthymia. The CNS coordinated a treatment plan including medication, cognitive behavioral therapy, referral to Mental Health, and monitoring through telephone and/or in-person visits. Monitoring occurred at two weeks, one month, and two months after the initial visit. The authors found no significant difference in depression symptoms, patient satisfaction, or rates of antidepressant prescribing or adequate dosing between patients with CNS services versus those without. Patients in the intervention group did have significantly more recorded depression diagnoses and referrals to mental health in the medical record. Specific data on the follow-up frequency of patients in the usual care group were not provided. However, CNS’s often chose to use watchful waiting with patients in the intervention group (disagreeing clinically with depression scale diagnoses), thus affecting the fidelity of the intervention.

Overall Conclusion The Swindle, et al. study, due to reasons outlined above, adds no new information that helps determine a follow-up schedule for newly diagnosed Major Depression patients. Given the lack of additional information, the previous consensus-based recommendations still seem valid. However, recognizing the discrepancy between this recommendation and the HEDIS guidelines (which, albeit not evidence-based, are a standard on which health plans are judged) the GDT suggests clarifying the previous recommendation, by adding that the MINIMUM recommended follow-up frequency for patients who are starting treatment with antidepressants for Major Depression is one patient contact within the first month, and at least one additional patient contact four to eight weeks after the first contact. Research on this topic does not differentiate between modalities for follow-up (in-person visits, phone calls, email messages). The GDT believes that the “active ingredient” is the follow-up per se, and not the modality of follow-up; therefore we recommend that any of these types of contacts are acceptable. 2004 Guideline

Supporting Evidence For Follow-Up Frequency in the Acute Phase Treatment of MDD  There is no evidence that determines the optimal number or frequency of follow-up for adults in the acute phase (first 12 weeks of treatment) of Major Depression.  There is no evidence that suggests that in-person visits during acute phase follow-up are superior to phone contacts.  Despite the lack of evidence, HEDIS requires three follow-up contacts in the first 12 weeks of treatment with antidepressants, one of which must be with a prescribing clinician. HEDIS allows one of the three follow-up contacts to be by telephone, but currently the other two contacts are defined as in-person visits.

The GDT recommends targeting at least one contact within the first month and at least one additional contact four to eight weeks thereafter to evaluate treatment adherence, symptom response, potential side effects, suicidal ideation, and the need for treatment adjustment. This recommendation is based on medication discontinuation patterns seen in short-term trials of antidepressants (where patient dropouts tend to occur within the first month or between the second and third month of treatment), and the clinical experience and consensus of the GDT. Additional contacts may be needed for patients who are not tolerating or responding to treatment.

There is no evidence that patients who are tolerating and responding to treatment will achieve additional benefit with three contacts (as HEDIS suggests) as opposed to two contacts as outlined above (meaning extra patient and clinician time and resources may be utilized in some cases for no appreciable added benefit). Since there is no evidence that directly addresses this question, the GDT decided to base its recommendation on indirect evidence from the literature, recognizing that this recommendation would also be consensus-based.

The GDT recognizes that this recommendation may be viewed by some as an “opposition” to the current HEDIS standard (which is based solely on expert opinion without reference [that we found] to any systematic literature review to support it). However, by specifying a minimum number of visits in the Depression Guidelines; clinicians, teams, and regions still have the option to base performance benchmarks on the HEDIS criteria.

The GDT believes also that antidepressant continuation rates (also a HEDIS measure and also addressed in this guideline) are founded on better evidence and are better proxies for processes and outcomes of care. The recommendation for follow-up, with at least some basis in evidence (however indirect), provides flexibility for clinicians and teams to focus on and address other aspects of quality depression care, while also providing a “prompt” for teams to examine their care processes if the number of contacts falls below this minimum recommendation.

In March, 2004, the FDA issued a directive that the ten most commonly used antidepressants (fluoxetine, paroxetine, sertraline, bupropion, citalopram, fluvoxamine, mirtazapine, nefazodone, escitalopram, and venlafaxine) carry a warning that thoughts about suicide sometimes occur in people taking antidepressants. The findings have been noted in antidepressant studies of children and adolescents. Even though to date there have not been specific concerns raised about depressed adults being treated with antidepressants in primary care settings, the FDA chose to issue the directive for all patients as a precautionary measure.

The essence of the FDA direction is to advise patients of the possibility that thoughts about suicide may arise, particularly at the onset of treatment and with changes in treatment (dosage and/or medication changes), and to encourage patients to inform clinicians immediately if these thoughts occur. Regardless of the treatment option selected, the GDT believes that primary care patients should be screened for suicidal ideation, intent, or plan at the diagnosis of Major Depression, with each follow-up visit for depression, and with any adjustments in treatment. Consultation with mental health should occur as indicated.

7. Follow-Up For Patients In The Continuation Phase (Months Four To 12) of Treatment of MDD 7 After achieving symptom remission, the GDT recommends at least one follow-up contact* during the fifth or sixth month of treatment in patients with Major Depression. Assess for continuing symptom remission and dosage/treatment adjustment during this contact. The GDT recommends additional patient follow-up to consider either continuing treatment beyond the continuation phase, or attempting a trial of treatment discontinuation. Consensus-based

Rationale:

2008 Guideline No new evidence was found, the recommendation remains unchanged. 2006 Guideline No new evidence was found. Research on this topic does not differentiate between modalities for follow-up (in-person visits, phone calls, email messages). The GDT believes that the “active ingredient” is the follow-up per se, and not the modality of follow-up; therefore recommends that any of these types of contacts are acceptable. 2004 Guideline

Supporting Evidence for Follow-Up Frequency In The Continuation Phase Treatment of MDD Clinical Evidence(70) identified one RCT that addressed patient follow-up during the continuation phase of MDD treatment.  Three hundred eighty-six people aged 19 and older, with recurrent Major Depression or dysthymia, who had largely recovered after eight weeks of antidepressant treatment were randomized to a relapse prevention program (two primary care visits and three telephone calls) versus usual care for one year. Patients in relapse prevention had significantly improved depressive symptoms over one year (p = 0.04), but no significant difference in relapse rates (35% in both groups).  While this study supports follow-up after symptom remission, we found no studies comparing different numbers or appropriate timing of follow-up contacts for patients with MDD. Furthermore, this study also included patients with dysthymia, and did not provide separate outcome data for patients with Major Depression only.  The Depression Outcomes Report V(161) reports show that adherence with antidepressant treatment continues to decline between the third and sixth month of treatment. Premature discontinuation of antidepressants is associated with sub-optimal patient outcomes (see recommendations and rationale on length of treatment with antidepressants). Conclusion We found only one RCT, conducted in a mixed population (MDD or dysthymia), that addressed follow-up during continuation phase treatment of MDD. We found no studies addressing different numbers or timing of follow-up contacts for patients in the continuation phase of MDD. The optimal number and timing of follow-up contacts is therefore undetermined. Adopting a strategy of five follow-up contacts, as suggested by the Clinical Evidence review, would have major impact on patient convenience, patient expense, clinician time, and access to care.

Nevertheless, the Clinical Evidence study, our review of evidence on duration of treatment and our own observational evidence from the Depression Outcomes report suggest that some level of follow-up is beneficial. Due to these considerations, the GDT believes (by consensus) that a minimum of one follow-up contact in the fifth or sixth month of treatment should be made to monitor for symptom relapse, to adjust treatment, and to stress ongoing treatment adherence. This would potentially capture most of the patients who have discontinued antidepressants prematurely.

Some patients will be eligible for, or desire, discontinuation of antidepressant treatment after successful continuation phase treatment. Therefore, additional patient follow-up should occur as the decision is made to either continue treatment past the continuation phase, or attempt a trial of treatment discontinuation. There is no evidence to support this recommendation, which is based upon usual clinical care and consensus of the GDT.

8. Follow-Up For Patients In Maintenance Phase (Beyond 12 Months) of Treatment of MDD 8A For asymptomatic patients with Major Depression who are continuing on antidepressants beyond 12 months, the GDT recommends at least one annual follow-up contact to assess for continuing symptom remission, the need for ongoing treatment, and dosage/treatment adjustment. Consensus-based

8B The GDT recommends that additional follow-up for asymptomatic patients with Major Depression who are continuing on antidepressants beyond 12 months should be based on patient preference and response. Consensus-based Rationale:

2008 Guideline No new evidence was found, the recommendations remain unchanged. 2006 Guideline No new evidence was found. Research on this topic does not differentiate between modalities for follow-up (in-person visits, phone calls, email messages). The GDT believes that the “active ingredient” is the follow-up per se, and not the modality of follow-up; and therefore recommends that any of these types of contacts are acceptable. 2004 Guideline

Supporting Evidence for Follow-Up Frequency in the Maintenance Phase Treatment of MDD There is no evidence that determines optimal number or frequency of follow-up for asymptomatic patients on long-term antidepressant treatment for Major Depression. The GDT believes that a minimum of one annual follow-up contact should be made with patients on maintenance phase treatment, to assess for ongoing symptom control and potential treatment adjustment.

9. Discontinuation of Antidepressants in Patients with MDD 9A Fluoxetine may be discontinued, without tapering, with a relatively low risk of adverse effects. Evidence-based 9B The GDT recommends tapering other antidepressants (other SSRIs, TCAs, SNRIs, NRIs, and DAs) over a two to four week period. Consensus-based Rationale:

2008 Guideline No new evidence was found, the recommendations remain unchanged. 2006 Guideline Our search yielded one RCT addressing the issue of discontinuing antidepressants:  Sunder, et al. (2004)(162) designed a study to differentiate between symptoms of antidepressant discontinuation vs. depression relapse in women treated with sertraline or placebo for postpartum depression. Both sertraline and placebo were tapered over three weeks, starting at week 18. The authors found that a three week taper did not lead to emergence of symptoms typical of SSRI antidepressant withdrawal. The study was not designed to compare a three week taper with a more rapid discontinuation schedule.

We found no further studies addressing methods of discontinuing fluoxetine. Overall Conclusion Although the Sunder study is limited to postpartum women, it is consistent with earlier studies suggesting that antidepressants with short half lives (such as sertraline) should be tapered. Therefore, the previous recommendation that fluoxetine may be discontinued without tapering with a relatively low risk of adverse effects, while other antidepressants should be tapered over a two to four week period, is still valid. 2004 Guideline One new study was found since the previous revision of the Depression Guidelines that addressed this issue.  Judge(163) studied outpatients aged ≥ 18 with a diagnosis of unipolar depressive disorder successfully treated with fluoxetine or paroxetine whose Montgomery-Asberg Depression Rating Scale (MADRS) score was 12 or less (indicating symptom remission). Patients (n = 150) received a blinded drug equivalent to their current daily maintenance dose (fluoxetine 20 to 60 mg or paroxetine 20 to 50 mg) at visit one. Patients were then randomized to two different treatment groups comparing fluoxetine (n = 75) and paroxetine (n = 75) with periods of treatment interruptions lasting three to five days in each group.  Mean change following treatment interruption for Discontinuation Emergent Signs and Symptoms (DESS) was 0.2 for the fluoxetine group and 2.2 for the paroxetine group (p = 0.001 favoring fluoxetine-treated patients). Mean change in the MADRS was 0.2 for fluoxetine patients and 1.8 for paroxetine patients (p = 0.021).

 Paroxetine-treated patients also had significantly greater increases in Clinical Global Impressions–Severity (CGI-Severity scores) than did fluoxetine-treated patients following treatment interruption. The deterioration from baseline within the paroxetine treatment group was also significant for both MADRS (p = 0.010) and CGI scores (p = 0.001).  This study did not evaluate for discontinuation side effects beginning after five days of treatment interruption, when side effects might be expected to appear with a long half-life antidepressant such as fluoxetine.

Two studies were found both of which looked at the effects of discontinuing SSRIs.  Zajecka(164) compared fluoxetine (varying treatment lengths) with placebo in 395 patients (274 women, 121 men, mean age ± SD = 40 ± 10 years) who were randomly assigned to continuation treatment with fluoxetine (n = 299) or placebo (n = 96).  Subjects were men and women who initially met DSM-III-R(73) criteria for Major Depression and had a 17-item HAM-D score ≥ 16 and whose depressive symptoms significantly improved during the Acute Phase of a multicenter examination of fluoxetine in the maintenance treatment of depression. (Improvement was defined as a HAM-D 17 score ≤ 7 after 12 weeks of acute treatment with fluoxetine 20 mg daily).  Upon completion of this acute phase of treatment, subjects were assigned by random allocation to double-blind placebo (n = 96) or to one of three arms of ongoing active treatment with fluoxetine 20 mg daily (n = 299) for various periods of time. (These three arms were pooled for analysis purposes in this study.)  Fluoxetine treatment was discontinued without a tapering-off period in patients assigned to placebo.  Patients were seen at weeks one, two, four, and six after randomization. Reports of new or worsened adverse events were similar for both groups at each visit after randomization.  The authors concluded that abrupt discontinuation of fluoxetine was well-tolerated.  Rosenbaum(165) compared discontinuation syndromes in patients with a history of unipolar (Major) Depressive Disorder on sertraline, paroxetine, and fluoxetine as compared with placebo in 231 patients. Fluoxetine had the least problems when discontinued, followed by sertraline and paroxetine.

No studies were found since the previous revision of the Depression Guidelines comparing discontinuation of higher doses of fluoxetine (40 to 60 mg/day) with lower doses (10 to 20 mg/day). All studies found included lower and higher dose fluoxetine patients in the same treatment group.

It takes approximately 5.5 half lives for medications to be “cleared” from the bloodstream. Medications which short half lives (and thus more rapid clearance) are more prone to produce symptoms upon discontinuation than medications with longer half-lives. The half-life of fluoxetine is 96 hours, sertraline is 24 hours, and paroxetine is 17 to 22 hours.

No evidence was found for tapering TCAs. The two to four week time period recommended by the GDT is consistent with clearance of these agents, based on their half-lives. Conclusion There is some evidence that fluoxetine can be discontinued without a high risk of many adverse effects. This is consistent with its known long half-life. Extrapolating from the Rosenberg study and principals of pharmacology, SSRIs with shorter half-lives should be tapered, rather than discontinued. There is no evidence that determines the optimal tapering regimen. The two to four week time period recommended by the GDT is consistent with clearance of these agents, based on their half-lives. Pharmacotherapy of Antidepressant Medications: Half-life (Active Metabolite)(166) Half-Life in Hours Medication (Active Metabolite) SSRI Fluoxetine (Prozac) 24 - 72 (146) Sertraline (Zoloft) 26 (66) Paroxetine (Paxil) 24 Citalopram (Celexa) 33 TCAs Desipramine (Norpramin) 12 to 28 Nortriptyline (Pamelor) 18 to 56 Amitriptyline (Elavil) 9 - 46 (18 - 56) Imipramine (Toframil) 6 - 28 (12 - 28) Doxepin (Sinequan) 11 to 23 Others Bupropion (Wellbutrin) 10 to 21 Venlafaxine (Effexor) 4 (10) Nefazodone (Serzone) 4 - 5 (4 - 18) Mirtazapine (Remeron) 20 to 40

10. Treatment Preferences For MDD In Different Ethnic Groups 10 Because patient preferences for treatment may vary based on their ethnicity and culture, the GDT recommends asking patients from different ethnic groups about treatment preference, when discussing treatment options for MDD. Evidence-based Rationale:

2008 Guideline No new evidence was found, the recommendation remains unchanged.

2006 Guideline We found one study that addressed the preferences of one particular ethnic group.  Dwight-Johnson, et al. (2004)(167) used conjoint analyses to assess the preferences of low income Latinos. They found that this population preferred individual over group treatment, combination therapy over counseling or medication alone, and all treatment settings equally. Overall Conclusion The GDT believes that the Dwight-Johnson study is consistent with our previous analysis and recommendation, which remains that patients from different ethnic groups should be asked about their treatment preferences for MDD. 2004 Guideline

Supporting Evidence for Treatment Preferences for MDD in Different Ethnic Groups PubMed (1/1/2001 through 4/1/2003) and PsychInfo (1985 through 4/1/2003) databases were searched and no new evidence on this topic was found since the previous revision of the Depression Guidelines.

One article was found from another search that did not show up in the above search due to indexing issues in Pub-Med.  Cooper, et al.(168) conducted a telephone survey of 829 adult patients (659 non-Hispanic whites, 97 African Americans, 73 Hispanics) recruited from primary care offices across the United States who reported one week or more of depressed mood or loss of interest within the past month and who met criteria for major depressive episode in the past year.  Within this cohort, they examined differences among African Americans, Hispanics, and non-Hispanic whites in acceptability of antidepressant medication and acceptability of individual counseling.  African Americans (adjusted OR = 0.30; 95% CI: 0.19 to 0.48) and Hispanics (adjusted OR = 0.44; 95% CI: 0.26 to 0.76) had lower acceptance of antidepressant medications compared with Whites.  African Americans had somewhat lower odds (adjusted OR = 0.63; 95% CI: 0.35 to 1.12), and Hispanics had higher odds (adjusted OR = 3.26; 95% CI: 1.08 to 9.89) of finding counseling acceptable than non-Hispanic whites.  Racial and ethnic differences on preferences for treatment modalities were found. Clinicians should consider patients' cultural and social context when negotiating treatment decisions for depression.

The AHRQ(169) report did not find any data on patient preference and ethnic background.

Two studies were found previously on this topic.  Dwight-Johnson's(167) longitudinal study surveyed 1,187 English and Spanish speaking patients regarding their treatment preferences for depression. Nearly all had MDD. Patients were given five treatment options to choose from; including free medication for six months; individual or group counseling; and watchful waiting. Eighty-three percent of the total sample reported wanting active treatment for depression; of these, 27% preferred antidepressant medication, 29% individual counseling, and 26% group counseling. Patient characteristics of those who chose counseling included being African American and having a greater knowledge of counseling. It is important to note that treatment preference may have been influenced by cost (total cost for medication was $480, individual counseling $300, and group counseling $75). Patients were not necessarily actively diagnosed with depression at the time of the survey but had to have experienced a two-week period of depression over the prior two-year period.  Chilvers(170) examined treatment preference in 323 general practice MDD patients, patients could either choose counseling or medication, or agree to be randomized into either treatment arm. The study did not analyze results by ethnic group. The study concluded that patients who chose their care did better than those who were randomized into treatment. Also, patients taking antidepressant medication got better faster than patients receiving counseling.

Consult the National Diversity Handbooks on culturally competent care approaches in Latinos; Asian/Pacific Islanders; African American; and Lesbian, Bisexual, Gay, and Transgender groups. To order, please contact Kaiser Permanente’s National Diversity Institute for Culturally Competent Care. All orders for the products must be submitted in writing. Download the order form at this website: http://diversity.kp.org/2main-library/online-resources.html and fax to (510) 271-5757. Overall Conclusion Patients from different cultural/ethnic backgrounds may have different understandings of and frames of reference on depression. Therefore, they may express different treatment preferences for Major Depression. Many primary care clinicians are not aware of these cultural considerations. Since patient outcomes or satisfaction may be related to choice of treatment, the GDT recommends approaching the treatment of Major Depression in adult patients from different cultural and ethnic backgrounds in the context of the patient’s cultural beliefs.

11. Patient Self-Management Strategies for Improving Symptoms of MDD

Internet Resources 11A The GDT recommends scientifically validated internet-based patient self-help materials as an optional adjunct strategy (in addition to antidepressants or psychotherapy) for treating symptoms of MDD. Evidence-based: B Exercise 11B The GDT recommends exercise as an adjunctive strategy (in addition to antidepressants or psychotherapy) for treating the symptoms of MDD. Evidence-based :B Bibliotherapy 11C The GDT recommends scientifically validated bibliotherapy as an optional adjunct strategy (in addition to antidepressants or psychotherapy) for treating the symptoms of MDD.* Consensus-based Befriending 11D The GDT recommends befriending as an optional adjunct to antidepressants or psychotherapy for treating the symptoms of MDD.† Consensus-based Patient-Initiated Combined Phone/Computer Programs 11.E. There is insufficient evidence for or against using patient-initiated combined phone/computer programs in the treatment of MDD. Evidence-based: I Light Therapy 11F The GDT makes no recommendation for or against light therapy as a primary or adjunctive treatment for nonseasonal forms of MDD. Evidence-based: I Music Therapy 11G The GDT makes no recommendation for or against music therapy as an adjunct to antidepressants or psychotherapy for treating the symptoms of MDD. Evidence-based: I Life Review Therapy 11H The GDT makes no recommendation for or against life review therapy as an optional adjunctive depression management strategy for depressed older adult patients who are concurrently receiving regular social services care. Evidence-based: I

* Bibliotherapy: Advising people to read specific written material based on cognitive-behavioral approaches to depression treatment.

† Befriending: Consists of a designated befriender who meets the depressed person to talk and socialize with for at least one hour per week. © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 80 National Adult Depression Clincial Practice Guideline

Evidence Grade Evidence for Recommendations 11A: Fair; F, G, and H: Insufficient. Search Strategy Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. The Clarke (2005)(171) study was not identified by the search due to PubMed Indexing, but was identified by a GDT member and reviewed due to relevance. Systematic reviews and meta-analyses with search dates outside the range of current searches were excluded.See Appendix B for more information on the search strategy. 2010 Update New evidence was found, recommendations have been changed based on expert/consensus opinion.

Our recent search yielded two relevant RCTs (Craft, 2007(172); Meyer, 2009(173)) that address the different categories of self-management strategies. The studies included patients with symptoms of depression, which consisted of participants with minor depression and dysthymia as well. Studies provided little detailed information about concurrent use of antidepressants or psychotherapy in the intervention groups. One RCTs (Meyer, 2009(173)) evaluated the effectiveness of an internet-based therapy and one RCT (Craft, 2007(172)) assessed an exercise intervention. Please refer to Evidence Tables 11.1 and 11.2 for study details. Exercise  Craft et al. (2007)(172) conducted a randomized pilot study to compare the effectiveness between a home-based versus a clinic-based exercise intervention for depressive symptoms in low-income, minority women. A total of 32 women were assigned to home-based (N = 16) or clinic-based (n = 16) exercise program for 3 months. Overall, both interventions were associated with improvements in depressive symptoms (effect size: -0.97 and -1.3 for home and clinic based, respectively) and time spent in physical activity. However, at 3-month follow-up, there were no significant between-group effects for depressive symptoms, self- reported physical activity, body composition, or cardiovascular fitness. It is important to note that the study is limited by lack of control group, (it is essentially a pre-post study with post comparisons of the two groups) small sample size, lack of power, short duration, and low generalizability. Therefore, interpretation of results should be done with caution. Please refer to Evidence Table 11.1 for study details. Overall Conclusion Results from one low-quality study identified does not warrant changes to the 2008 recommendation. Although the study found modest short-term improvement in depressive symptoms with exercise, no long-term effect was observed and it was not designed to substitute exercise for antidepressant or psychotherapy treatments; thus, it can not be definitively concluded that exercise may be used effectively instead of antidepressant medication or structured psychotherapy.

Internet/Computer  Meyer et al. (2009)(173) randomized 396 participants from an internet depression forum in Germany to internet-based psychotherapy intervention plus treatment-as-usual (n = 320) or to wait-list control plus treatment-as-usual (n = 76) for nine weeks and followed-up at 18 weeks and six months. Continuation rates were reported at 54.5% at nine weeks, 36.9% at 18 weeks, and 25% at six months. About three quarter of the sample were women, many were unemployed, and 58% currently received treatment for depression. At nine weeks, intent-to-treat (ITT) analysis found significant reduction in depression symptoms and social functioning in the internet group compared to no change in wait-list controls (effect size for depression symptoms: d = 0.3; effect size for social functioning: d = 0.36). Changes were also maintained at six-months follow-up among completers (d = 0.74). In addition, 25.4% of those in the internet group vs. 1.9% of the wait-list control reached the criteria of clinical significant improvement/ recovered (change of at least 8.46 points on BDI, with post test score of < 14.29, p < 0.001). Based on findings, authors suggested that “the program could serve as an adjunctive or stand-alone treatment tool for patients suffering from symptoms of depression.” However, limitations such as no placebo-controlled group, participants not clinically diagnosed with MDD, high attrition rate, selection bias, and low generalizability warrant cautious interpretation of results. Please refer to Table 11.1 for study details. Overall Conclusion Only one trial on internet-based self-study intervention was identified and outcomes from the trial did not warrant changes to the 2008 recommendation. The trial found positive results among participants assigned to the internet intervention in terms of social functioning and reduction in depressive symptoms compared to wait-listed control. Authors stated some participants were concurrently under other treatments for depression; however, it was unclear whether all participants were clinically diagnosed with MDD, which makes it difficult to draw a definitive conclusion on the effectiveness of the internet program exclusively.

Editorial note: no new evidence was found on bibliotherapy. The wording of the recommendation was modified by consensus approval of the GDT to be consistent with the wording of the internet-resources recommendation. In addition, no new evidence was found for combined phone/computer programs; however, the language for this recommendation was also modified by consensus approval to reflect the insufficient evidence based on only one previously identified study. 2008 Guideline New evidence was found, the recommendation remains unchanged.

One relevant RCT(174) was identified that studied the effect of providing patients with personalized workbooks that addressed various aspects of depression in addition to providing them with usual care. No differences in Beck Depression Inventory scores were seen between groups, although the patients in the group given workbooks were more likely to report that they felt well educated about depression. Please refer to Table 11.1 for study details.

Overall Conclusion We found only one trial on the above list of patient self-management strategies in our 2008 update. This negative trial on adjunct bibliotherapy is the first trial identified since the original guideline recommendations. The overall evidence is mixed. However, even in this new trial, patients gained some benefit from understanding their condition. Since there is little apparent harm in providing patient education materials as an adjunct to other clinician-directed therapy, the GDT retained its belief in the use of bibliotherapy as an optional adjunct strategy.

Bibliotherapy was the only health intervention for which new evidence was found. A change in symptoms as a result of bibliotherapy is the only health outcome addressed in this new evidence. The overall evidence on bibliotherapy remains mixed, so our recommendation remains unchanged. 2006 Guideline Our recent search yielded a number of studies that address the different categories of self- management strategies. Most studies were designed to compare these self-management strategies with treatment or with different intensities or types of the same general self- management intervention. Many studies included patients with symptoms of depression, but were not designed to specifically study (nor did they specify the number of patients with) MDD. Few compared self-management strategies with “traditional” first-line treatment approaches; most studies provided little if any detailed information about concurrent use of antidepressants or psychotherapy in the intervention groups. Please refer to Table 11.1 for study details.

In reviewing the evidence as noted below, the GDT concluded that due to limitations in the current body of evidence, there is insufficient evidence to recommend for or against these self- management strategies as first-line “monotherapy” for patients with MDD. However, when appropriate (as discussed below), pending appropriately designed studies, the GDT extrapolated the findings to make consensus recommendations for considering selected self-management strategies as an adjunct to other evidence-based treatment for MDD. Exercise Dunn (2004)(175) found that mild to moderately depressed subjects partaking in a public health dose of exercise (17 kcal/kg/week) for at least three days a week had a significantly greater reduction in depression symptoms when compared with those partaking in a low dose (7 kcal/kg/week) or no exercise. None of the subjects were involved in another treatment for depression.

Clinical Evidence (Issue 14, January 2006) found one systematic review examining the effectiveness of exercise as a treatment option for depression.  The review found limited evidence that exercise may improve symptoms compared with no treatment [standardized mean difference in effect size -1.1, 95% CI: -1.5 to -0.6; weighted mean difference in Beck depression inventory -7.3, 95% CI: -10.0 to -4.6, and that exercise may be as effective as cognitive therapy (standardized mean difference -0.3, (95% CI: -0.7 to 0.1)]. However, according to the authors, the following methodological problems rendered the results inconclusive: randomization was adequately concealed in only three RCTs, intention to treat analysis was undertaken in only two, and assessment of outcome was blinded in only one RCT.(176) © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 83 National Adult Depression Clincial Practice Guideline

 One RCT involving older adults and included in the systematic review above found no significant difference among groups (aerobic exercise, sertraline, and combination treatment) in the proportion of people who recovered (60% with exercise, 69% with sertraline, and 66% with combination treatment). A ten month follow-up of this RCT found significantly lower relapse rates with exercise than with antidepressant drugs (30% with exercise, 52% with sertraline, and 55% with combination treatment; p = 0.28 for exercise vs. either treatment). However, about half of the people in the medication group engaged in exercise during follow-up, making it difficult to draw firm conclusions. The authors conclude that “the clinical importance of the observed difference at ten months remains unclear.”(177) Overall Conclusion The evidence comparing exercise with antidepressants or psychotherapy as first-line strategy for treatment of adults with Major Depression is relatively sparse. The study populations, inclusion criteria, and outcome measures are heterogeneous. The GDT does not believe that there is sufficient evidence at this time to recommend for or against exercise as a sole treatment option for MDD. However, exercise is often recommended for other health reasons, and is (in appropriately selected patients) a low risk self-management strategy. Extrapolating from the available evidence, the GDT believes that exercise is an adjunctive strategy (in addition to antidepressants or psychotherapy) for treating the symptoms of MDD. Bibliotherapy No new evidence was found. Overall Conclusion Many of the limitations noted with studies of exercise above also apply to studies of bibliotherapy found in earlier iterations of this guideline. In light of these past findings, the GDT believes that the previous recommendation should stand: Bibliotherapy is an optional adjunct strategy (in addition to antidepressants or psychotherapy) for treating the symptoms of MDD. Computer/Internet  Christensen, Griffiths, & Jorm (2004)(178) placed subjects with depression (and not being treated by a psychologist or psychiatrist) into one of three groups: 1) “Blue Pages,” – and internet program to improve depression literacy, 2) “MoodGYM” – an internet-based cognitive behavioral therapy, or 3) attention control. The researchers found that both Blue Pages and MoodGYM were significantly more effective than control in reducing symptoms of depression; neither internet intervention was more effective than the other. There was no information on how many patients in each study arm were being treated with antidepressants.

 Clarke, et al. (2005)(171) conducted a follow-up to their 2002 study examining the effectiveness of the internet-based intervention “Overcoming Depression in the InterNet (ODIN),” available at www.believebetter.org. The authors concluded that the 2002 trial found no significant differences between the internet and control interventions because participant usage of the internet site was low. In the 2005 update they attempted to increase participant adherence by using postcard and telephone reminders. The authors did in fact find that the addition of the reminders yielded significant results: those in the either intervention group (postcard or telephone reminders) showed greater decreases in CES-D depression scores than those in the treatment-as-usual control group who did not have access to the site at all. This difference was even greater in those who had more severe depression at baseline. However, enrollment rates in the study were very low, and more patients dropped out of the treatment groups than the control group. Overall Conclusion The specific web-based interventions studied by Christensen, Griffiths, and Jorm, and the 2005 Clarke intervention were found to be effective for reducing symptoms of depression, although the data do not suggest that these sites can be used in lieu of antidepressants or psychotherapy. It should also be noted that the interventions examined in the previously reviewed studies by Clarke(179) and Patten(180) in the 2004 update were ineffective. The effectiveness of web-based interventions may depend on a number of factors, potentially including patient motivation to utilize the resources, the specific content utilized and the usability of the website. The GDT believes that some internet-based interventions may be beneficial adjuncts in reducing symptoms of depression, but based on the currently available (heterogeneous) evidence, the recommendation should be limited to specific interventions (Blue Pages, Mood GYM, and ODIN).

Note: The GDT acknowledges that internet sites are dynamic and continually evolving. Prior to referral to the aforementioned sites, care should be taken to ensure the information provided is still accurate and up-to-date. Befriending  Clinical Evidence Volume 14 found one small RCT that provided insufficient evidence to assess befriending in people with mild to moderate depression. It found that befriending significantly increased the proportion of women with remission of mild depression symptoms at 13 months compared with waiting list control (86 women with chronic depression, aged 18 years and older, primarily aged 25 to 40 years; 65% with befriending vs. 39% with control; p < 0.05; NNT = 4, 95% CI: 2 to 18).(181) Overall Conclusion The Clinical Evidence update above is consistent with previously reviewed evidence suggesting some benefit of befriending in patients with depression. None of the studies specified how many patients were receiving other forms of depression treatment, nor did they differentiate between patients with Major and Minor Depression (the latter often resolves spontaneously). However, given the potential for some effect, and the low risk of befriending as a strategy, the GDT makes a consensus extrapolation from the available evidence to consider befriending as an option for patients as an adjunct to (but not a substitute for) treatment of Major Depression.

Automated Telephone Programs We found no new evidence to support for or against the use of automated telephone programs. Overall Conclusion The GDT previous recommendation stands; use of automated telephone programs is not currently recommended as adjunctive therapy for MDD. Light Therapy Note: These analyses address the use of light therapy for nonseasonal forms of MDD. The use of light therapy for Seasonal Affective Disorder (SAD) is currently being systematically reviewed by the Cochrane Collaborative. Seasonal Affective Disorder is beyond the scope of these current recommendations. Therefore, conclusions are limited to nonseasonal Major Depression.  Leppamaki, et al. (2004)(182) examined the effect of three interventions on mood improvement: 1) aerobics in bright light, 2) aerobics in normal light, and 3) relaxation and stretching in bright light. They found that a significant number of subjects who responded to one of these treatments were given light therapy. This study should be interpreted with caution, however, since it is unclear how many participants had Major Depression or Seasonal Affective Disorder (SAD - a subtype of Major Depression where light therapy is considered to be effective); nor did the authors provide information on the concurrent use of other treatments.  In a study examining the effectiveness of adjunctive bright light for nonseasonal Major Depression, Martiny, et al. (2005)(183) treated all subjects with sertraline and concomitantly had them exposed to either dim light or bright light. At the end of the five week study period, the authors found a significant reduction in HAMD scores in the bright light group (p < 0.01). This group also had significantly higher response (p = 0.006) and remission (p = 0.015) rates when compared with the dim light group. While these results are promising, it should be noted that the two groups had unequal durations of treatment (30 minutes for dim light vs. 60 minutes for bright light), and it is unclear how this factor might have affected the overall results.

The Cochrane Collaboration has reviewed the evidence on light therapy for treatment of nonseasonal depression.(184)  Twenty studies were included in the review. Seventeen studies reported on participants mostly suffering from MDD. Ten studies had both unipolar and bipolar patients in their sample. Inclusion and exclusion criteria varied among studies. Almost all studies took place in the hospital or long-term care facility. Only two studies assessed outpatients. None of the studies were multicenter. Only five studies reported on the time of the year when the study was performed.

 Bright light therapy was administered in a wide range of intensities. The duration of active treatment varied between 30 minutes and nine hours. Eleven studies administered bright light in the morning. Most of the studies applied bright light as adjunctive treatment to drug therapy, sleep deprivation, or both. Light was administered adjunctive to sleep deprivation in nine studies, and in two additional studies the participants were awakened before their usual wake up time for light treatment. Standardized adjunctive pharmacotherapy was applied in seven studies, and in ten studies, concomitant drug treatment of the participants was kept unchanged.  All included studies described themselves as randomized, but presented little methodological detail to elaborate on the truly random nature of allocation. Blinding of assessment in administration of light therapy is more difficult than in studies with drug intervention, since the active treatment due to its brightness looks dissimilar to the control treatment. Subjects cannot fail to perceive the treatment and cannot be literally blind to treatment, though they may not know which is intended as the active treatment.  In general, the quality of reporting was poor. All but two trials reported the randomization procedure without adequate information on allocation concealment. Blinding procedures were also generally inadequately described. Many studies did not report the number of dropouts and did not specify reasons for drop-out. The trials did not report if intention-to-treat analysis was performed.  According to the criterion of 50% decrease in the HDRS score, there was no difference between groups: 20 out of 39 patients (51%) in the bright light group and 17 out of 32 patients (53%) in the control treatment group were not improved (three studies, 71 patients, relative risk (RR) 0.94, CI: 0.61 to 1.46). The treatment response in the bright light group was better than in the control treatment group, but did not reach statistical significance in random effects models. The result was mainly based on studies of less than eight days of treatment.  In studies using a light box, a fixed effect model approach showed that bright light was more effective than the control treatment (12 studies, 275 patients, standardized mean difference (SMD) = -0.50, CI: -0.75 to -0.25), and the statistical significance remained even when a random effects model was applied (SMD = -0.47, CI: -0.86 to -0.08). The response to bright light was significantly better than to control treatment in high-quality studies (SMD = -0.90, 95% CI: -1.50 to -0.31), in studies applying morning light treatment (SMD = -0.38, CI: -0.62 to -0.14), and in sleep deprivation responders (SMD = -1.02, CI -1.60 to -0.45).  Evaluation of the effect of combination of concomitant drug and morning bright light showed that there was no difference between the two morning light conditions with or without pharmacotherapy. With a fixed effect model approach, both conditions were statistically significantly in favor of bright light over control treatment (combination treatment: nine studies, 243 patients, SMD = -0.32, CI: -0.60 to -0.08; light only: two studies, 54 patients, SMD = -0.57, CI: -1.14 to -0.01), but with a more conservative random effects model the statistical significance was lost (combination treatment: SMD = -0.36, CI: -0.79 to 0.07; light only: SMD = -1.03, CI: -2.63 to 0.58).

 Many reviews did not report adverse effects systematically. Hypomania was more common in the bright light group compared with the control treatment group (RR = 4.91, CI: 1.66 to 14.46; NNH = 8, CI: 5 to 20). The reviewers noted that categorizing the drop-out subjects as "failures" might overestimate the number of subjects with this adverse effect as well as with other poor outcomes.  The reviewers conclude that in patients suffering from nonseasonal depression, light therapy may offer modest antidepressive efficacy when administered in the morning, during the first week of treatment and as an adjunctive treatment to sleep deprivation responders. These benefits need to be balanced against the potential for hypomania. Finally, the reviewers note that “due to limited data and heterogeneity of studies these results need to be interpreted with caution.” Overall Conclusion In discussing the results of the above studies and in particular, the details of the Cochrane review, the GDT believes that, based on the information available, it would be difficult to formulate specific recommendations for patients with nonseasonal MDD on how to specifically utilize light therapy as a self-help strategy. Due to the heterogeneity of the studies, and pending further clarification, the GDT concluded that there is insufficient evidence at the current time to recommend for or against the use of light therapy as a self-help strategy for patients with nonseasonal forms of MDD. Music We found no new evidence to support for or against the use of music therapy. Overall Conclusion The GDT’s previous recommendation stands: There is currently insufficient evidence to recommend for or against music therapy as an adjunct to antidepressants or psychotherapy for treating the symptoms of MDD. Life Review  Serrano & Latore (2004)(185) tested life review therapy on a population of older adults (65 to 93) with clinically significant symptoms of depression and receiving social services regularly. The life review consisted of “autobiographical retrieval practice that entailed focusing on a particular life period each week – childhood, adolescence, adulthood, and summary.” When compared with controls, the life review therapy group had significantly greater improvements in depressive symptoms. This study was conducted in Spain; it is unclear if it is generalizable to populations in other countries. Overall Conclusion As with other self-management strategies, this study was not designed to test the relative efficacy of this strategy vs. “standard” (psychotherapy or antidepressant) treatment for MDD. Due to the limited population studied (and the unknown generalizability), the GDT believes that currently there is insufficient evidence to recommend for or against life review therapy an optional adjunctive depression management strategy.

2004 Guideline Supporting Evidence for Self-Management Strategies for Improving Depressive Symptoms in Patients with MDD Effect of Exercise Three RCTs and one systematic review were found that addressed this issue.  Singh(186) studied patients age 60 and older with Beck Depression Inventory (BDI) score of greater than 12 and a diagnosis of either unipolar major or minor depression or dysthymia according to DSM-IV diagnostic criteria. The patient population was 37% male and 63% female.  In phase one, patients (n = 32) were randomized to two treatment groups comparing ten weeks of supervised exercise in a laboratory setting (intervention group), with health education lectures (control group).  In phase two (weeks 11 to 20), (n = 15) intervention patients received unsupervised exercise at home, laboratory or health club setting (n = 15, 18 ±2 weight lifting exercise sessions), while control patients (n = 14) received no further intervention. The BDI score at 20 weeks decreased significantly from 21 ±2.0 to 9.2 ±2.8 for the exercise group (p = 0.036), while the score for the control group decreased from 18.4 ±1.7 to only 14.4 ±2.2.  At the 26 month follow-up, the BDI score for the exercise group decreased from 21 ±2.0 to 13 ±2.2, and the score for the control group decreased from 18.4 ±1.7 to 14.4 ±2.2, p = 0.036 (favoring exercise group). The exercise group showed a statistically significantly reduced depression severity compared with control group at both 20 weeks and 26-month follow-up. The difference between BDI scores between groups may not be clinically significant. The effect may not be evident if exercise is not continued. Over time, the severity of depression also improved in the control group.  McNeil(187) studied older adult outpatients with a mean age of 72.5 years and a BDI score of 12 to 24. Patients (n = 30) were randomized to three treatment groups comparing exercise (walking between 20 to 40 minutes, three times a week) with social contact (two home visits (20 to 40 minutes each week by an undergraduate psychology student) and a wait-list (control group) for a period of six weeks. The total BDI score decreased from 16.6 to 11.1 for the exercise group, 16.0 to 11.8 for the social contact group, and 15.2 to 14.7 for the control group (p < 0.05, favoring exercise or social contact). Exercise and social contact both resulted in significant reductions in both total and the psycho-social subscale of the Beck Depression Inventory. The exercise condition, however, resulted in decreased somatic symptoms of the BDI (p < 0.05).  Mather(188) studied outpatients 53 years and older with a diagnosis of depression and a score of at least ten on the Geriatric Depression Scale (GDS). The patient population was 16% male and 84% female. Patients (n = 86) were randomized to two treatment groups comparing exercise (n = 43, 45 minutes of predominantly weight-bearing exercise; two sessions per week) with a nonexercise social control group (health education talks, n = 43) for ten weeks.

 Change in 17-item Hamilton Rating Scale for Depression (HRSD) from baseline at ten weeks for the exercise group was 55% and for the control group was 33% (p = 0.05, favoring exercise group). Response was defined as a ≥ 30% reduction in HRSD score from baseline, a threshold that is lower than the usual 50% decrease in symptoms used in most other studies (thus “setting the bar lower” for a positive effect). The study found that ten weeks of twice-weekly exercise was associated with a modest reduction in depression symptoms in a group of older people with depression. There was preponderance of women in the exercise group.  North(189) systematically reviewed 80 studies on the effect of exercise on depression. Patients ranged from 11 to 55 years with a mean age of 31.8 ±12.4 years. Twenty studies included males only and 16 studies included all females. Studies included looked at the effect of different variables on depression (sixty three studies looked at age effect on depression and thirty six studies were included for the effect of gender.) Studies varied from four weeks to 24 weeks with the majority of studies being between five to 12 weeks. The studies compared exercise (aerobic endurance and/or muscular strength, varying in number of sessions) with comparison groups (no intervention control, leisure activity, or psychotherapy).  The overall Effect Size (ES) of the studies included, was -0.53 ±0.85, indicating that patients in exercise groups decreased their scores an average of 0.53 standard deviations more than subjects in the comparison groups (p < 0.001). A significant, negative co- relational relationship was found between mean age and ES (p < 0.05), suggesting that the older the subjects, the greater the decrease in depression with exercise. The ES for males and females were not significantly different (p > 0.05) suggesting equal benefit of exercise on depression in both genders.  The overall results indicate that exercise has a beneficial effect on improving symptoms of depression. There are multiple differences in the designs of the studies included in this meta-analysis, including mode of exercise, length of the exercise programs and types of control groups. This meta-analysis also excluded people older than 55. No heterogeneity data was reported. Results should be interpreted with caution due to internal validity issues.

Our search and Clinical Evidence(70) identified one systematic review (search date 1999, 14 RCTs, 851 people).  This review found limited evidence that exercise versus no treatment may improve depressive symptoms, and that exercise may be as effective as cognitive therapy. However, it suggested that these results were inconclusive because of methodological problems in all of the RCTs; randomization was adequately concealed in only three of the RCTs, intention-to- treat-analysis was undertaken in only two, and assessment of outcome was blinded in only one of the RCTs.

Older Adults  The systematic review identified one RCT (156 people with Major Depression, mean age 57 years) comparing aerobic exercise, sertraline hydrochloride (a selective serotonin reuptake inhibitor), and combined treatment for 16 weeks. It found that the proportion of people who recovered (those no longer meeting criteria for depression or with a Hamilton Depression Rating Scale score < 8) was not significantly different across the treatment groups (60% with exercise vs. 69% with sertraline vs. 66% with combined treatments). A ten-month follow-up of this RCT found lower rates of relapse with exercise versus medication (30% with exercise vs. 52% with sertraline vs. 55% with combined treatment). However, about half of the people in the medication group engaged in exercise during follow-up, making it difficult to draw firm conclusions about effects of exercise. The clinical importance of the observed difference at ten months remains unclear. (Note that this RCT did not include a control group.) Conclusion There is evidence that exercise, at least in the short term, may be helpful in reducing symptoms of depression. Most studies were not designed to substitute exercise for antidepressant or psychotherapy treatments, so we can not conclude that exercise may be used effectively instead of antidepressant medication or structured psychotherapy. Most of these studies do not describe how many patients in the exercise group were receiving other forms of depression treatment, and many did not differentiate between patients with Major Depression and other forms of depression. Given the beneficial effect of exercise in general and on many often comorbid medical conditions, the GDT believes that exercise can be recommended as an adjunctive strategy for patients with MDD. The type of exercise will depend in part on the presence or absence of other medical conditions. Effect of Bibliotherapy (Patient Handouts and Other Reading Material) Two RCTs that addressed this issue were found.  Jamison(190) studied patients with mean age of 40 years and a score of ten or greater on the Hamilton Rating Scale for Depression 21-item version (HRSD) and score of ten or greater on the 21-item Beck Depression Inventory (BDI). All patients met the DSM-III-R criteria for mild to moderate Major Depression. Patients (n = 80) were randomized to two treatment groups comparing cognitive bibliotherapy (n = 33) with control group (wait list, n = 39) at four weeks (treatment phase) and three months (follow-up phase).  In treatment phase, the HRSD score decreased from 20.2 to 9.9 for the bibliotherapy group and decreased from 19.6 to 19.0 for the control group (p < 0.05, favoring bibliotherapy). BDI scores showed comparable results with p < 0.05 (favoring bibliotherapy).  In the follow-up phase, HRSD score further decreased, from 10.0 to 9.2 for the treatment group and decreased from 18.7 to 10.0 (p < 0.05, favoring treatment when starting from baseline). (Note that the control group experienced a large decrease in depression scores in the follow-up phase, to within a point of the intervention group). BDI score again showed similar outcomes (p < 0.05, favoring treatment when starting from baseline).

 This study suggests that cognitive bibliotherapy for depression is an effective treatment for depression, with participants experiencing more rapid symptom improvement compared with nonparticipants. Treatment gains in the intervention group were maintained over a three-year follow-up (Smith(191)) period, as participants (n = 50) were less depressed than when they began the program.  There was a significant decrease in HRSD and BDI scores from pretreatment to follow-up (p < 0.05 each), with no changes from post treatment to follow-up (p > 0.05 each). This study suggests that there maybe long-range benefits to participants in structured, minimal- contact bibliotherapy programs for depression.  There was no control group in the three-year follow-up period. Sensitivity analysis was not included to account for patients who completed the initial study but did not participate in the follow-up (some of whom may have relapsed).  Scogin(192) studied 57 female and ten male patients 60 years and older with score of ten or higher on the Hamilton Rating Scale for Depression (HRSD) and score of eight or higher on the Mental Status Questionnaire. Patients (n = 67) were randomized to three treatment groups comparing behavioral bibliotherapy (n = 23, reading a copy of Control Your Depression (Lewinsohn(193)), cognitive bibliotherapy (n = 22, reading a copy of Feeling Good (Burns, 1980(194))) and delayed treatment (control group) (n = 22), for an initial study period of four weeks and a six month follow-up.  The two treatment groups were assessed before treatment (first time), immediately following treatment (second time) and six months later (third time). The control group participants were assessed at the first time and at one month following the second time, at which point their own treatment began, and a third time immediately following treatment. HRSD Score (first time, second time and third time) for the behavioral bibliotherapy group were 17.8 to 9.7 to 9.1, and were 16.3 to 7.5 to 8.9 for the cognitive bibliotherapy group. Control group scores were 16.4 to 15.9 to 7.2.  There were statistically significant differences between cognitive bibliotherapy and control group (p < 0.05, favoring cognitive bibliotherapy), and between behavioral bibliotherapy and control group (p < 0.05, favoring behavioral bibliotherapy).  There were no significant differences between the two bibliotherapy groups. This study supports the efficacy of self-paced bibliotherapy for mild to moderate depression in older adults. Bibliotherapy’s effect for mild to moderate depression in older adults was maintained after two years.(195) HRSD scores post-treatment and at a two-year follow-up for the treatment groups (behavioral and cognitive bibliotherapy, n = 22) decreased from 8.1 to 7.4, p < 1.00, indicating no significant effect for time.  There were no male participants and no control group in the two-year follow-up study.  Sensitivity analysis not included to account for patients who completed the initial study but did not participate in the follow-up (some of whom may have relapsed).

Our search and Clinical Evidence(70) identified two systematic reviews (search date not stated and search date 1999).  The first review identified six small, short-term RCTs of bibliotherapy versus waiting list control in 273 people (described as adults in four RCTs and older adults in two RCTs; no age range provided) recruited by advertisement through the media and probably with only mild depression. The mean effect size of bibliotherapy was 0.82 (95% CI: 0.50 to 1.15). Seventy nine percent of the people in the waiting list control group had a worse outcome than the average person in the bibliotherapy group.  The second systematic review identified eight randomized and nonrandomized trials in younger and older people, but only one of them included people with depression. It found that, in people with combined anxiety and depression, anxiety, or chronic fatigue, bibliotherapy may improve symptoms over two to six months compared with standard care. The RCT identified by the second review that included people with depression found that bibliotherapy versus standard care significantly improved symptoms of anxiety over four weeks as assessed using the Hamilton Depression Rating Scale, but found no significant difference in symptoms of depression at four or 12 weeks.  Clinical Evidence found no systematic review or RCTs specifically in older adults. Conclusion There is evidence, albeit not unanimous (or as strong as the evidence for exercise), that bibliotherapy may be helpful in reducing symptoms of depression. Most of these studies do not describe how many patients were receiving other forms of depression treatment, and many did not differentiate between patients with Major Depression and other forms of depression. But the majority of studies support the use of bibliotherapy and the GDT believes that bibliotherapy is an optional adjunctive strategy for patients with MDD. Effect of Befriending The McNeil study(187) discussed earlier noted a statistically significant improvement in depressive symptoms in patients randomized to the social contact group.

Our search and Clinical Evidence identified one small additional RCT of befriending versus waiting list control.  This trial had 86 women with chronic depression, aged > 18 years, primarily aged 25 to 40 years, based in London, UK. Initial identification was by postal screening of women registered with, but not attending, primary care. It found that befriending versus waiting list control significantly increased the proportion of women with remission of symptoms at 13 months (65% with befriending vs. 39% with control; p < 0.05; NNT 4, 95% CI: 2 to 18).

Older Adults We found no systematic review or RCTs specifically in older adults. Conclusion These two small studies provide some evidence suggesting that befriending may be helpful in reducing symptoms of depression. The studies did not describe how many patients were receiving other forms of depression treatment, and it did not differentiate between patients with Major and Minor Depression (the latter often resolves spontaneously). Due to the available evidence the GDT believes that befriending is an option for patients as an adjunct to (but not a substitute for) treatment of Major Depression. Effect of Music Therapy We found one RCT that addressed this issue.  Hanser(196) studied older adults (61 to 86 years old, 77% female) with diagnosis of Major or Minor Depressive Disorder, based on a structured interview using the Schedule of Affective Disorders and Schizophrenia.  Patients (n = 30) were randomized to three treatment groups comparing home based structured music therapy (n = 10), with self-administered music therapy (n = 10) and a wait-list control group (n = 10) for eight weeks.  Geriatric Depression Scale (GDS) scores (pre-test to post-test) was 17.30 to 7.70 for the home based music therapy, 17.60 to 12.30 for the self-administered music therapy, and 15.30 to 16.20 for the control group (p < 0.05, favoring the two music therapy groups).  Follow-up results at nine months revealed no significant differences on the GDS score from post-test results in all three groups. This study supports the use of music therapy strategies with older adults experiencing symptoms of depression. Conclusion This one small study suggests that music therapy may be helpful in reducing symptoms of depression. The study was not large enough to differentiate between patients with Major and Minor Depression (the latter often resolves spontaneously). While there seems to be little apparent harm in recommending music therapy as adjunctive treatment (particularly if patients enjoy music), formal music therapy is associated with added cost without clear proven benefit. Pending more and larger studies, the GDT believes there is insufficient evidence to recommend for or against formal music therapy as an adjunctive strategy for patients with MDD. Effect of Depression Internet Sites or Automated Telephone Programs Two RCTs were found that addressed this issue.  Clarke(171) studied a combination of depressed and nondepressed participants (n = 299) who were randomized to two treatment groups comparing access to a Depression Internet site (n = 144, depression cases n = 107) with usual care (n = 155, depression cases n = 116), for a period of 32 weeks. Much of the Internet site content was adapted from group CBT psychotherapy manuals. The mean (SD) age for the internet group was 43.3 (12.2) years with 73.6% females.

 The mean age for the control group was 44.4 (12.4) years with 77.4% females. In depressed patients, mean (SD) scores on the Center for Epidemiologic Studies— Depression scale (CES-D) (baseline to week 32) were 30.7 (12.9) to 22.2 (12.8) in the internet group and 31.3 (11.5) to 25.2 (14.2) in the control group (p = 0.12).  Stratified analyses by high vs. low baseline CES-D scores, gender, and age greater or less than 45 all showed no statistically significant between group differences. The study found no differences between the control and experimental conditions on self-reported depression (CES-D) over the study period, indicating a lack of treatment effect.  Patten(180) studied patients with Major Depression diagnosed by the Composite International Diagnostic Interview (95% CIDI) who had a mean age 45.2 ±11.9 years. The population was 90.1% female, and 9.9% male. Patients (n = 786) were randomized to two treatment groups comparing use of web and telephony-based program (n = 420) with control group (n = 366) for three months.  The intervention consisted of an interactive computer program accessible through the internet or by interactive voice telephone. The percentage of patients exceeding Center for Epidemiological Studies Depression rating scale (CES-D) score of more than 15 in the active group was 37.4% (baseline of 35.7%) and 34.1% (baseline of 33.3%) for the control group (p = not stated). The study did not find any significant differences between the groups. Conclusion Based on the available evidence, the GDT does not recommend Internet or automated telephone- based programs for the treatment of MDD. 12. Behavioral Health Education Classes For Adults With MDD (Cognitive Behavioral Skills or Problem-Solving Classes) 12 For patients with mild to moderate MDD, the GDT recommends behavioral health education classes as an adjunctive treatment option. However, these classes should not be used in lieu of either antidepressant medication or psychotherapy. Evidence-based Rationale:

2008 Update No new evidence was found, the recommendation remains unchanged. 2006 Update No new evidence was found, the recommendation remains unchanged. It should be pointed out that there are several elements of behavioral health education classes that could have an impact on depressive symptoms, including but not limited to the content of the curriculum (which may be cognitive, behavioral, or problem-solving), the class setting, or the social aspects of a class setting. The curriculum was different in the studies cited in the 2004 update, and may be heterogeneous from setting to setting. It is therefore not currently possible to define which of the variables in of behavioral health education classes are the ‘active ingredients’ of treatment, or to which degree each variable contributes to patient outcome.

2004 Guideline

Supporting Evidence for Behavioral Health Education Classes in Improving Depressive Symptoms in Patients with MDD  Brown(197) studied adults 16 to 65 years old (70% female) with a Beck Depression Inventory (BDI) score of 22.2 (consistent with mild to moderate Major Depression) and a diagnosis of unipolar depression according to Research Diagnostic Criteria (RDC). Patients receiving other forms of treatment concurrently for depression were included.  The number of patients with severe Major Depression was not disclosed, although severe depression was not mentioned as an exclusion criterion. Patients with concurrent substance abuse were excluded. The study did not specify if patients with chronic Major Depression were excluded. Patients (n = 63) were randomized to three treatment groups and a control group. The “Coping with Depression” course curriculum was standardized across the three treatment conditions, and consisted of 12 sessions over an eight week period plus a visit or phone contact at one and six months post-treatment.  The study compared group class format (n = 25), individual tutoring (n = 13) and phone contact (n = 14) against a wait-list control group (n = 11). Participants in the three treatment groups improved more during the eight-week period than did the wait-list control group (p < 0.05). There were no statistically significant differences among the three treatment groups, when compared at eight weeks (treatment duration), one and six months follow-up sessions. Among the participants in the three treatment groups, only 25% still met the criteria for depression at the six-month follow-up session. From an economic point of view, the in-person class condition was by far the most cost effective.  The difference in response between those receiving concurrent treatment and those not receiving other treatment for depression was not specified. 34 of 122 individuals chose not to participate in the study, with differences between enrolled and not enrolled group not specified. Among patients participated in the study, dropout rate was 4.6%.  Dowrick(198) studied adults, ages 18 to 65, with DSM-IV diagnoses of MDD (52% single episode, 19% recurrent) dysthymia (16%), adjustment disorder (4%) or other depressive disorders (9%).  Suicidal patients and patients with concurrent substance abuse were excluded from the study; it is unclear if patients with severe Major Depression who were not suicidal were included. Patients (n = 452) were randomized to three treatment groups comparing six individual sessions of problem-solving treatment delivered in a setting convenient for the patient (usually the patient’s home) by behavioral health, allied health, or nursing personnel (N = 128), eight group sessions (2.5 hours each) of a course on prevention of depression (n = 108), and a control group (n = 189).  Outcomes were assessed at six and 12 months using intention-to-treat-analysis.  Mean difference in Beck Depression Inventory (BDI) score for the problem-solving group at six months was -2.63 (95% CI: -4.95 to -0.32), p = 0.026. At 12 months, the BDI score was -1.00 (95% CI: -3.31 to 1.31), p = 0.398.

 The prevention of depression group had a BDI mean difference of -1.50 (95% CI: -4.16 to 1.17), p = 0.272 at six months and 1.11 (95% CI: -1.30 to 3.52), p = 0.901 at 12 months (not significant).  There were significant improvements in SF36 scores (mental role, social function, and mental health) at six months for patients in the depression prevention group compared with controls at six months (p = 0.042, 0.048, and 0.028 respectively).  There were also significant improvements in SF36 scores (mental role, social function, and mental health) at six months for patients in the problem-solving therapy group compared with controls at six months (p = 0.030, 0.012, and 0.005 respectively). Neither treatment group had statistically significant improvement in any of these SF36 domains at 12 months, compared with controls. Statistical comparison of SF 36 scores comparing the two treatment groups with each other was not assessed.  At six months 17% fewer patients in the problem-solving group were depressed compared with controls (NNT = 6) and 14% fewer patients assigned to prevention of depression were depressed compared with controls (NNT = 7). At 12 months there were no differences between either study condition and controls.  More patients completed problem-solving therapy than the course on prevention of depression (the authors attribute this difference to better acceptance of the former treatment).  This study concludes that both problem-solving treatment and the course on prevention of depression reduced the severity and duration of depressive disorders over the short term, and improves subjective mental and social functioning. Results in this mixed population (patients with different types of depression, not all MDD) were not stratified by condition. The number of different individuals delivering the problem-solving therapy was not specified, the problem-solving therapy protocol was not specified, and the inter-provider variability of adherence to the therapy protocol was not assessed. Therefore, this may not be directly comparable to the problem-solving therapy delivered by trained mental health personnel in traditional behavioral health settings. Other Considerations Behavioral health education experts on the GDT report that these classes in KP target patients with acute depressive symptoms. KP Behavioral Health education classes for Major Depression exclude patients with severe depression symptoms, and like the Brown and Dowrick studies, exclude patients with concurrent substance abuse.

From the available literature and KP experience, therefore, the role of behavioral health education classes for patients with severe Major Depression or substance abuse is not clear. Controlled studies are needed to verify and more accurately quantify the initial benefit seen in pre-post analyses of Behavioral Health Education classes for MDD in KP Northern California and KP Northwest.

Overall Conclusion There is limited evidence that behavioral health education classes may be effective in reducing symptoms and improving functioning for some patients with MDD. There is insufficient evidence that health education classes should be used in lieu of antidepressants or structured psychotherapy for treatment of MDD. Therefore, the GDT believes that health education classes (if available) are an optional adjunctive treatment for patients with mild to moderate MDD, but does not recommend that health education classes be used instead of antidepressants or psychotherapy at this time. 13. Antidepressants To Avoid During Pregnancy or Breastfeeding

Evidence Grade Evidence for Recommendation 13A: Fair Search Strategy Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. The Pedersen (2009)(199) study was not identified by the search due to PubMed Indexing, but was identified by a GDT member and reviewed due to relevance. See Appendix B for more information on the search strategy. Rationale:

2010 Update New evidence has been identified, and recommendations have been changed based on both new evidence and expert/consensus opinion.

Our recent search yielded 11 relevant studies, including six cohort studies (Pedersen 2009(199); Wichman 2009(200); Jordan 2008(201); Diav-Citrin 2008(202); Kallen and Olausson 2008(203); Oberlander 2008(204)) and 5 case-control studies (Andrade 2009(205); Toh 2009(206); Ramos 2008(207); Salkeld 2008(208); Maschi 2008(209)) that addressed adverse effects associated with the use of antidepressant medication during pregnancy. Outcomes examined included congenital malformation (n = 5), neonatal hypertension (n = 2), neonatal withdrawal syndrome (n = 2) and maternal adverse events (n = 2). No new studies were identified that evaluated potential risks associated with antidepressant use during lactation. Please refer to 13.2 for study details. Congenital Malformations  Pedersen et al. (2009)(199) conducted a retrospective cohort of 493,113 children born in Denmark between 1996-2003 to assess the association between SSRI during the 1st trimester of pregnancy and congenital malformations. Results indicated that filled prescription for SSRIs was not associated with overall major malformation, but was significantly correlated with septal heart defects [OR = 1.99 (95% CI: 1.13 - 3.53)]. In particular, septal heart defects were highly associated with Sertraline [OR = 3.25 (95% CI: 1.21 to 8.75)] and Citalopram [OR = 2.52 (95% CI: 1.04 to 6.1)]. In women with one or more redemptions for antidepressants (mostly multiple SSRIs), there was a two-fold increase in risk septal heart defects [OR = 4.7 (95% CI: 1.74 to 12.7)]. However, the absolute increase in prevalence of septal heart defects was low [unexposed: 0.5% vs. any SSRI exposure: 0.9% vs. more than one SSRI: 2.1%].  Wichman et al. (2009)(200) examined whether the use of SSRIs during pregnancy was associated with congenital heart disease (CHD), in particular, ventricular septal defects (VSDs), and PPHN among 25,214 deliveries at the Mayo Clinic. Of the 25,214 deliveries, 808 of study participants took a SSRI at some point during pregnancy and results found three cases of CHD and no cases of persistent pulmonary hypertension (PPHN) or VSD in this group. Sertraline was the most frequently prescribed SSRI (36.6%). The prevalence of CHD was similar between the exposed (4%) and unexposed (8%) neonates, p = 0.23. None of the newborns from the 134 mothers who took paroxetine were diagnosed with VSDs. Thus, authors concluded that there was no association between CHD or PPHN and SSRI use during pregnancy. However, the study was underpowered to detect a small association and other major methodological concerns warrant cautious interpretation of results.

 Ramos et al. (2008)(207) conducted a case-control study of pregnant women (N = 2,339) with psychiatric disorder prior to pregnancy to evaluate the effect of duration of antidepressant use during the 1st trimester of pregnancy and the risk of major congenital malformation (MCM). Results found no significant association between antidepressant use during 1st trimester and MCM [adjusted OR = 1.1 (95% CI: 0.75 - 1.62)]. Subgroup analysis also indicated nonsignificant difference between duration of antidepressant used and risk for MCM [adjusted OR = for 1 to 30 days vs. 0 day: 1.23 (95% CI: 0.77 - 1.98); 31 to 60 days vs. 0 day: 1.03 (95% CI: 0.63 - 1.69); 561 days vs. 0 day: 0.92 (95% CI: 0.50 - 1.69)]. Additionally, the class of antidepressant used was also not significantly associated with major birth defects.  Oberlander et al. (2008)(204) investigated the incidence of congenital anomalies following prenatal exposure to SSRI monotherapy and/or in combination with benzodiazepines (BZ) using maternal and neonatal data linked to prenatal prescription records for all live births in British Columbia from 1998 to 2001 (N = 119,547). After adjusting for confounders, no significant risk differences were detected for major congenital anomalies for SSRI only, BZ only, or SSRI + BZ compared to no exposure. However, SSRI + BZ was significantly associated with increased risk for cardiovascular congenital defects [regression-adjusted incidence risk difference: 1.18 (95% CI: 0.18 - 2.18)], whereas SSRI alone was significantly associated with increased in risk for ASD [regression-adjusted incidence risk difference 0.21 (95% CI: 0.05 - 0.36)]. Among the SSRI used, citalopram was the only SSRI significantly associated with cardiovascular congenital defects [RR = 2.28 (95% CI: 0.19 - 4.36)] while fluoxetine + BZ significantly increased the risk for major congenital anomalies [RR = 5.18 (95% CI: 0.3 - 10.07)], although numbers were very small (n = 7 and n = 3, respectively). In addition, no association was detected between risk and 1st trimester medication dose/day.  Diav-Citrin et al. (2008)(202) reported on the risk of paroxetine and fluoxetine compared to nonteratogens exposure during pregnancy and major congenital anomalies. A total of 2,276 women who contacted the Israeli, Italy, and Germany Teratology Information Services (TIS) were followed-up (rates ranged: 44 to 91%). Among participants, 463 were exposed to paroxetine, 346 were exposed to fluoxetine and 1467 were exposed to nonteragens (controls). Rates of major anomalies were significantly greater in the paroxetine and fluoxetine group compared to controls (5.2% vs. 6.3% vs. 2.9%, p < 0.05), mostly from cardiovascular anomalies. No significant differences in rates of noncardiovascular anomalies were detected among the three groups (3.4% for paroxetine vs. 3.2% for fluoxetine vs. 2.4% for control). After adjusting for confounders, cardiovascular risk remained significant for fluoxetine [OR = 4.47 (95% CI: 1.31 to 15.27)] and smoking ≥ 10 cigarettes/day [OR = 5.4 (95% CI: 1.76 to 16.54)]. Neonatal Pulmonary Hypertension  Andrade et al. (2009)(205) reported on a retrospective case-control study of 1104 women exposed to antidepressants (SSRIs, tricyclics, an miscellaneous) during the 3rd trimester and matched controls (n = 1104) that found no significant association between SSRIs use during late pregnancy and PPHN in newborn. PPHN prevalence was 2.14 per 1000 [95% CI: 0.26 to 7.74] vs. 2.72 per 1000 [95% CI: 0.56 to 7.93] for infants whose mothers were exposed and not exposed to SSRI in the 3rd trimester. However, the study was underpowered to detect a difference and other major methodological concerns limit the generalizability of results.

 Kallen and Olausson (2008)(203) assessed the effect of SSRI use during pregnancy and PPHN in newborns using data from the Swedish Medical Birth Register. A total of 506 infants were born between 1997 and 2005 with PPHN and after adjusting for maternal age, BMI, smoking status and parity, a significant association between maternal use of SSRI and PPHN in births after 34 weeks was detected in women who reported drug use in early pregnancy [RR = 2.38 (95% CI: 1.19 - 4.25]. For women who reported SSRI use in early and later in pregnancy, the risk increased to 3.57 with wide confidence interval (95% CI: 1.16 - 8.33). SSRI use among the women included citalopram, sertraline, fluoxetine, and paroxetine; however, the study was underpowered to evaluate the effect of specific SSRI on neonatal PPHN. Neonatal Behavioral Syndrome  Maschi et al. (2008)(209) conducted a case-control study of 200 cases and 1,200 controls to investigate the association between antidepressant use during pregnancy and adverse effects, particularly, poor neonatal adaptation. After adjusting for possible confounders, results found no statistically significant difference in the incidence of poor neonatal adaptation in the exposed group compared to the unexposed control, although there was a trend for an increased risk in newborns exposed during the 2nd and 3rd trimester. However, the study was underpowered to detect small differences between the two groups and misclassification error could have occurred due to the conglomeration of conditions that constitute poor neonatal adaptation.  Jordan et al. (2008)(201) investigated the severity of neonatal behavioral syndrome (NBS, e.g., irritability, jitteriness, hypo- or hypertonia, hyperreflexia, apnea, hypoglycemia, etc.) among infants of mothers with psychiatric illness taking SSRI during pregnancy (n = 46) compared to infants born to women with psychiatric illness not treated with medication (n = 59). No significant differences in the overall number of NBS (28% of SSRI-treated pregnancies vs. 17% in non-treated pregnancies), need for transfer to a higher level nursery for NBS (11% vs. 10%), or length of hospital stay (2 vs. 6 days) was detected between the two groups. However, study was underpowered with relatively small sample size. Summary of Findings for Neonatal Outcomes For infant adverse events, evidence of potential cardiovascular congenital defects was reported in three studies. One large cohort study found that multiple antidepressant redemptions (mostly SSRIs) and the combination of SSRIs and benzodiazepines increase the risk for cardiovascular congenital defects. Additionally, citalopram (n = 2), sertraline (n = 1) and fluoxetine (n = 1) were shown to be significantly associated with cardiovascular congenital defects, although the studies had small sample sizes which make it difficult to generalize results. The trend in recent studies suggests a possible SSRI class effect on associations with cardiovascular congenital defects. Conversely, two studies found no significant differences between antidepressant exposure and non-exposure for major congenital and congenital cardiovascular malformations. Two studies found conflicting results on the effect of antidepressant use and persistent pulmonary hypertension in newborns, with the one study suggesting an SSRI class effect (but being underpowered to detect if the effect was related to only specific SSRIs).

Maternal Adverse Events  Toh et al. (2009)(210) evaluated a subgroup of 199 women who participated in the multi- centered case-control Slone Epidemiology Center Birth Defects Study, who received SSRI during pregnancy, and who gave birth to non-malformed and non-hypertensive newborns. Gestation hypertension was detected in 19.1% vs. 9% and of women with and without exposure [RR = 1.9 (95% CI: 1.35 - 2.67)] to SSRI and hypertension with preeclampsia was detected in 9% vs. 2.4% [3.16 (95% CI: 1.89 - 5.29)] in women with and without exposure. Adjusted relative risk for hypertension with preeclampsia for women who discontinued SSRI before the end of the 1st trimester was 1.37 (95% CI: 0.5 - 3.76) and 4.86 (95% CI:2.7 - 8.76) for those who continued SSRI. However, the study was underpowered to assess the attributable risk associated with specific SSRIs.  Salkeld et al. (2008)(208) conducted a case-control to investigate the effect of antidepressant use during 3rd trimester of pregnancy on postpartum hemorrhage among 2,460 cases and 23,943 matched controls. Results did not suggest a significant association between risk for postpartum hemorrhage and late-term exposure to SSRIs relative to non-SSRIs [adjusted OR = of SSRIs within 90 days before index date: 1.30 (95% CI: 0.98 - 1.72) vs. 1.12 (95% CI: 0.62 - 2.01) for non-SSRIs; p = 0.065]. Sensitivity analysis at 30, 60, and 180 days before index date also found consistent findings. However, cautious interpretation of outcomes is warranted due to unclear definition of postpartum hemorrhage and difficulty with drug adherence measurement. For maternal health, one study suggested no significant association between antidepressant use during pregnancy and postpartum hemorrhage while the other found increased in risk for hypertension with preeclampsia for women who continue on SSRI through late-pregnancy.

There were several important concerns that warrant cautious interpretation of the results. First, most studies extracted data related to drug intake from pharmacy registries, interviews, or physician prescriptions, which are not indicative of actual drug adherence. Second, specific SSRIs could not be evaluated individually in some studies due to power limitation and were often lumped together by class of SSRI, tricyclics or antidepressant drugs in general. Third, major congenital malformations were defined differently among studies to either include or exclude congenital cardiovascular defects. Fourth, several outcomes such as PPHN and NBS do not have explicit criteria or diagnosis and frequently require expert evaluations. The combinations of these limitations plus heterogeneous study methodologies make it difficult to draw definitive conclusion. Overall Conclusion Overall, updated evidence combined with previously reviewed evidence suggests no significant associations between major neonatal non-cardiovascular congenital malformations (n = 5 new studies) and neonatal behavioral syndrome (n = 2 new studies) with antidepressant use during pregnancy. In addition, two new studies did not observe significant increases in risk associated with treatment dose or duration (Oberlander 2008(204); Ramos 2009(207)).

Newer studies provided conflicting evidence on neonatal cardiovascular congenital anomalies and neonatal pulmonary hypertension. Overall (including previously reviewed evidence) evidence continues to suggest an association of paroxetine use in pregnancy with congenital cardiovascular malformations; the newer studies reviewed raise the possibility of a potential SSRI class effect. Maternal adverse events were reported in two studies, one of which found no significant association between antidepressant use during pregnancy and postpartum hemorrhage while the other found increased in risk for hypertension with preeclampsia for women who continue on SSRI through late-pregnancy.

The new available evidence is based on heterogeneous poor- to fair-quality studies, with limited assessment on attributable risk associated with specific SSRIs due to small sample size. Studies showed conflicting results. Combined with previously reviewed evidence, there still appears to be an association of paroxetine use during pregnancy and fetal cardiovascular malformations, therefore the 2008 recommendation against new starts of paroxetine in pregnancy remains unchanged. The newer studies suggest an association with pre-natal use of citalopram (two studies), sertraline and fluoxetine (one study each) and congenital cardiovascular malformations.

Other new studies suggest (albeit not consistently) associations between SSRI use and fetal pulmonary hypertension and maternal pre-eclampsia. Consequently, the GDT has added a new recommendation recommending caution in starting other selective serotonin re-uptake inhibitors (SSRIs) in pregnant women. A single study, with detection bias limitations, suggests a synergistic association between prenatal use of SSRIs + benzodiazepines with fetal cardiovascular malformations compared with benzodiazepines alone.

The GDT continues to recommend that the balance of risks and benefits of medication treatment and the risks of untreated depression be discussed with the mother.

The recommendations for infant adverse effects due to antidepressant exposure from breastfeeding remain unchanged from 2008 due to no new evidence identified at this time. 2008 Guideline New evidence was found, the recommendation remains unchanged.

In our search exploring antidepressant efficacy for treatment of Major Depression in adults, we did not distinguish between adults in general and women who were pregnant or breastfeeding. In some antidepressant efficacy studies (particularly of newer medications) pregnant or breastfeeding women are excluded; however, they are not excluded from all studies. Our evidence search for this problem formulation did not identify any studies specifically relating to efficacy of antidepressants in pregnant or breastfeeding women. Thus, we have extrapolated from the “general efficacy evidence” that the efficacy of first-line treatment options for adults with Major Depression would be similar in pregnant or breastfeeding women.

Five systematic reviews with meta-analyses of pooled data and a single case-control cohort study were selected for analysis. These publications addressed the adverse effects associated with the use of antidepressant medication on gestational outcomes. These outcomes included spontaneous abortion, congenital malformation, neonatal withdrawal syndrome or other neonatal central nervous system abnormality. There was some overlap of included studies in these meta- analyses; however, different outcomes were being evaluated. Please refer to Evidence Tables 13.1 and 13.2 for details.  A meta-analysis of six cohort studies of women taking antidepressants in pregnancy(211) reported a rate of spontaneous abortion of 12.4% compared with 8.7% in women not taking antidepressants. The risk ratio was calculated to be 1.45. (95% CI: 1.19 to 1.77). No significant difference in risk was seen between classes of antidepressants. (In this study, eight different antidepressants results were blended together).  Lattimore et al. published a meta-analysis of data from nine prospective cohort studies of the effect of maternal SSRI use during pregnancy.(212) This meta-analysis did not analyze results by different medications in this class. It also included some studies in which intervention group women were using other psychotropic medications (primarily benzodiazepines); the extent to which this inclusion biases the results is unknown. Nonsignificant increases were seen in the rates of prematurity, low birth weight, special-care nursery admissions, and the diagnosis of poor neonatal adaptation. None of the effects cited in this study reached statistical significance at the p = 0.01 level.  Moses-Kolko et al. reported that a meta-analysis of data from five cohort studies showed that compared with early or no SSRI exposure, late gestational exposure was associated with an overall risk ratio of 3.0 (95% CI: 2.0 to 4.4) for neonatal behavior syndrome.(213) This self- limiting syndrome has been characterized as including neonatal irritability, agitation, tremors, increased muscle tone and respiratory and digestive disturbances.

 A meta-analysis of nine studies of SSRI exposure in the first trimester and throughout pregnancy addressed outcomes including spontaneous abortion, major malformation, cardiovascular malformation, and minor malformation.(214) The authors reported an association between maternal use of any SSRIs and spontaneous abortion (12.5% vs. 7.6% OR = 1.7 (95% CI: 1.28 to 2.24)), but no statistically significant increased risk of major or minor malformations were detected.  Bar-Oz, et al.(215) reported the results of a meta-analysis of seven studies that compared the pregnancy outcomes of women using paroxetine in the first trimester with those of women using other potentially teratogenic drugs or other antidepressants. They reported a 74% relative increase in the risk for cardiovascular malformation in the infants of women exposed to paroxetine in the first trimester compared with women who were not taking antidepressants (95% CI: 1.22 to 2.42). This was similar to the increase in risk of 70% for paroxetine exposure when compared with other antidepressants. The increase in risk for other abnormalities was not statistically significant. However, detection bias may have influenced the results, as significantly more women reported using paroxetine than other SSRIs for anxiety disorders, and women using SSRIs had approximately twice as many prenatal ultrasounds compared with women who took no antidepressants. This study also used teratogens and other anti-depressants as controls, no true controls.  In response to earlier reports of persistent pulmonary hypertension of the newborn (PPHN) associated with maternal use of antidepressants, Chambers et al.(216) studied the occurrence of this diagnosis in the infants of women who used antidepressants during pregnancy. Data collected from 377 women whose infants were diagnosed with PPHN was compared with data collected from 836 controls. The two groups were comparable in terms of maternal education, ethnicity, age, body mass index, maternal diabetes, smoking status, and NSAID use. Fourteen infants with PPHN were born to mothers who had used SSRIs after the 20th week of gestation, compared with six infants in the control group (OR = 6.1, 95% CI: 2.2 to 16.8). Please refer to Table 13.2.

Two meta-analyses were identified in the peer-reviewed medical literature that addressed the potential risks associated with antidepressant use during lactation. Please refer to Table 13.3 for details.  Rubin et al.(217) collected 129 publications on breastfeeding and maternal use of CNS-acting medications. Their findings indicated that the majority of CNS-acting drugs, including all antidepressants do not reach a concentration of greater than 10% of the maternal dosage when ingested via breast milk.

 Weissman et al.(218) pooled the data in 57 studies of medication levels in the breast milk of nursing mothers using antidepressant medication. The infant plasma level of most medications (an intermediate, biological outcome) was found to be less than 10% of that of the mother. However, 22% of infants exposed to fluoxetine and 17% of the infants exposed to citalopram demonstrated plasma drug levels that exceeded 10% of the maternal level (a level that researchers have adopted by consensus as defining an elevated level*). In addition to weaknesses in the Bar-Oz study noted above, recommendations on paroxetine are based on meta-analyses of studies that have not been evaluated for quality. The evidence about fluoxetine and citalopram in breastfeeding is insufficient because the outcome variable is intermediate, not clinical. The studies showing increased risk to the fetus with SSRIs are insufficient because they are somewhat inconsistent, mostly lump all SSRIs together, and the ORs are < 2.0, which is often taken as a threshold for inferring causation from an observational study. There is significant heterogeneity for several studies (Hemels, Lattimore, Rahimi), and the model used for analysis was not known for the other two (Moses-Kolko, Bar-Oz). There were significant biases or potential biases cited for most of the meta-analyses. Therefore, all of the recommendations in this problem formulation are consensus-based, because of the overall insufficient nature of the evidence. Other Considerations The baseline rate of all fetal malformations is 3%; for fetal cardiac malformations the baseline rate is approximately 1%. Ten to 25% of pregnant women and 10 to 20% of postpartum women experience an episode of MDD.(219, 220) Untreated or relapsing depression during this time is associated with adverse maternal outcomes (including suicide), increased risk of obstetrical complications(212) low birth weight, premature birth, and fetal loss(221) and short- and long-term neurological and cognitive-behavioral issues in these children, including increased risks of depression later on in the child.(212, 222) One study(223) suggests that up to 68% of women who stop antidepressants during pregnancy will experience a relapse of depression, compared with 26% of women who continue treatment (NNH = 2.4). Therefore, the GDT believes that, when treating women who are pregnant or breastfeeding, the clinician should:  Discuss pregnancy and what is known regarding antidepressant teratogenicity, perinatal, neonatal and long-term effects.  Discuss what is known regarding effects of maternal depression on pregnancy and infant development.  Advise that pregnancy does not ”protect” against the onset or effects of depression.  For patients already taking antidepressants, discuss risks of depression relapse.

The Bar-Oz meta-analysis shows an increased risk of cardiac fetal abnormalities associated with paroxetine exposure. In addition, the FDA has required a black box warning for fetal abnormalities associated with the use of paroxetine in pregnant women. Therefore, the GDT has made specific recommendations against new paroxetine starts during pregnancy.

Overall Conclusion: Potential adverse affects of prenatal antidepressant exposure include increased risk of fetal malformations (for paroxetine), transient pulmonary complications, and transient neonatal behavioral syndromes. Long-term risks to the child from exposure in-utero and breast feeding seem to be relatively small, based on limited observational evidence.

Based on available evidence, the risk of untreated depression seems to outweigh the small increase risk to the fetus from in-utero antidepressant exposure. Avoidance of new starts of paroxetine during early pregnancy seems prudent due to the increased risk in cardiac malformations compared with other antidepressants, especially in light of an FDA black box warning on paroxetine for use in pregnancy. If the mother is already using paroxetine when pregnancy is detected, the risk of teratogenicity due to exposure may have already occurred; hence increased fetal surveillance for malformations seems clinically indicated. The potential risk of depression relapse for the mother seems to outweigh the small increased fetal risk of continued antidepressant exposure; however, the GDT recommends that the balance of risks and benefits be discussed with the mother.

Evidence for actual infant adverse effects due to antidepressant exposure from breastfeeding is limited at this time. In theory, higher levels of infant antidepressant exposure could increase the risk for adverse effects. Therefore, given the availability of other antidepressant options, in breastfeeding women, avoiding new starts of medications with long half-lives (fluoxetine) or increased neonatal plasma levels (fluoxetine, citalopram) seems prudent, although the concerns may mostly be theoretical, based on small numbers of infants studied, and are of unknown clinical significance. However, for women who wish to breastfeed who are continuing antidepressants taken during pregnancy, most fetal exposure will have already occurred in-utero. In the absence of neonatal behavioral syndromes or pulmonary symptoms, the risk of antidepressant discontinuation for the mother and the effect on maternal-fetal bonding is probably greater than neonatal risks of continued exposure during breastfeeding. However, the GDT also recommends a discussion of the balance of risks and benefits with mothers in this situation.

Appendix A: Criteria for Grading the Evidence

Appendix B: Supporting Documentation

1. First-Line Treatment of Major Depressive Disorder (MDD)

Problem Formulation 1 Clinical Question: What first-line treatment methods should be used to treat adults with MDD? Intended Use of the To assist primary care physicians and other health care professionals Guideline: in treating adults with Major Depression. Population: All adult (age 19 and older) patients with Major Depression Health Problem: MDD * Health Intervention:  Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs)  Psychotherapy (Interpersonal Therapy, Cognitive Behavioral Therapy, Problem-Solving Therapy)  Combination of antidepressants and psychotherapy  No treatment Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics Health Outcomes  Change in symptoms  Office/UCC/ER visits (associated with the  Quality of life  Hospitalizations intervention):  Missed school/work days  Mortality Sexual problems Side Effects Dry mouth Abdominal pain Associated With Drowsiness Seizures Dizziness the Intervention: Headache Elevated blood Blurred vision Nausea pressure Weight gain Insomnia Constipation GI bleeding Agitation/ Diarrhea Fall nervousness

* SSRI = Selective Serotonin Reuptake Inhibitor TCA = Tricyclic Antidepressant DA = Dopamine Agonist SNRI = Serotonin Norepinephrine Reuptake Inhibitor NRI = Norepinephrine Reuptake Inhibitor Cognitive Behavioral Therapy = Brief structured treatment, incorporating elements of cognitive therapy and behavioral therapy. Behavioral therapy is based on learning theory and concentrates on changing behavior. Interpersonal Therapy = Standardized form of brief psychotherapy primarily intended for outpatients with unipolar nonpsychotic depressive disorders. It focuses on improving the person’s interpersonal functioning and identifying the problems associated with the onset of the depressive episode. Problem-Solving Therapy = Consists of three stages: (1) identifying the main problems for the person; (2) generating solutions; and (3) trying out the solutions.

PubMed "Antidepressive Agents/therapeutic Only items with 8/2005 0/222 use"[ All Fields] OR "Antidepressive abstracts, to Agents/therapeutic use"[MESH] OR Humans, 9/2007 "psychotherapy"[MESH] OR Randomized (cognitive[All Fields] AND Controlled Trial, "behavior therapy"[MeSH Terms]) English, All OR "interpersonal therapy"[All Adult: 19+ years Fields] OR ("Problem- Only items with 9/2009 to 0/70 solving"[MeSH Terms] AND abstracts, 10/2009 "therapy"[MeSH Subheading])) Humans, Meta- analyses, English, All Adult: 19+ years National Depression Systematic Dec. 6, N/A Institute Review, 2004 for Clinical Meta-analyses Excellence and RCTs (NICE) Systematic 2007 - 6/ N/A Review, 2009 Meta-analyses Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 3/131 Group Reviews 2007 - 4/86 2009 Clinical Chapter: Depressive Disorders Systematic Jan. 2006 N/A Evidence Reviews and RCTs 2007 - 0/2 2009

* Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search, regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted more than once in the number included. Systematic reviews and meta-analyses with search dates outside the range of current searches were excluded.

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Hand N/A Systematic 2007 to 1/1 Searches Reviews and 2009 Meta-analysis PubMed ("depression/drug effects"[MESH] Randomized, 01/01/03 17/236 OR "depression/drug controlled trials, - therapy"[MESH] OR All adults: 08/01/05 "depression/therapy"[MESH] OR 19+ years, "Major Depressive Disorder" [All English, Human Fields]) AND ("Antidepressive Agents/adverse effects"[MESH] OR "Antidepressive Agents/therapeutic use"[All Fields] OR "Antidepressive Agents/therapeutic use"[MESH] OR "psychotherapy"[MESH] OR (cognitive[All Fields] AND "behavior therapy"[MeSH Terms]) OR "interpersonal therapy"[All Fields] OR ("Problem- solving"[MeSH Terms] AND "therapy"[MeSH Subheading])) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT]) Systematic Cochrane Depression 03/05/03 1/295 reviews Systematic Clinical Depression reviews and 03/05/03 1/80 Evidence RCTs

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed (((((((((((depression/drug Clinical trials, 1998 3/222 therapy[MESH] OR All adults 19+ - depression/therapy[MESH]) OR years, English, 03/2001 ("depressive disorder/drug Human therapy"[MESH] OR "depressive disorder/therapy"[MESH])) OR ("dysthymic disorder/drug therapy"[MESH]OR "dysthymic disorder/therapy"[MESH])) AND ("Serotonin Uptake Inhibitors"[MESH] OR "Antidepressive Agents, Tricyclic"[MESH])) AND notpubref[sb]) AND Randomized Controlled Trial[ptyp]) AND English[Lang]) AND notpubref[sb]) AND "adult"[MeSH Terms]) ("depression/drug effects"[MESH] Meta-analysis, 01/01/01 1/5 OR "depression/drug All Adult: 19+ - therapy"[MESH] OR years English, 04/01/03 "depression/therapy"[MESH] OR Human "Major Depressive Disorder"[All Controlled 01/01/01 4/124 Fields]) AND ("Antidepressive Trials, All - Agents/adverse effects"[MESH] OR Adult: 19+ years 04/01/03 "Antidepressive Agents/therapeutic English, Human use"[MESH] OR "psychotherapy"[MESH] OR (cognitive[All Fields] AND "behavior therapy"[MeSH Terms]) OR "interpersonal therapy"[All Fields] OR ("Problem- solving"[MeSH Terms] AND "therapy"[MeSH Subheading])) Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. Casacalenda(1) study was indexed as a review article in PubMed and did not show up in the search results due to the way PubMed indexing is done. The GDTdecided to include this study, since it met the inclusion criteria. Other Information Source:  Evidence report on the Treatment of Depression-Newer Pharmacotherapies. AHRQ(169)

Evidence Tables

First-Line Treatment of MDD

Table 1.1: Summary of Systematic Reviews and Meta-Analyses Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Mukai et al. Databases: MEDLINE, N: 18 RCTs (10 SSRIs Limited data suggest (2009) PsycINFO, and head-to-head or  2 comparative trials found no significant difference in efficacy between TCAs vs. SSRIs that dual-action PubMed (January 2003– placebo; 2 TCAs vs. agents such as TCAs Treatment of January 2009). SSRIs; and 6 SNRIs vs.  3 studies found no significant difference between venlafaxine vs. SSRIs and SNRIs do not depression in the placebo, TCA or SSRI) appear to confer any elderly: A review Search terms: % F: Participants  1 study of duloxetine vs. placebo found significant improvement in depression (reductions in HAM-D and GDS, additional efficacy of the recent Antidepressant, SSRI, primarily female p<0.001) than placebo with addition reduction in pain (p<0.001) and cognition (p=0.013). benefits over single- literature on the SNRI, TCA, depression, Duration: 6 – 100 wks action agents such as efficacy of single- randomized controlled Sample size: range 28  Data from 5 studies using various measures (including changes in MADRS, HAM-D, or Geriatric Depression Scale SSRIs in the versus dual- trials, human trials, and – 376 [GDS] scores; response rates; and remission rates) suggested no additional efficacy benefit for the SNRI venlafaxine treatment of action individual antidepressant compared with SSRIs or TCAs. depression in the antidepressants. names. Inclusion criteria: elderly. published double-blind Outcome measures: design; placebo control Limitations: Response (reduction of at or active comparator heterogeneity among least 50% from baseline group; aged ≥59 years; study sample, design, scores on HDRS, patients with a dosing and duration; MADRS, or 1-2 on CGI); diagnosis of MDD; inconsistent diagnosis remission (MADRS <9 to published meeting of MDD or <12 or HAMD<7 to <10); abstracts; publications comorbididites, and tolerability in any outcome definitions (withdrawals due to AEs) language; studies and measures; conducted in the underpowered; small community, nursing, number of studies  Method: home, outpatient, and included; limited - Meta-analysis was hospital settings; head-to-head not conducted; studies that enrolled comparison studies; patients with comorbid low generalizability, - no assessment of dementia or medical no attempt to look for publication bias (e.g. illnesses; and studies of unpublished studies. funnel plot analysis); maintenance therapy for depression. - no information on study funding was Published meeting reported abstracts that meet the criteria above were also considered.

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Gartlehner et al. Databases: MEDLINE, N: 203 studies Current evidence (2008a) EMBASE, PsychLit, [including 105 head-to-  Of the 203 included studies, 140 (69.0%) were financially supported by pharmaceutical companies and 19 (9.3%) by does not warrant the Cochrane, International head trials; 66 placebo governmental agencies or independent funds. For 44 (21.7%) studies, we could not determine the funding source. choice of one Comparative Pharmaceutical Abstracts trials; 6 SR; 23 second-generation benefits and (1980 - April 2007). observational studies antidepressant over harms of second- Examined Center for (>740,000 subjects); 15 another on the basis generation Drug Evaluation and studies with pooled of differences in antidepressants: Research database data. efficacy and background (CDER) for unpublished effectiveness. paper for the research. Invited pharma Nevertheless, there American College to submit dossiers. Inclusion criteria: were some of Physicians. - Population: Adult differences with Search strategy: AHRQ inpatients and respect to onset of assisted in formulating outpatients with MDD. action and adverse key questions and data - Intervention: 12 AD events that may be analysis. Search terms: listed previously relevant for the (‘adverse events’, - Study design: choice of a ‘harms’, ‘drug reactions’, Experimental and medication. ‘toxicity’, with ‘major observational head-to- depressive disorder head studies Limitations: low [MeSH]’ and 12 specific - Minimum study generalizability due to second-generation duration: 6 wks highly selected antidepressants - Minimum sample size: patient populations in (bupropion, citalopram, none for experimental efficacy studies; duloxetine, escitalopram, designs; n ≥100 for indirect comparisons fluoxetine, fluvoxamine, observational studies due to lack of head- mirtazapine, nefazodone, to-head evidence paroxetine, sertraline, resulted in low power trazodone and and wide confidence venlafaxine). ‘Humans’ intervals; residual and ‘English” language. publication bias; Note: the 7 studies that suggest some differences with respect to onset of action were all supported by manufacturer of inconsistency and Outcome measures: mirtazapine and after 4 weeks of treatment, most response rates were similar. variability among - Outcomes of Overall studies in terms of rate of adverse events drug dose and (AEs) duration of treatment; - Discontinuation because small number of of AEs studies for individual - Specific AEs (e.g. comparisons. gastrointestinal symptoms, weight gain, dizziness and others) - Severe AEs (e.g. suicidality, hyponatremia, sexual dysfunction and others)

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Method: Indirect comparison was calculated using meta- regressions of placebo- controlled trials using individual drugs as covariates.

When number of trials was insufficient for metaregression, modified network meta-analysis was used.

- meta-analysis of head- to-head comparisons (both random and fixed- effects model) - test of heterogeneity (I2) index) - adjusted direct comparison using meta- regressions of placebo trials using individual drugs as covariates - when there’s insufficient trials available for meta- regressions, used modified network meta- analysis - publication bias assessed by funnel plots

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

120 National Adult Depression Clincial Practice Guideline

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Gartlehner et al. Databases: MEDLINE, N: 104 studies [81 General tolerability Overall, the spectrum (2008b) EMBASE, PsychLit, head-to-head trials of AEs was similar nd Cochrane, International (>17,000 subjects) ; 21  AE profiles of second-generation antidepressants were similar with nausea, vomiting, diarrhea, dry mouth, sweating, between different 2 - Comparative risk Pharmaceutical Abstracts observational studies headache, dizziness, sexual dysfunction and weight gain were commonly reported AEs. However, individual drugs gen antidepressants; for harms of (1980 - April 2007). (>740,000 subjects)] differed in frequencies of specific AEs. however, different second- Examined CDER for frequencies of generation unpublished research. About 63% of patients in efficacy trials experienced at least one AE. specific AEs might be antidepressants: Invited pharma to submit Inclusion criteria: clinically relevant and A systematic dossiers. - Population: Adult Discontinuation rates influence the choice review and meta- inpatients and of treatment. analysis. Search strategy: outpatients with MDD.  Overall, about 15% of patients treated with 2nd-gen antidepressant discontinue because of intolerable AEs. (‘adverse events’, - Intervention: 12 AD ‘harms’, ‘drug reactions’, listed previously  No significant difference was detected between 2nd-gen antidepressants and SSRIs (refer to Figure 2). However, Limitations: ‘toxicity’, with ‘major - Study design: pooled estimated indicated higher discontinuation from AEs for patients taking venlafaxine than SSRIs(RR: 1.42 comparative risk for depressive disorder Experimental and (95% CI: 1.15-1.75)] rare AEs were [MeSH]’ and 12 specific observational head-to- Gastrointestinal AEs (refer to Figure 3) insufficient to draw second-generation head studies firm conclusion; antidepressants - Minimum study  Venlafaxine had a statistically significantly higher rate of nausea and vomiting than SSRIs as a class [RR: 1.53 (95% heterogeneity (bupropion, citalopram, duration: 6 wks CI: 1.26 - 1.86); NNH = 9 (95% CI 6, 23)]. between experimental duloxetine, escitalopram, - Minimum sample size: and observational fluoxetine, fluvoxamine, none for experimental Other AEs studies; low quality mirtazapine, nefazodone, designs; n ≥100 for assessment and paroxetine, sertraline, observational studies  Compared with other 2nd-gen antidepressants, paraoxetine frequently led to higher and bupropion to lower rates of misclassification of trazodone and sexual dysfunction; mirtazapine and paraoxetine led to higher weight gains; and sertraline to higher rates of diarrhea. AEs based on venlafaxine). ‘Humans’ However, differences did not lead to different discontinuation rates. variation in and ‘English” language. definitions; poor reporting – lack of Outcome measures: objective scale; - Outcomes of Overall under-reporting in rate of adverse events some studies; and (AEs) evidence was too - Discontinuation because sparse to assess risk of AEs of harms for all 66 - Specific AEs (e.g. possible comparisons gastrointestinal between 2nd-gen symptoms, weight gain, antidepressants. dizziness and others) - Severe AEs (e.g. suicidality, hyponatremia, sexual dysfunction and others)

Method: - when RCTs sufficient, meta-analyses (fixed and random effects) of RR = was conducted (only reported random effects);

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations otherwise, evidence were synthesized qualitatively - test of heterogeneity (I2) was applied to both random and fixed effects model - sensitivity analysis was conducted when I2>60% according to population characteristics, dosages or drug formulations - When pooled outcomes were significant, NNH was calculated - publication bias was assessed using funnel plots - due to lack of data on individual comparisons, assessments were made with SSRI as a class

Cipriani et al. Databases: Cochrane N: 117 RCTs (25,928 Only 7 of 117 trials were in primary care settings; 15 unpublished studies from industry were included, it was not Escitalopram and (2009a) collaboration depression, subjects) specified how many of these favored the funder’s antidepressant and it was not clear how many of these studies were sertraline might be anxiety and neurosis % F: 64% also included in the FDA trial database the best choice when Comparative review group controlled Mean duration: 8.1 starting a treatment efficacy and trial registers (1991 – wks No funnel plots or assessment of publication bias was noted for moderate to acceptability of Nov, 30, 2007). Asked Mean sample size: severe major 12 new- pharmaceutical 109.8 (range: 9-357) depression because generation companies, regulatory Heterogeneity they have the best antidepressants: agencies, and study 63% trials were done in possible balance a multiple- investigators to supply all Europe and North  Overall, heterogeneity was moderate, although for most comparisons the 95% CI included values that showed very between efficacy and treatments meta- available information. America. high or no heterogeneity, reflecting the small number of included studies for each pair-wise comparison. acceptability. analysis 53 studies included Search terms: people <65 years. Efficacy Reboxetine, Not specified. fluvoxamine, Inclusion criteria: only  Escitalopram, mirtazapine, sertraline, and venlafaxine were significantly more efficacious than duloxetine, fluoxetine, paroxetine, and Outcome measures: RCTs that compared fluvoxamine, paroxetine, and reboxetine (refer Figure 3) duloxetine were the Response (>50% any of the following 12 least efficacious and reduction of baseline new-generation  Reboxetine was significantly less efficacious than all the other 11 antidepressants. acceptable drugs,

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations HAM-D, MADRS, or who antidepressants making them less scored much improved on (bupropion, citalopram,  When using Fluoxetine as reference: Mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious favorable options CGI) and dropout rates duloxetine, than fluoxetine, and fluoxetine was more efficacious than reboxetine when prescribing an during 8 wks of tx escitalopram, fluoxetine, Acceptability acute treatment for (dropouts). fluvoxamine, major depression. milnacipran,  duloxetine and paroxetine were less well tolerated than escitalopram and sertraline; fluvoxamine less well tolerated Comparative efficacy mirtazapine, than citalopram, escitalopram, and sertraline; venlafaxine less well tolerated than escitalopram; reboxetine less well Furthermore, in terms analyses for the 12 drugs paroxetine, reboxetine, tolerated than many other antidepressants, such as bupropion, citalopram, escitalopram, fluoxetine, and sertraline; of acceptability, were done using sertraline, and and escitalopram and sertraline were better tolerated than duloxetine, fluvoxamine, paroxetine, and reboxetine. reboxetine was the fluoxetine as reference venlafaxine) as least tolerated agent drug. monotherapy in acute-  fluoxetine was better than reboxetine among the 12 phase tx of adults with antidepressants and Method: unipolar major Ranking of Efficacy and Acceptability (refer to Figure 4) was significantly less - when dichotomous depression. effective than all the efficacy outcomes were  Mirtazapine, escitalopram, venlafaxine, and sertraline were among the most efficacious treatments, and other 11 drugs. not reported tx response Study quality was rated: escitalopram, sertraline, bupropion, and citalopram were better tolerated than the other remaining antidepressants Therefore, reboxetine at 8 wks was estimated adequate, unclear, or should not be used as - Responders to inadequate, according  Cumulative probabilities of being among the four most efficacious treatments were: mirtazapine (24·4%), a routine first-line treatment were calculated to the adequacy of the escitalopram (23·7%), venlafaxine (22·3%), sertraline (20·3%), citalopram (3·4%), milnacipran (2·7%), bupropion acute treatment for on an intention-to-treat random allocation (2·0%), duloxetine (0·9%), fluvoxamine (0·7%), paroxetine (0·1%), fluoxetine (0·0%), and reboxetine (0·0%). major depression. basis concealment and - pair-wise meta-analyses blinding.  Cumulative probabilities of being among the four best treatments in terms of acceptability were: escitalopram Limitations: using random-effects (27·6%), sertraline (21·3%), bupropion (19·3%), citalopram (18·7%), milnacipran (7·1%), mirtazapine (4·4%), Short duration and model Studies that scored fluoxetine (3·4%), venlafaxine (0·9%), duloxetine (0·7%), fluvoxamine (0·4%), paroxetine (0·2%), and reboxetine follow-up; - multiple-treatments adequate or unclear (0·1%). sponsorship bias; lack meta-analysis were included. of information on - heterogeneity was randomization and assessed using forest Exclusion criteria: allocation plots placebo concealment; - sensitivity analyses groups present and variations in multiple- based on dose and RCTs of women with treatments and direct imputation were post-partum depression comparisons; conducted selection bias - meta-regression (placebo-controlled analysis was conducted trials mainly designed to examine sponsorship for regulatory effect approval tend to include patients with mild form of disease); residual confounding; numbers needed to treat or harm were not calculated, making it difficult to assess the absolute differences in each analysis; statistical significance (defined as p<0.05 in

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations this analysis) was not adjusted for multiple comparisons, so many differences could have been due to chance.

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Cipriani et al. Databases: The N: 22 RCTs (14 Some statistically (2009b) Cochrane Depression, compared escitalopram  Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR = 0.67, significant differences Anxiety and Neurosis vs. SSRI; 8 compared 95% CI 0.50 to 0.87). favoring escitalopram Escitalopram Group (CCDAN) escitalopram vs. over other versus other Controlled Trials Register (venlafaxine,  Escitalopram was also more effective than citalopram in terms of remission (OR = 0.53, 95% CI 0.30 to 0.93). antidepressive agents antidepressive was searched, together bupropion and for the acute phase agents for with a supplementary duloxetine)  Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to treatment of MDD depression search of MEDLINE, % F: not reported duloxetine, for discontinuation due to any cause (OR = 0.62, 95% CI 0.38 to 0.99). were found, in terms (review). PsycINFO, EMBASE, Age: Adults >18 years of efficacy (citalopram LILACS, CINAHL, Duration: 6 – 24 wks and fluoxetine) and Cochrane review. PSYNDEX and hand Mean sample size: acceptability searches. Trial databases 280.8 + 103.9 (range (duloxetine). There is of drug-approving 202-547) insufficient evidence agencies were hand- to detect a difference

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations searched for published, Inclusion criteria: between escitalopram unpublished and ongoing RCTs comparing and other controlled trials. (July escitalopram against antidepressants in 2008) any other early response to antidepressant treatment (after two Search terms: (including non- weeks of treatment). CCDANCTR-Studies: conventional agents However, the Diagnosis = Depress* or such as potential for Dysthymi* or “Adjustment hypericum) for patients overestimation of Disorder*” with MDD (regardless of treatment effect due or “Mood Disorder*” or the diagnostic criteria to sponsorship bias “Affective Disorder” or used); aged >18 years; should also be borne “Affective Symptoms” studies in which less in mind. and Intervention = than 20% of the Escitalopram. participants might be Limitations: CCDANCTR-References: suffering from bipolar publication bias due Keyword = Depress* or depression to commercial Dysthymi* or “Adjustment were included sponsorship; unclear Disorder*” or “Mood allocations; selective Disorder*” or “Affective Exclusion criteria: reporting present in Disorder” or “Affective Participants diagnosed many studies; Symptoms” with comorbid physical and Free-Text = or mental conditions; Escitalopram concurrent primary Outcome measures: diagnosis of Axis I or II The primary outcome was disorders. response (>50% reduction in HAM-D or MADRS or 1-2 on CGI scores)

1) Early response: between 1 and 4 weeks, 2) Acute phase treatment response: between 6 and 12 weeks, 3) Follow-up response: between 4 and 6 months

Method: - meta-analysis using random effects model - Responders and remitters to treatment were calculated on the intention-to-treat (ITT) basis - When there were

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations missing data “last observation carried forward” (LOCF) method was used - heterogeneity was assessed using I2 and forest plots - Funnel plot was used to assess publication bias - sensitivity analyses were also conducted to account for excluded trials, imputation, wish bias, and sponsorship

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Nakagawa et al. Databases: Cochrane N: 16 RCTs (2277 There is inadequate (2009) Collaboration Depression, subjects)  No statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other evidence to conclude Anxiety % F: not reported antidepressive agents, with wide CIs. whether milnacipran Milnacipran & Neurosis Controlled Age: Adults >18 years is superior, inferior or versus Trials Registers Mean Duration: most  However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse the same as other antidepressive (CCDANCTR-Studies studies were 6-12 wks events (OR = 0.55; 95% CI 0.35 to 0.85). antidepressive agents agents for and CCDAN-References) Median sample size: in terms of efficacy, depression (searched in December 120 (range: 41-302)  There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events acceptability and (review). 2006; updated in August of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs. tolerability in the 2008). Trial databases of Inclusion criteria: acute phase Cochrane review. drug-approving agencies RCTs comparing treatment of major were hand-searched for milnacipran with any depression. However, published, other active there is some unpublished and ongoing antidepressive agents evidence in favor of controlled trials. Hand (including non- milnacipran over searches also conducted. conventional agents) as TCAs in terms of monotherapy in the dropouts due to Search terms: acute phase of major adverse events CCDANCTR-Studies: depression; age >18 (acceptability) and the Diagnosis = Depress* or years. rates of experiencing Dysthymi* or “Adjustment adverse events Disorder*” Exclusion criteria: (tolerability). or “Mood Disorder*” or Studies using ICD9 to “Affective Disorder” or diagnose depression; “Affective Symptoms” participants diagnosed Limitations: data and Intervention = with comorbid physical reporting Milnacipran; or mental conditions; of most studies was CCDANCTR-References: concurrent primary incomplete; selective Keyword = Depress* or diagnosis of Axis I or II reporting present in Dysthymi* or “Adjustment disorders. many studies; small Disorder*” or “Mood number of studies Disorder*” or “Affective included; may be Disorder” or “Affective underpowered to Symptoms” and Free- detect significant Text = Milnacipran. difference; no Outcome measures: sensitivity analysis to Response (>50% examine other reduction of baseline modulating effects; HAM-D, MADRS, or who high drop-out rates scored much improved on noted which reduce CGI) outcome reliability; most studies were Method: funded by industry. - meta-analysis using random effects model - Responders and remitters to treatment were calculated on the

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations intention-to-treat (ITT) basis - When there were missing data “last observation carried forward” (LOCF) method was used - heterogeneity was assessed using I2 and forest plots - Funnel plot was used to assess publication bias - sensitivity analyses were also conducted to account for excluded trials, imputation, wish bias, and sponsorship

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Omori et al. Databases: Cochrane N: 53 RCTs (48 RCTs Treatment efficacy No substantial (2009) Central Register of for efficacy analysis difference exists in Controlled Trials, (N=6440); 49 for  no significant differences in response and remission rates between fluvoxamine and other ADs as a class (TCAs, the effectiveness Efficacy, MEDLINE, tolerability analysis heterocyclics, etc.) (refer to table 2) in early or end of acute phase of treatment. between fluvoxamine tolerability and EMBASE, CINAHL, (N=8244)) and any of the ADs side effect profile pycINFO, PSYINDEX, % F: not reported Tolerability including TCAs, such of fluvoxamine for LILACS Age: > 18 years as amitriptyline or major and hand searches (thru Duration: Mean 5.5  The total number of dropouts for any reason or for side effects was not significantly different between fluvoxamine clomipramine, depression: June 2, 2006). Not wks (range 2 – 10 wks) and other ADs as a class and between fluvoxamine and individual comparator ADs (refer to table 3). in terms of response Meta-analysis. limited to English Sample size: 38 RCTs or remission in any language. Trial databases had <100 subjects  Side-effect profile: there is evidence of differing side-effects profiles, especially when comparing gastrointestinal side clinical settings. of drug-approving effects between fluvoxamine and TCAs. Nausea or vomiting and weight loss or anorexia were experienced agencies were hand- Inclusion criteria: significantly more frequently with fluvoxamine than with TCAs and some of other ADs (mianserin, milnacipran and in terms of patients searched for published, RCTs comparing newer ADs). On the contrary, constipation and dry mouth were more common with TCAs than with fluvoxamine. acceptability, there unpublished and ongoing fluvoxamine with all was no difference in controlled trials. Pharma other active ADs in dropouts for any companies were asked to acute phase treatment reason or for side submit studies that meet of major depression in effects between inclusion criteria. patients aged 18 or fluvoxamine and other older. The diagnosis ADs as a class Search strategy: must have been (TCAs, SSRIs, etc.) Diagnosis or Keyword = made based on or individually. Depress* or Dysthymi* or established ‘Adjustment Disorder*’ or operationalised Therefore, the initial ‘Mood Disorder*’ or diagnostic criteria selection of an ‘Affective Disorder’ or such as DSM-IV. antidepressant ‘Affective symptoms’ and medication will and Intervention Exclusion criteria: should largely be or Free-text = depressive patients with based on the fluvoxamine. primary diagnosis of anticipated side effect other Axis I or Axis II profile and patient’s Outcome measures: disorders or a serious preference. Response at the end of concomitant medical acute phase (between 6 Illness; depression with Limitations: Probable and 12 weeks) (< 50% psychotic features and publication bias; reduction of HAMDS or those in which more many studies were MADRS) and tolerability than 20% of the sponsored by (dropouts for any reason participants suffered pharmaceutical and side effects). from bipolar depression; companies; effects Secondary outcome was or fluvoxamine was maybe overestimated; remission (<7 HAMDS). used as an several comparisons augmentation strategy. with small number of Method: subjects were highly - RRs were calculated heterogeneous; error using random-effects in reporting due to model lack of standardized - if significant difference instruments to was detected, NNT was measure side effects;

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations calculated and variability in - heterogeneity was reporting. assessed by I2 and forest plots - ITT analysis was applied; otherwise, LOCF was used - publication bias assessed by funnel plot - sensitivity analyses for sponsorship, wish bias, and excluded trials were conducted - confidence interval was set at 99% and statitistical significance set at p=0.01

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Cipriani et al. Databases: MEDLINE N: 59 RCTs (55 RCTS Results found a trend (2009c) (1966 to 2008), EMBASE and 9303 available for  A total of 59 studies, mostly of low quality, were included in the review, involving multiple treatment comparisons in favor of sertraline (1974 to 2008), the efficacy; 57 RCTs and between sertraline and other antidepressant agents. over other Sertraline versus Cochrane Collaboration 9950 for tolerability) antidepressive agents antidepressive Depression, Anxiety and % F: not reported  Evidence favoring sertraline over some other antidepressants for the acute phase treatment of major depression both in terms of agents for Neurosis Controlled Age: Adults >18 years was found, either in terms of efficacy (fluoxetine) or acceptability/tolerability (amitriptyline, imipramine, paroxetine efficacy and depression Trials Register and the Mean Duration: not and mirtazapine). acceptability, and (review). Cochrane Central reported further suggest that Register of Controlled Sample size: 17  However, some differences favoring newer antidepressants in terms of efficacy (mirtazapine) and acceptability sertraline might be a Cochrane review. Trials up to July 2008. studies included <100 (bupropion) were also found. In terms of individual side effects, sertraline was generally associated with a higher strong candidate as Hand searches also subjects rate of participants experiencing diarrhea. the initial choice of conducted. Trial antidepressant in databases of drug- Inclusion criteria: people with acute approving agencies were RCTs allocating MDD. hand-searched for patients with MDD to published, sertraline versus any Limitations: Overall unpublished and ongoing other antidepressive low quality of included controlled trials. agent; age >18 years. studies, not all pre- specified outcomes Search terms: Exclusion criteria: were reported in CCDANCTR-Studies: Studies using ICD9 to included studies and Diagnosis = Depress* or diagnose depression; outcomes of clear Dysthymi* or “Adjustment participants diagnosed relevance to patients Disorder*” with comorbid physical and clinicians were or “Mood Disorder*” or or mental conditions; not reported in any of “Affective Disorder” or concurrent primary the included studies; “Affective Symptoms” diagnosis of Axis I or II no analysis of and Intervention = disorders. publication bias due Sertraline; CCDANCTR- to insufficient quantity References: Keyword = of studies; only few Depress* or Dysthymi* or studies reported “Adjustment Disorder*” or remission rates – “Mood Disorder*” or underpowered to “Affective Disorder” or detect clinical “Affective Symptoms” and significance; limited Free-Text = Sertraline. head-to-head comparison studies Outcome measures: for individual ADs. Efficacy (the number of patients who responded or remitted), acceptability (the number of patients who failed to complete the study) and tolerability (side-effects).

Method: - meta-analysis using

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations random effects model - Responders and remitters to treatment were calculated on the intention-to-treat (ITT) basis - When there were missing data “last observation carried forward” (LOCF) method was used - heterogeneity was assessed using I2 and forest plots - Funnel plot was used to assess publication bias - sensitivity analyses were also conducted to account for excluded trials, imputation, wish bias, and sponsorship

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Cipriani et al. Databases: MEDLINE, N: 56 RCTs (8507 Treatment response Results found (2008) EMBASE, Cochrane patients available for consistent although Collaboration for examining efficacy;  No significant difference in efficacy was detected between sertraline and TCAs [RR: 0.95 (99% CI: 0.38 – 1.09)] or not statistically Does randomized Depression, Anxiety and 8387 available for other antidepressants, and slightly better than SSRI (refer to Figure 3). significant trend in evidence support Neurosis Register of acceptability) favor of sertraline sertraline as first- Controlled Trials (1966- % F: Not reported  Statistically significant difference in efficacy in favor of sertraline over SSRI [RR=0.88 (99% CI: 0.78- 0.99), p = over other line August 2007). ƒ Duration: 6- 24 wks 0.009; NNT = 17], particularly sertraline over fluoxetine [RR: 0.85 (99% CI: 0.74-0.98); p = 0.004; NNT=12] antidepressants, antidepressant Sample size: 6 studies particularly SSRIs for adults with Search terms: had <100 subjects Acceptability and fluoxetine. acute major Diagnosis= depress* or Sertraline may be a depression? A dysthymic* or adjustment Inclusion criteria:  No significant difference in acceptability was detected between sertraline and TCAs [RR: 0.83 (99% CI: 0.66 – 1.04)], candidate as the systematic review disorder* or mood RCTs comparing SSRI [RR: 0.9 (99% CI: 0.68 – 1.18)], or any other antidepressants (refer to Figure 4). initial choice of and meta- disorder* or affective sertraline with all other antidepressant analysis. disorder or affective active antidepressants treatment for people symptoms, and as monotherapy in High heterogeneity was detected for comparison of sertraline vs. fluvoxamine (I2=53.4 and 57.9%); vs. paroxetine with MDD. intervention (or free text)= acute phase (8-wk tx) tx (I2=64.2 and 59.3%) for efficacy and acceptability; and vs. other antidepressants for acceptability (I2=42.7%) sertraline. English and of depression. non-English-language Participants were both Funnel plots did not suggest evidence of publication bias. Limitations: low articles. sex and > 18 years with generalizability; primary diagnosis of In the conclusions section, the authors site “cardiovascular physicians belief and clinical care practices” in treating most included Outcome measures: MDD. depression in patients with cardiovascular disease” as observational evidence supporting their conclusion of sertraline studies were Treatment response and “as a candidate for initial choice of antidepressant.” funded by the treatment acceptability. Exclusion criteria: maker of - response was defined Quasi-randomized sertraline; high as proportion of patients trials; concurrent heterogeneity in some who had reduction of at medical disorder; subgroup analysis; least 50% from baseline postpartum depression. some demographic scores on HDRS or information on patient MADRS or “much population were not improved” on CGI. available; different -tx acceptability was dosing schedules proportion of patients who make it difficult to left the study by any determine cause during first 8 wks. differences (or lack thereof) Method: between - Responders were equivalent calculated according to effective doses of ITT basis or LOCF ADs; There was Method: substantial - meta-analysis using overlap of studies random effects model in this analysis - Responders calculated and the analysis on ITT basis conducted in - When there were Cipriani et al. missing data “last (2009a) thus observation carried many of the same forward” (LOCF) method limitations (short

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations was used duration of - heterogeneity was included trials, assessed using I2 few trials - Funnel plot was used to conducted in assess publication bias primary care - sensitivity analyses settings) apply; were also conducted to Trials including account for excluded patients with trials, imputation, wish medical disorders bias, and sponsorship were excluded - NNT was calculated from this analysis, when RRs were also limiting statistically significant applicability to the - confidence interval was primary care set at 99% and setting. statitistical significance set at p=0.01

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Van den Broek Databases: PubMed, N: 7 RCTs (N=947) No significant et al. (2009) Cochrane database of % F: not reported  No overall significance treatment effects were detected for response or withdrawal of TCA vs. venlafaxine (refer to difference in Systematic Race not reported tables 2 and 3). treatment effect Efficacy of Reviews, Cochrane Age: not reported between venlafaxine venlafaxine Controlled Trial Register Duration: range 43  There was heterogeneity between studies in the estimates of response. and TCAs was compared with and DARE, and manual days – 8 wks detected and analysis tricyclic searches. If necessary, Sample size: range 50 of tolerability by total antidepressants unpublished data were - 82 treatment dropouts in depressive requested from authors. and dropouts disorder: A meta- because of side analysis. Search strategy: Inclusion criteria: effects did not search terms were Trials were included if suggest poorer ((‘depressive they were double-blind tolerability for Disorder’[TIAB] NOT randomized venlafaxine or TCAs. Medline[SB]) OR studies comparing ‘depressive venlafaxine with a TCA However, because of Disorder’[MeSH Terms] for the treatment of the heterogeneity of OR ‘depression’[MeSH depression. the odds ratios, one Terms] OR cannot conclude that Depression[Text Word]) they are of equal AND efficacy © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 143 National Adult Depression Clincial Practice Guideline

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations (‘venlafaxine’[Substance Name] OR Limitations: Small Venlafaxine[Text Word]) sample size; AND (‘imipramine’[MeSH underpowered; short Terms] OR study duration; imipramine[Text heterogeneous Word]) AND Randomised studies; publication Controlled Trial[ptyp] bias assessment was AND not reported (no ‘humans’[MeSH Terms]. funnel plot); majority Outcome measures: of studies were Response (50% reduction sponsored by in HADRS or MADRS) venlafaxine manufacturer. Method: - analysis was based on ITT method - fixed and random-effect models were used for meta-analysis - heterogeneity was assessed using I2

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Weinmann et al. Databases: Medline, N: 17 RCTs (2 had Remission rates The analysis does not (2008) EMBASE, patients > 65 years; support a clinically PsycINFO, PSYNDEX, N=3523 for response  There was no statistically significant difference between venlafaxine and the SSRI group [random-effect RR: 1.04, significant superiority Re-evaluation of Cochrane Central analysis; N=3142 for (95% CI: 0.96 - 1.13); fixed RR: 1.07 (0.99-1.15); NNT = 34; I2= 18%] of venlafaxine over the efficacy and Register of remission analysis) SSRIs. However, tolerability of Controlled Trials, % F: not reported Response rates higher rate of study venlafaxine vs. Cochrane Database of Race not reported withdrawal due to SSRI: meta- Systematic Reviews, Age: adult >18 years  Venlafaxine was not significantly superior to the SSRI group [random-effect RR: 1.05, (95% CI:1.00–1.10); fixed RR: AEs was associated analysis. DARE and guideline Duration: ranged 6-24 1.06 (1.01-1.12); NNT = 27; I2=32%] with venlafaxine. databases and manual wks (most were 6-8 searches (1966-Mar wks) Tolerability 2007). Sample size: range 68- Limitations: 382  The total rate of treatment discontinuation did not differ between venlafaxine and SSRIs (RR: 1.05, 95% CI=0.93-1.2, inconsistent remission Search strategy: NNH=100). definitions from combination of Inclusion criteria: included studies; text and index terms as a double-blind RCTs in  However, there were significantly more dropouts due to adverse effects in the venlafaxine vs. SSRIs group small number of modification of the search which venlafaxine was [RR=1.38, 95% CI: 1.08 - 1.77, NNH=32] head-to-head strategy compared to comparison studies; of the Cochrane citalopram, underpowered; Depression and Anxiety escitalopram, fluoxetine, Subgroup analyses did not demonstrate clinically significant effect of venlafaxine compared to SSRIs (refer to table 1) possible publication group. fluvoxamine, paroxetine bias; and presence of or sertraline with or some heterogeneity; Outcome measures: without a placebo no Response (50% reduction control; depression was in HAM-D or MADRS) diagnosed according to and remission (HAM-D < ICD, DSM or 7 or MADRS < 10). Research Diagnostic Criteria (RDC); at least Method: 6 weeks of treatment; - analysis was based on used HAM-D or MADRS ITT method; otherwise as outcome parameters LOCF was used - fixed-effect models was Exclusion criteria: used for meta-analysis conference abstracts - heterogeneity was unless full-text assessed using I2 publication could be - sensitivity analyses obtained; Long-term were also preformed on studies >6 months age, type of trial, duration; more than appropriateness of ITT, 20% of participants had treatment setting, dose, a primary diagnosis of and intervention vs. dysthymia or more than control. 15% had a primary - funnel plot was used to diagnosis of bipolar evaluate publication bias disorder; measures based on (CGI) or Patient Global Improvement (PGI)

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Watanabe et al. Databases: Cochrane N: 25 RCTs (N=4842; 9 Efficacy Although mirtazapine (2008) collaboration depression, trials of TCA, 12 of is highly likely to have anxiety and neurosis SSRI, 2 of SNRI, and 2 Early phase (at 2 wks) (refer to Table 2 and Figure 2) better efficacy profile Mirtazapine review group controlled of other) than paraoxetine or versus other trial registers % F: Not reported  Mirtazapine was not superior or inferior to TCAs in terms of response [RR: 0.9 (99% CI: 0.69-1.18)] or venlafaxine in terms antidepressants (CCDANCTR) (- June Age : elderly (>65 remission [RR: 0.87 (99% CI: 0.52-1.47)] of early response, in in the acute- 2,2006). Trial databases years) included in 16 view of similar phase treatment of drug-approving trials; no other info  Mirtazapine was superior to SSRIs in both response [RR: 1.36 (99% CI: 1.13-1.64); NNT=11] and remission efficacy of of adults with agencies were hand- provided [RR: 1.68 (99% CI: 1.2-2.36); NNT=25] mirtazapine and other major searched for published, Median Duration: 6 o In addition, mirtazapine was significantly better than paroxetine in response [RR=2.02 (99% CI: ADs, results suggest depression: unpublished and ongoing wks (range 5-24 wks) 1.09-3.75); NNT=8], but not in remission. that clinicians should systematic review controlled trials. Hand Sample size: range 22 also focus on other o While mirtazapine was significantly better than sertraline in remission [RR=1.73 (99% CI: 1.01- and meta- searches of references. - 412 2.98); NNT=12], but not in response. practically or clinically analysis. Pharma companies were relevant asked for studies that Inclusion criteria: . Mirtazapine was significantly superior to SNRI in terms of response [RR: 1.77 (99% CI: 1.08-2.89); NNT=6] but considerations such meet inclusion criteria. RCTs of mirtazapine for not in remission [RR: 2.21(99% CI: 0.93-5.26)] as differences in the acute-phase tx; > 18 o No significant difference was detected in response and remission between mirtazapine and side effect profiles, to years; diagnosed with trazodone [response RR: 1.11 (99% CI: 0.6-2.04); remission RR: 1.0 (99% CI: 0.29-3.4)] tailor treatment to Search strategy: unipolar MDD based on best fit an individual Search terms: “depress*, DSM-IV or other explicit Sensitivity analysis (included only trials without imputed data) patient’s needs. dysthymic*, adjustment clinical criteria disorder*, mood o Mirtazapine was superior to SSRI I response [N=1789; RR: 1.39 (99% CI: 1.06-1.82); NNT=11)] and Limitations: None of disorder*, affective Exclusion criteria: remission [RR: 1.78 (99% CI: 1.2-2.64); NNT=17]; significantly better than paroxetine in response [N=726; the trials reported disorder, and affective Patients with RR: 2.02 (99% CI: 1.09-3.75); NNT=8]; better than sertraline in remission [N=596; RR: 1.73 (99% CI: 1.01- whether allocation symptoms”; and depression with 2.98); NNT=13] concealment was ‘mirtazapine’ psychotic feature; 20% End of acute phase (at 6 wks) adequately of participants with performed; Outcome measures: bipolar depression; o No statistical significant differences were detected, except for superior remission outcome in comparison of publication bias due Primary outcome was concurrent Axis 1 or II martazapine with paroxetine [RR: 1.34 (99% CI: 1.04-1.73); NNT=10) to pharmaceutical response (> 50% disorders; presence support for included reduction in HAMD-D or serious concomitant o However, significant heterogeneity and publication bias (p=0.01) was observed. studies; heterogeneity MADRS scores); medical illness. End of continuation phase (at 24 wks) in study duration and secondary outcome was dosing that may lead remission (< 8 on HAM- o Only 1 study examined mirtazapine with paroxetine at continuation phase and no significant differences were results to bias toward D) detected (refer to Table 2). mirtazapine; and Tolerability in terms of generalizability due to dropout rates due to any Tolerability (Refer to Table 3) efficacy trials reason or due to AEs o There were no significant differences between patients treated with TCAs (RR: 0.87 (95% CI: 0.7-1.08)], recruiting mainly were also considered. SSRIs (RR: 1.07 (95% CI: 0.92-1.26)], SNRI (venlafaxine) [RR: 0.82 (95% CI: 0.58-1.16)], other AD symptomatic (trazodone) [RR: 0.93 (95% CI: 0.58-1.5)] volunteers. Outcomes were stratified by early phase (at 2 wks o Subgroup analysis showed that patients treated with mirtazapine were more likely than those after tx), conclusion of treated with sertraline to withdraw due to any reason [RR: 1.33 (95% CI: 1.01-1.75); NNH=14] acute-phase (6-12 wks), and conclusion of o In terms of AEs, mirtazapine dropouts due to AEs were similar to SSRI [RR: 1.22 (95% CI: 0.87-1.73)], SNRI continuation-phase (4-6 [RR: 0.59 (95% CI: 0.27-1.29)], and trazodine [RR: 0.66 (95% CI: 0.3-1.46)] months) o Subgroup analysis found mirtazapine had lower withdrawals due to AEs compared with sertraline [RR: 2.58

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Clinical assessments (95% CI: 1.28-5.24); NNH=11] were categorized based on RR = difference of 0.1 as: A (mirtazapine is Assuming that a difference in RR = of more than 0.1 is clinically important difference in efficacy, mirtazapine was clinically better than clinically not worse and probably better than paroxetine, sertraline and velafaxine and was uncertain to be clinically comparator); B (not significantly better or worse than other ADs in efficacy at 2 week during treatment phase. worse and probably better than comparator); After acute-treatment phase, mirtazapine was certainly clinically not worse and probably better than fluoxetine, C (uncertain); D (not paroxetine and venlafaxine; with uncertain inferiority or superiority relative to other ADs (refer to Table 4). better and probably worse); and E (worse than comparator)

Method: - meta-analysis was based on random-effect model - applied ITT analysis; otherwise LOCF were used - Heterogeniety was assessed using I2 - Funnel plot used to examine publication bias - sensitivity analyses were conduced for exclusion trials, imputation method, and sponsorship - p-value was set at <0.01 and CI 99% for statistical significance

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Arroll et al. Databases: The N: 14 RCTs (10 TCAs, Both TCAs and (2009) Cochrane Depression, 2 SSRIs, and 2 included  Both TCAs and SSRIs are significantly more effective than placebo for both discrete and continuous outcomes. SSRIs are effective Anxiety and Neurosis both classes vs. for depression treated Antidepressants Group (CCDAN) placebo)  Evidence is clear for major depression and levels of depression greater than minor depression. in primary care, but versus placebo Controlled Trials Register % F: not reported more adverse effects for depression in was searched, together Age: Adults 18-65  Based on this evidence, tricyclic antidepressants could be considered and the dose kept at or below 100mg per day, can be expected with primary care with a supplementary Duration: 4 – 24 wks and waiting at least 4 weeks for a response may be worth considering. TCAs. (review). search of MEDLINE, Mean sample size: 52 PsycINFO, EMBASE, – 380  There is no dose information on SSRIs and no comment provided on the appropriate duration of treatment for either Cochrane review. LILACS, CINAHL and TCAs or SSRIs. PSYNDEX (Sept 2007). Inclusion criteria: TCAs Limitations: Most of Authors of selected RCTs TCAs or SSRIs the studies were studies were asked if they versus placebo in adults  RR= 1.24 (95% CI: 1.11-1.38) and NNT= 7 to 16 (median NNT 9) (patient expected event rate ranged from supported by funds knew of additional (>18 years); patients 63% to 26% respectively) from pharmaceutical published or unpublished had to be recruited from companies and were studies. a primary care setting. SSRIs of short duration; For continuous publication bias were Search terms: outcomes the HAM-D,  RR = 1.28 (95% CI: 1.15 - 1.43) for SSRIs and NNT= 7 to 8 {median NNT 7) (patient expected event rate noted in funnel plot; Not specified. MADRS was required. ranged from 48% to 42% respectively). some studies had small sample size; Outcome measures: Exclusion criteria: An NNT of 7 means that one patient will benefit from treatment and six will not although up to half may get better on heterogeneity in The primary outcome was Older Patients (>65 placebo. intervention duration depression years); participants Adverse events and treatment reduction, and on a diagnosed with strategies. continuous measure of comorbid physical or  There appeared to be more adverse effects with TCAs than with SSRIs, however rates of withdrawal from depression symptoms mental conditions. study medication due to adverse effects were very similar between the two antidepressant classes.

Method:  Adverse effects not leading to medication cessation seemed to be more common with TCAs than SSRIs. - meta-analysis was based on random-effect  NNH for withdrawal due to side effects ranged from 4 to 30 for TCAs (excluding three studies with no harmful model when I2>50% events leading to withdrawal) and 20 to 90 for SSRIs. - applied ITT analysis; otherwise, missing data were approximated - Heterogeniety was assessed using I2 - Funnel plot used to examine publication bias - sensitivity analyses were conduced for exclusion trials, imputation method, and sponsorship - p-value was set at <0.01 and CI 99% for statistical significance

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Hansen et al. Databases: MEDLINE, N: 27 RCTs (4 head-to- Trials shorter than one year: relapse prevention This review confirms (2008) EMBASE, the Cochrane head and 23 placebo- the benefits of Library, controlled trials)  Pooled RR = of relapse was .54 (95% CI=.46–.62), and the NNT to prevent one additional relapse over a continuation- and Meta-analysis of PsycINFO, International % F: not reported mean time of 8 months was 5 (CI=4–6). Heterogeneity among these trials was moderate (I2=47%). maintenance-phase major depressive Pharmaceutical Mean Age : 40-50 treatment of major disorder relapse Abstracts, Center for Duration: 6-110 wks Trials one year or longer: recurrence prevention depression with and recurrence Drug Evaluation and Range sample size: 23 second-generation with second- Research, FDA, and -932  Pooled RR = of recurrence was .56 (CI=.48–.66) and the NNT to prevent one additional recurrence over a antidepressants. generation manual searches mean time of 16 months was 5 (CI=4–6). Heterogeneity among these trials was moderate (I2=30%). antidepressants. (January 1980 – April Inclusion criteria: Limitations: limited 2007). CDER database head-to-head trials Adverse Events quality and quantity of was also searched for comparing one head-to-head unpublished research antidepressant with  RR = of dropping out for any reason was statistically significantly lower for active treatment than for placebo comparison studies submitted to FDA. another and placebo- (relative risk=.75, CI= .69–.83). and studies that controlled trials; adult addressed clinical Search strategy: (>18 years); depressive  Loss to follow-up because of adverse events was not statistically significantly different between active question; low Not specified. illness patients that treatment and placebo (relative risk= 1.42, CI=.92–2.20). generalizability; demonstrated response residual publication Outcome measures: to treatment or bias - most studies Loss of response or remission; reported were sponsored by remission (continuation- relapse or recurrence pharmaceuticals; phase relapse or rates, regardless of unclear demographic maintenance-phase whether characteristics of recurrence), defined as participants were included patients; increased in HAM-D or randomly assigned some heterogeneity MADRS scores above to treatment groups among studies; predefined cut-off point after successful variations in dosage (set by study). acute-phase or and treatment continuation-phase duration. Method: treatment (that is, - meta-analysis was extension versus based on random-effect randomized substitution model trials). - applied ITT analysis; otherwise LOCF were For placebo-controlled used evidence; only studies - Heterogeniety was that assessed using I2 randomly assigned - Funnel plot used to participants after examine publication bias demonstrating either an acute-phase response or lack of relapse during the continuation phase were included.

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Nelson et al. Databases: MEDLINE, N:10 RCTs (N=2377 Efficacy Second-generation (2008) EMBASE, Cochrane patients) Ads are more (1966 – August 2006). % F: mean ranged 46 –  Those assigned to drug treatment had significantly greater response [OR: 1.4 (95% CI: 1.24-1.57)] and remission effective than placebo Efficacy of Meeting abstracts from 76% [OR: 1.27 (95% CI: 1.12-1.44)] than placebo (refer to figure 2 and 4) during acute second geriatric psychiatric and Age : mean age ranged treatment of adults generation psychiatric professional 68 – 80 years  Response rates were also higher in the longer trials [10-12 weeks OR: 1.73 (95% CI: 1.42-2.09)] compared to shorter >60 years in terms of antidepressants society meeting and hand Duration: 6-12 wks trials [6-8 weeks OR: 1.22 (95% CI: 1.05-1.42)] response and in late-life searches were also sample size: 84 – 368 remission, but the depression: A conduced.  NNT for response =13 and remission = 20 magnitude is small meta-analysis of Inclusion criteria: and variable. the evidence. Search strategy: Acute phase, parallel  No single class of medication was superior to another as evidenced in the overlapping ORs Search terms: group, double-blinded, For every 100 antidepressants, placebo-controlled trial Tolerability patients treated, 8 fluoxetine, sertraline, of 2nd-gen AD (non- would show a paroxetine, citalopram, TCAs) marketed in US;  There was an increased in odds for discontinuation on medication [OR: 1.22 (95% CI: 1.06-1.4); I2=48.2%], response and 5 a escitalopram, patients had increased discontinuation due to AEs on medication [OR: 1.84 (95% CI: 1.51-2.24); I2=61.1%] (refer to figure 3) remission in excess of venlafaxine, duloxetine, nonpsychotic, unipolar placebo and for every mirtazapine, bupropion, MDD not associated 2 patients who nefazodone, and with other medical Funnel plot did not illustrate presence of publication bias. responded, one trazodone disorder; patients in discontinued community dwelling and prematurely because Outcome measures: aged 60+ years; of AEs. Response (>50% number of patients, improvement from outcomes and dropouts Therefore, clinical baseline on HAMD or obtainable. Trials can decision to employ MADRS); and remission include unpublished Ads will need to (as defined by individual reports or poster. weigh modest studies). benefits with more robust effects on Method: prevention of relapse - meta-analysis was or recurrence and based on fixed-effect potential AEs. In model addition, duration of - Heterogeniety was treatment appeared to assessed using I2 response as well. - Funnel plot used to examine publication bias Limitations: Possible - p-value was set at <0.20 patient selection bias; and CI 95% for statistical high heterogeneity; significance low generalizability; small number of trials included; underpowered; all trials were sponsored by manufacturer of one of the drugs; and possible residual confounding.

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Deshauer et al. Databases: MEDLINE, N: 6 RCTs (1299 Treatment response Statistically significant (2008) EMBASE, Cochrane patients) improvements in Central Register % F: Not reported  Pooled analysis of the 6 trials showed that selective serotonin reuptake inhibitors were superior to placebo in response to treatment Selective of Controlled Trials Duration: 6-8 months treatment response at 6–8 months [OR: 1.66 (95% CI: 1.12–2.48); I2 = 63.9%] but not in remission or serotonin (1966- May 2007). Mean sample size: 217 acceptability after 6–8 reuptake  Subgroup analysis showed a statistically significant treatment effect among patients with depression who had no months of SSRI inhibitors for Search terms: Inclusion criteria: comorbidities [OR: 2.13 (95% CI 1.11–4.08); I2 = 76.8%] but not among those who had comorbidities [OR: 1.32 (95% therapy were unipolar index terms associated Trials had to involve CI 0.84–2.06); I2 = 30.8%] observed with greater depression: a with “serotonin uptake patients who had a effects in patients systematic review inhibitors” and the text diagnosis of major Remission without comorbidities. of classic long- terms “SSRI,” depression (by DSM- term randomized “fluoxetine,” “Prozac,” MD), aged >18 years,  Pooled difference between SSRIs and placebo was not statistically significant [OR: 1.46 (95% CI 0.92–2.32); I2 = Limitations: controlled trials. “sertraline,” “Zoloft,” and who were randomly 38%]. Small number of “paroxetine,” assigned to receive studies identified; “Paxil,” “fluvoxamine,” monotherapy with a  However, participants without comorbidities had a significantly higher remission rate if they were taking SSRIs than if underpowered; weak “Luvox,” “citalopram” and SSRI or placebo; Trials they were taking placebo [OR: 2.06 (95% CI 1.41–3.01); I2 = 0%) while whereas the difference for participants with studies due to unclear “Celexa”. reporting a 1- to 2-week comorbidities was not statistically significant [OR: 0.87 (95% CI: 0.44–1.72); I2 = 0%] description of placebo run-in period methodological were eligible; there issues, short follow-

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Outcome measures: were no comorbidity Treatment acceptability up, outcomes Treatment response, restrictions. reported as “response remission, and treatment  No statistically significant difference between SSRIs and placebo [OR: 0.87 (95% CI: 0.67–1.14); I2 =21.3%] to treatment” instead acceptability. Definition of long-term of “full remission” with - response was defined treatment was treatment Secondary outcomes preset cut-offs, trials as proportion of patients over a period of at least could have who had reduction of at 6 months.  None of the trials provided information on back-to-work status or the need for specific rescue therapies, overestimated active least 50% from baseline including admission to hospital for psychiatric reasons, psychotherapy, pharmacotherapy or electroconvulsive long-term scores on HDRS Trials were limited to therapy interventions by using - remission was defined those published in last-observation by cut-point (score of <7 English.  5 studies reported quality of life at the end of the trial carried forward on HDRS) analysis, and possible -tx acceptability was total  One of the 5 trials reported improvements in all domains of a multi-domain quality-of-life score; one publication bias (4 of number of drop-outs. reported a quality-of-life summary statistic favoring SSRIs (p < 0.01); the 3rd reported 10-cm visual 6 studies were secondary outcomes: analogue scale also favoring SSRIs; and one reported quality-of-life improvements restricted to mood commercially quality of life; admission subscales. sponsored). to hospital; psychotherapy;  2 trials that reported on suicide or self-harm, there was a total of 1 completed suicide among patients receiving pharmacotherapy or placebo and none among patients receiving SSRI electroconvulsive therapy; self-harm (including attempted and completed suicide); and back-to- work status.

Method: - meta-analysis of RR = was based on random- effect model - Funnel plot was used to assess publication bias - Heterogeniety was assessed using I2 Barbui et al. Databases: Cochrane N: 40 RCTs (6391 Dropouts paroxetine was not (2008) collaboration depression, patients; 3704 received superior to placebo in anxiety and neurosis paroxetine vs. 2687  No positive effect of paroxetine in terms of the proportion of patients who discontinued treatment for any reason terms of tolerability Effectiveness of review group controlled placebo) [random effect RR = 0.99, 99% CI 0.88–1.11)] (participants paraoxetine in trial registers, % F: Not reported discontinuing the treatment of GlaxoSmithKline Clinical Mean duration: not Efficacy treatment for any acute major Trial Register, MEDLINE, reported reason) and was depression in EMBASE (1966 - Mean sample size: not  Greater proportion of patients who received paroxetine had a statistical significant improvement of 50% or more modestly better than adults: a 12/2006) were searched reported compared to placebo [random effect RR = 0.83 (99% CI 0.77–0.90)]; no statistically significant between-study placebo in terms of systematic re- for published and heterogeneity (I2 = 9.2%). depression measures examination of unpublished trials. 63% trials were done in (paroxetine exerted a published and Europe and North  A statistically significant positive effect of paroxetine in terms of mean difference [standardized mean difference – modest unpublished data Search terms: America. 0.31 (99% CI: –0.40 to –0.22)]; there was no statistically significant between study heterogeneity (I2 = 31.5%). antidepressant effect from randomized Keyword = “major 53 studies included relative to placebo, © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 164 National Adult Depression Clincial Practice Guideline

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations trials. depression” or people <65 years. 11% absolute risk “depression” and free-text  Number needed to treat (NNT) to avoid 1 additional failure = 9 (99% CI: 7–14) difference). =“paroxetin*”; Inclusion criteria: only Tolerability “randomized controlled RCTs hat compared Limitations: trial” or “random any of the following 12  Significantly more patients assigned to receive paroxetine left the study because of side effects [random effect RR = Studies were not allocation” or “double- new-generation 1.77 (95% CI: 1.44–2.18)]; there was no statistically significant between-study heterogeneity (I2 = 2.0%). designed or powered blind method.” antidepressants to measure primary (bupropion, citalopram,  Number needed to harm (NNH) = 17 (95% CI: 14–25); outcome; non- Outcome measures: duloxetine, adherence; absolute Treatment discontinuation escitalopram, fluoxetine,  Significantly more patients assigned to receive paroxetine than of those given placebo reported any adverse event numbers of patients was the primary outcome fluvoxamine, [random effect RR = 1.15 (95% CI: 1.11–1.19)]; there was no statistically significant between-study heterogeneity (I2 with suicidal and response was milnacipran, = 17.6%). tendencies were low secondary outcome. mirtazapine, and definition was - response was defined paroxetine, reboxetine,  NNH = 9 (95% CI: 7–11) (Figure 5). problematic; unclear as reduction of <50% sertraline, and whether suicidal from baseline scores on venlafaxine) as  No statistically significant difference between paroxetine vs. placebo in terms of patients reporting any serious tendencies are good HDRS, MADRS, or who monotherapy in acute- adverse event (Peto OR = 1.27, 95% CI 0.88–1.83); no between-study heterogeneity detected (I2 = 0%). proxy for suicide scored much improved on phase tx of adults with attempts. CGI. unipolar major Suicidal tendencies - tx discontinuation depression. (tolerability) was  Significantly more patients assigned to paroxetine experienced suicidal tendencies than of those given placebo (US proportion of patients who Exclusion criteria: Food and Drug Administration codes 1 to 9) [Peto OR = 2.55 (95% CI: 1.17–5.54)]; no significant between-study left the study early for any placebo heterogeneity detected (I2 = 0%). reason, because of side groups present and effects; with any adverse RCTs of women with  NNH=142 (95% CI: 7–3333) events; with any serious post-partum depression adverse events; patients who completed or No statistical significances were detected between trials using 20-mg dose vs. >20-mg dose; among patients with attempted suicide or moderate to severe depression vs. mild depression; and published vs. unpublished studies. experienced worsening of suicidal thoughts or Funnel plot suggests possible publication bias. emotional liability.

Method: - meta-analysis of RR = was based on random- effect model - Heterogeniety was assessed using I2 - sensitivity analysis was conducted to evaluate fixed-effect model - p-value was et at 0.01 for statistical significance

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations Barbui et al. Databases: MEDLINE, N: 8 RCTs (>200,000 Relation between (2009) EMBASE, (January 1990 patients)  metaregression suggested a promoting effect of SSRI exposure on the risk of suicide among adolescents and a exposure to SSRIs to June 2008). % F: 8 – 74% protective effect among adults and elderly individuals and the risk of suicide Selective Age : 10+ is influenced by age,  Among adolescents, exposure to SSRIs significantly increased the risk of completed or attempted suicide serotonin Search strategy: Duration: not reported 2 and prescribing reuptake Search terms: Mean sample size: not [random effect OR: 1.92 (95% CI 1.51–2.44); I =0.0%] SSRIs to patients with inhibitors and risk “antidepressive agents” reported major depression is  Among adults, SSRI exposure significantly decreased the risk of completed or attempted suicide [random-effect of suicide: a or “antidepressive agents 2 safe. systematic review second generation” AND Inclusion criteria: OR: 0.57 (95% CI 0.47–0.70); I =52.5%] However, children of observational “suicide” observational cohort and adolescents  Among elderly people (aged 65 or more years), exposure to SSRIs had a significant protective effect [random- studies. or “suicide attempted” and case–control 2 should be followed studies that reported effect OR: 0.46 (95% CI 0.27–0.79) I =0.0%] very closely because Outcome measures: data on completed or of the possibility of ICD 9-10 definitions of attempted suicide  visual inspection of the funnel plot suggested possible selection bias (lack of small studies that failed to show an increased of risk completed or attempted among people exposed excess risk associated with SSRI exposure) suicidal thoughts and suicide. Suicide attempts to SSRIs and among Subgroup analysis suicide. Paroxetine had to be sufficiently those who were not and venlafaxine may serious to have led to exposed to  Among adults, no individual antidepressant was significantly associated with completed or attempted suicide. be better avoided for medical contact. antidepressants; studies most adolescents. that reported relative  Among adolescents, exposure to paroxetine [random-effect OR: 1.77 (95% CI 1.05–2.99); I2=48.1%] and venlafaxine Method: risk [RR] estimates Limitations: [random-effect OR: 2.43 (95% CI 1.47–4.02); I2=0.0%) was significantly associated with increased risk - meta-analysis of RR = suitable for re-analysis; Confounding and was based on rfixed and only biases inherent to andom-effect models studies that used ICD 9- observational studies - publication bias was 10 definitions of included; confounding evaluated by funnel plot completed or attempted by severity of illness, - Heterogeniety was suicide were retained. gender, age; assessed using I2 presence of - sensitivity analyses and Study participants were publication bias; small metaregression were of both sexes and any sample of studies used to examine study age with a diagnosis of included; using completed suicide; major depression. underpowered to formal diagnosis of Studies adopting proxy detect small depression, external measures to identify differences between control group; quality patients with depression drugs – lack of long- score >7, data for both were included. term head-to-head adolescents and adults; comparison studies. age; and outlier studies. Patients may have had additional comorbidities that may have influenced selection of treatment and have unaccounted for effects on suicide risk. 

Author & Search Database Study (N) Conclusions/ Title / Method Characteristics Results Limitations

Table 1.2 Intervention and Inclusion & Limitations / dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value Proudfoot, et al. Inclusion: 18-75 Outcomes measured Participants randomized 8 weeks Primary outcome Received pharmacotherapy: (2004) Clinical 274 general practice by self-report. into: measure was BDI-II Rx1: 55.5% efficacy of patients, suffering from score at eight weeks. Rx2: 55.5% (p not reported) computerised depression, mixed Patients not masked Rx1: Computerised CBT Secondary outcome cognitive- anxiety and depression, to treatment. "Beating the Blues" (N = measures were Beck behavioural or anxiety disorder 146): 15-minute Anxiety Inventory, At eight week post-randomization, therapy for (assessment by GHQ-12 No selective introductory video Work and Social computerised CBT group had significant anxiety and and CIS-R) attention control. followed by eight 50- Adjustment scale, ASQ improvement over Usual Treatment group in: depression in minute therapy sessions. CoNeg, ASQ CoPos. BDI (p=.0006) 0.0006 primary care: Exclusion: Data analyzers not These participants could Work and Social Adjustment (p=0.002) 0.002 randomised Concurrent blinded to treatment. also receive medication if ASQ, CoNeg (p<0.0001) <0.0001 controlled trial. psychological treatment the general practitioner ASQ, CoPos (p<0.008) <0.008 or counseling. Some data missing. chose to prescribe it, but Funding: not in person Change in BDI scores NHS Executive Authors have psychotherapy. 3 mos. 5 mos. 8 mos. London and commercial interests Rx1 -12.8 -15.3 -15.6 Ultrasis UK Ltd. in the specific Rx2: Usual Treatment (N Rx2 -6.3 -8.3 -9.8 computerized = 128): Received programs. whatever therapy general There was no significant difference found practitioner prescribed. between groups on the BDI (p=0.06). 0.06 Unclear how many patients in usual There was no interaction effect found for care who did not pharmacotherapy or duration of illness, or receive severity of illness. pharmacotherapy received BDI scores continued to decline over time (at psychotherapy – if 3, 5, and 8 month follow-up points), with lower many of these scores in the computerized CBT group. patients went untreated, it would 35% withdrawal rate in the intervention group. bias results in favor of the intervention group.

Table 1.3 Intervention and Inclusion & Limitations / dose – N and Final p Study Exclusion Criteria Age Biases N Duration Outcome Results NNT value de Jonghe (2004) Inclusion: 18-65 Different instruments Rx1: Primary outcome Both treatment groups improved over time on Psychotherapy Outpatient adults with produced varying Psychotherapy alone (N measure was several measures (per protocol effect sizes alone and DSM-IV criteria for Major success rates. = 107) using Short difference in HAM-D were minimal - moderate, 0.26-0.49, combined with Depressive Disorder Psychodynamic score assessments depending on the measure used, with the pharmacotherapy (with or w/out Patients and treating Supportive between baseline and lowest effect size on the primary measure). in the treatment dysthymia), and baseline physicians not blinded Psychotherapy (SPSP). week 24. Secondary No significant difference between groups on of depression HAM-D score of 12-24 to treatment. One refused measures were scores any measure in the Intention-to-treat sample. points (mild to moderate intervention, therefore N on CGI-I, CGI-S, and Funding: depression). Complex protocol = 106. SCL-D between No significant differences in time to remission Supported by an may not be baseline and week 24. between the combined (129 days) and unrestricted grant Exclusion: generalizable to the Rx2: psychotherapy (138 days) groups (p=0.122) from Wyeth Standard clinical real world. Combined SPSP and No statistically significant differences in Nederland. pharmacotherapy pharmacotherapy (N = dropouts between the two groups. research exclusion More patients in the 101). Antidepressant Small but statistically significant differences in criteria. psychotherapy only program was stepped HAM-D score at week 12 (1.8 points, p=0.046) arm were previously (noradrenaline, SSRI, in the per protocol group and at weeks 12 and unresponsive to nortriptyline, and 24 (approximately 2.5 points, p=0.009 and psychotherapy (26% nortriptyline with lithium) p=0.046) in the observed cases (completers) vs. 14%, biasing to address nonresponse. sample. No difference in HAM-D remission study in favor of Sixteen patients refused rates in the per protocol sample, significant combined treatment. intervention, therefore N difference in the observed cases sample at = 85. week 12 only (ARR = 6.2%, NNT 16, p=0.043). LOCF data analysis. Variable improvement in different secondary

measures at different times in the secondary Multiple measures; outcome measures in both the per protocol and Bonferroni adjustment observed cases samples. to significance level.

In both the Per Protocol and Observed Cases analyses, there were some small but statistically significant intra-group differences between baseline and week 24, in favor of combined therapy: Per Protocol: CGI-I (p<0.05) < 0.05 Per Protocol SCL-D (p<0.001) < 0.001

Observed Cases: HAM-D (p<0.046) < 0.046 Observed Cases SCL-D (p<0.001) < 0.001

Table 1.4 Intervention and Inclusion & Limitations / dose – N and Final p Study Exclusion Criteria Age Biases N Duration Outcome Results NNT value

Moore, et al. Inclusion: 18-65 No placebo control Patients randomly 8 weeks Primary outcome Decrease in MADRS score <0.05 (2005) Adult outpatients with assigned to: measure was change Rx1: -22.4 ± 12.9 Prospective, DSM-IV criteria for Major Statistical from baseline to Rx2: -20.3 ± 12.7 multicentre, Depressive Disorder, significance found Rx1: Escitalopram – 10 previous assessment randomized, baseline MADRS score may not translate mg daily during first in MADRS total score. 1.5 point difference in mean endpoint MADRS double-blind of at least 30. into clinical week; 20 mg daily for scores (Rx1 = 13/9, Rx2 = 15.4); calculation not study of the relevance. (2.1 remaining 7 weeks, (ITT reported by authors efficacy of Exclusion point difference in N = 138, Completer N = escitalopram Axis I disorders other MADRS scores of 132) versus citalopram than MDD; history of marginal clinical Responder rate (50% decrease from initial 7 0.008 in outpatient mania, bipolar disorder, significance). Rx2: Citalopram 40 mg MADRS score) treatment of schizophrenia or other daily for 8 weeks, (ITT N Rx1: 76.1% Major Depressive psychotic disorder, Industry funded. = 142, Completer N = Rx2: 61.3% Disorder. obsessive-compulsive 127) disorder, cognitive Remission rate 9 0.04 Funding: disorder including mental Rx1: 56.1% Provided by H. retardation or personality Rx2: 43.6% Lundbeck A/S disorder; substance through an abuse or use of Tolerability/adverse events 0.70 unrestricted antipsychotic, anxiolytic Rx1: 14.8% grant. or anticonvulsant Rx2: 16.4% medications prior to study.

Table 1.5 Intervention and Inclusion & Limitations / dose – N and Final p Study Exclusion Criteria Age Biases N Duration Outcome Results NNT value DuRubeis, et al. Inclusion: 18-70 Placebo control ended Patients randomly 16 weeks Primary outcome Outcome at 8 weeks (2005) Cognitive Diagnosis of MDD at 8 weeks. assigned to: measure was change in Response rate 0.006 therapy vs. according to DSM-IV HDRS score at 16 Rx1: 50% medications in criteria, English Unequal number of Rx1: Antidepressant weeks. Rx2: 43% the treatment of speaking, score of 20 or subjects in treatment medication, N = 120*, for Rx3: 25% moderate to higher on modified 17- groups. 16 weeks. severe item HDRS at screen Rx1 vs. Rx3 0.001 depression and baseline visits, Study conducted at Rx2: Cognitive therapy, separated by at least 7 two different sites: N = 60, for 16 weeks. Rx2 vs. Rx3 0.04 Funding: days. University of Supported by Pennsylvania and Rx3: Pill placebo, N = Rx1 vs. Rx2 0.40 grants from the Exclusion: Vanderbilt University. 60, for 8 weeks** National Institutes History of bipolar Outcome at 16 weeks of Mental Health. disorder, substance Response rate 0.92 GlaxoSmithKline abuse/dependence, Rx1: 58% (Brentford, current or past *Rx1 had twice as many Rx2: 58% Middlesex, United psychosis, another Axis I patients because Kingdom) DSM-IV disorder; responders to Rx1 at Remission rate 0.04 provided antisocial, borderline or week 16 were to be Rx1: 46% medications and schizotypal disorder; randomized a second Rx2: 40% pill placebos for suicide risk requiring time for a companion the trial. hospitalization; medical study of subsequent Site X Treatment Interaction 0.02 condition contraindicative relapse prevention. (greater change in Rx1 at Vanderbilt) to study medications, Authors attribute this difference to variance in nonresponse to **For ethical reasons, pill patient characteristics and therapists’ adequate trial of placebo was experience levels. paroxetine in year discontinued after 8 preceding. weeks; patients in this group were offered treatment without cost after 8 weeks.

Table 1.6 Intervention and Inclusion & Limitations / dose – N and Final p Study Exclusion Criteria Age Biases N Duration Outcome Results NNT value Otsubo, et al. Inclusion: 20-69 No placebo control. Patients randomly 8 weeks Primary outcome Intention-to-Treat Analysis NS (2005) A DSM-IV criteria for single assigned to one of two measures were No significant between-group difference for the comparative episode or recurrent Single blind study treatment groups (single- changes from baseline change in total scores of HAM-D (p = 0.14 NS) study of the Major Depression; either design. blind, parallel treatment): in the scores of HAM-D efficacy and “depressed mood” or and CGI. Rx1 Rx2 safety profiles “work & interests” score Dose level of Rx1: fluvoxamine, N = Baseline 21 23 between of 2 or more in HAM-D. fluvoxamine generally 36 Endpoint 12 11 fluvoxamine and lower than that of nortriptyline in Exclusion: previous studies. Rx2: nortriptyline, N = 38 No significant between-group difference for the Japanese Failure to respond to two change in total scores of CGI severity (p = 0.55 patients with or more prior Small sample size. For both treatment NS). Figures not reported. Major Depression antidepressant trials in groups: current episode; medical There was a 7 day drug- Response rate (HAM-D score reduction of 50% NS Funding: contraindications to free washout period. or more) Supported in part antidepressant therapy; Starting daily dose for Rx1: 55.6% by grants from significant hematologic, first week was 50 Rx2: 57.9% the Ministry of endocrine, or mg/day. Thereafter, Health, Labour, cardiovascular disease dose was flexible Response rate (CGI improvement scale scores NS and Welfare in conditions; acute suicidal between 25-150 mg of 1 or 2) Japan. tendencies, seizure taken 1-3 times per day. Rx1: 52.8% disorder, psychotic Patients were allowed to Rx2: 44.7% disorder not associated take lormetazepam 1-2 with depression, history mg a day at bedtime for Remission rate (HAM-D score of 7 or less) NS of drug or alcohol sleep if necessary. Rx1: 38.9% dependence; experience Rx2: 26.3% or receiving fluvoxamine or nortriptaline treatment. When compared with fluvoxamine, nortriptaline had more patients reporting adverse effects, specifically dysarthria (13.9% vs. 36.8%, p=0.02) and orthostatic dizziness (13.9% vs. 42.1%, p=0.01).

Table 1.7

Inclusion & Ag Intervention and dose Duratio p Study Exclusion Criteria e Limitations / Biases N and Final N n Outcome Results NNT value

Wehmeier, et Inclusion: 61-85 Study took place in two After a 7 day washout period, 5 weeks Primary outcome Change in HAM-D scores al.(2005) Geriatric patients with centers. One center enrolled patients were randomly measure was sum Fluoxetine Trimipramine Fluoxetine versus diagnosis of Major only inpatients while the other assigned to one of two score on HAMD-17. baseline 28.1 27.9 >0.05 trimipramine in Depression per DSM-III- center enrolled both inpatients treatment groups: endpoint 16.2 12.1 >0.05 the treatment of R criteria; score of ≥ 16 and outpatients. response 57.1% 60.0% >0.05 depression in on HAMD-17. Rx1: Fluoxetine 20 mg/day, N geriatric patients Small sample size – risk of = 20, final N = 15 Tolerability/adverse events Exclusion: type II error. Rx1: 54.5% Funding: Reduction of HAM-D Rx2: Trimipramine 150 Rx2: 66.7% Supported by Lilly total score of more than Low number of male patients mg/day, N = 21, final N = 18 Deutschland, Bad 25% between screening (2 total in study vs. 39 Homburg, visit and baseline visit; females). Germany serious suicidal risk; severe organic brain Findings can only be disorder, significant generalized to elderly patients. organic illness, history of seizures; history of Short duration. schizophrenia; recent history of drug or alcohol No placebo control. abuse.

Table 1.8

Inclusion & Ag Intervention and dose Duratio p Study Exclusion Criteria e Limitations / Biases N and Final N n Outcome Results NNT value

Sirey, Bruce, and Inclusion: 65-85 Patients were from Psychiatry Participants were randomly 24 weeks Primary outcome Intervention group showed greater 0.005 Alexopoulous Outpatient geriatric only, and not Primary Care. assigned to one of two measure was HAM-D improvement in depression than (2005) The psychiatry patients with groups: assessment at nonintervention group. No figures Treatment diagnosis of DSM-IV At baseline, the intervention admission and at 6, reported. Initiation Major Depressive group had a significantly lower Rx1: Pharmacotherapy as 12, and 24 weeks. Program: An Disorder; score of ≥ 17 HAMD score than the usual, N = 24 Remission rate 0.04 intervention to on HAMD-24. nonintervention group (mean Rx1: 42% improve 23.1 vs. mean 26.4, p<0.05), Rx2: Pharmacotherapy Rx2: 71% depression Exclusion: suggesting poor with Treatment Initiation outcomes in older Cognitive impairment, randomization. Lower Program (TIP)*intervention, At 12 and 24 weeks after seeking 0.05, adults existing antidepressant pretreatment scores in the N = 21 treatment, more intervention patients 0.04 therapy. intervention group might bias remained in treatment than Funding: remission results in favor of *TIP is an individualized, nonintervention patients (post hoc Supported by a the intervention group, when early intervention to analysis; no figures reported) grant from the in fact both groups could have address older adults’ National Alliance equal changes in HAMD attitudes about depression “Similar proportions of patients in each for Research in scores. and barriers to care. 7 group received supportive Schizophrenia sessions administered over psychotherapy” (numbers not and Affective No information given on type 24 weeks. reported). Disorders and a of pharmacotherapy (i.e. grant from NIMH antidepressant dose, type, to Dr. Sirey. and frequency)

Results only generalizable to elderly population.

Small study sample.

Lower than usual threshold used to define remission (HAMD <10 instead of <7).

Table 1.9 Intervention and Inclusion & dose p Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results value

Detke, et al. Inclusion: 18+ Lack of generalizability: Participants were 8 weeks (acute Primary outcome measures Acute phase (2004) Adult patients with patients had few to no randomized into one of phase) were HAMD total score, HAMD score reduction: Duloxetine in the DSM-IV Major comorbid conditions and, the following (double- HAMD subscales, MADRS, Rx1: -8.8 Rx1 vs. Rx2 0.001 acute and long- Depressive Disorder; few were taking blind) groups for 8 weeks: 6 months HAMA, VAS, CGI-S, and Rx2 -11.0 Rx1 vs. Rx3 <0.001 term treatment of CGI-S ≥ 4, HAMD-17 ≥ concomitant medications. (continuation PGI-I. Rx3: -12.1 Rx1 vs. Rx4 <0.001 Major Depressive 15. Rx1: Placebo, N = 93 phase) Rx4 -11.7 Disorder: a Fixed dose design is not placebo- and Exclusion: customary in clinical Rx2: Duloxetine 80 Estimated probabilities of response (%) paroxetine- Other Axis I disorders; practice. mg/day, N = 95 Rx1: 47 Rx1 vs. Rx2 controlled trial. recent primary Rx2 70 Rx1 vs. Rx3 0.005 diagnosis of anxiety No comparison of Rx3: duloxetine 120 Rx3: 77 Rx1 vs. Rx4 <0.001 Funding: disorder; bipolar duloxetine and paroxetine. mg/day, N = 93 Rx4 82 <0.001 Funding not disorder, psychosis, or reported; schizoaffective Secondary analyses likely Rx4: paroxetine, 20 Estimated probabilities of remission (%) however all disorder; recent history to be underpowered. mg/day, N = 86 Rx1: 30 Rx1 vs. Rx2 authors employed of substance abuse or Rx2 51 Rx1 vs. Rx3 by Eli Lilly and dependence; previous Industry funded Patients who showed a ≥ Rx3: 58 Rx1 vs. Rx4 < 0.01 Co. of response to two 30% HAMD improvement Rx4 47 ≤ 0.001 courses of Duloxetine used at higher at 8 weeks (N = 273) ≤ 0.05 antidepressant therapy, doses than currently entered the 6 month Continuation phase suicidal risk; serious recommended by the continuation phase: Patients in each active treatment group medical illness. manufacturer; probably not (Rx2, Rx3, Rx4) achieved significant equivalent to paroxetine Rx1: Placebo, N = 58 within-group improvement in total dose. HAMD, MADRS, HAMA, CGI-S, and Rx2: Duloxetine 80 PGI-I. mg/day, N = 70 Time to loss of response Rx3: duloxetine 120 Rx1 vs. Rx2 mg/day, N = 75 Rx1 vs. Rx3 Rx1 vs. Rx4 0.003 Rx4: paroxetine, 20 0.023 mg/day, N = 70 Frequently reported treatment-emergent 0.003 adverse events: Rx2: viral infection (5.7%) Rx3: diarrhea (4.0%) Rx4: headache (11.4%)

Table 1.10 Intervention and Inclusion & Ag Limitations / dose – N and Final Duratio p Study Exclusion Criteria e Biases N n Outcome Results NNT value

Sechter, et al. Inclusion: 18-70 No placebo control. Patients were 6 weeks Outcome measures No significant differences between Rx1 and (2004) A Adult outpatients with randomized into one of were differences in Rx2 on any of the following measures: comparative DSM-IV Major Industry funded the following groups: baseline in: HAMD-17 study of Depressive Disorder (milnacipran). total score, MADRS HAMD-17 total NS milnacipran and without psychotic Rx1: milnacipran 100 total score, CGI score Rx1 Rx2 paroxetine in features; MADRS total mg/day, N = 149 at 7, 14, 28, and 42 Baseline 23.7 23.4 outpatients with score ≥ 20. days. Endpoint 11.9 11.4 Major Depression Rx2: paroxetine 20 Exclusion: mg/day, N = 153 MADRS score NS Funding: Significant suicide risk; Rx1 Rx2 Sponsored by lack of response to two Baseline 29.8 29.6 Pierre Fabre adequate Endpoint 13.6 12.8 Medicament, antidepressant inventors and treatments; history of Responders (%) NS manufacturers of psychotic disorder; Rx1 Rx2 milnacipran. major personality HAMD-17 58.1 60.3 disorder; agoraphobia, MADRS 62.8 64.9 social phobia, or CGI 66.2 64.2 obsessive compulsive disorder; current Remissions (%) alcohol or drug abuse Rx1 Rx2 NS or dependence. HAMD-17 33.1 35.1 MADRS 45.3 47.7

Post-treatment discontinuation emergent symptoms: 0.032 Rx1: 13.0 Rx2: 31.8

Table 1.11

Inclusion & Limitations / Intervention and dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Allard, et al. Inclusion: 64-89 No placebo control. Participants randomized into one 6 months Primary outcome measure Both treatment groups showed (2004) Efficacy Male and female of two groups (double-blind, was change in MADRS score comparable improvements in and tolerability of outpatients 65 and older, Industry funded parallel group design): from baseline to 8 weeks, MADRS scores over time. venlafaxine in with DSM-IV Major and baseline to 22 weeks There were no statistically geriatric Depression and in need Rx1: Venlafaxine – IR 37.5 mg significant differences in outpatients with of antidepressant once daily during first week, ER 75 MADRS scores between the Major therapy; MADRS score mg once daily during following two two groups. Depression: a 20+; ≤ 20% change in weeks, increase to 150 mg/day double-blind, MADRS score between during following two weeks if no MADRS scores NS randomised 6- pre-study and baseline response, N = 76 Rx1 Rx2 month visits. Baseline 27.6 27.0 comparative trial Rx2: Citalopram – 10 mg once Week 8 12.0 11.5 with citalopram Exclusion: daily during first week, 20 mg once Week 22 9.6 9.6 Cognitive impairment, daily during following two weeks, Funding: alcohol or drug abuse, 30 mg during following two weeks MADRS responders NS Wyeth, Lederle psychotic disorder not if no response, N = 75 Rx1 Rx2 Nordiska AB, associated with Week 8 75.4% 72.5% Sweden depression, recent (1 Week 22 93.1% 93.2% year) psychiatric inpatient treatment; Spontaneously reported side acute suicidality; bipolar effects/adverse events: disorder, dementia, Rx1: 62% mental disorders due to Rx2: 43% a general medical condition, history of seizure disorder, significant cardiovascular or cerebrovascular disorder, uncontrolled hypertension; significant abnormalities assessed in prestudy physical exam.

Table 1.12 Intervention and Inclusion & Exclusion Limitations / dose p Study Criteria Age Biases N and Final N Duration Outcome Results NNT value

Montgomery, Inclusion: 18-85 No placebo control. After one week run-in 8 weeks Primary outcome measures MADRS scores (observed cases): NS Huusom, & Primary care patients, DSM- period, patients were were changes in MADRS Rx1 Rx2 Bothmer (2004) IV diagnosis of MDD; ≥ 18 Industry funded randomized into one of and HAMD-17 total scores. Baseline 28.7 29.0 A randomized score on MADRS. two groups (double-blind Week 8 8.0 8.6 study comparing Observed cases design): escitalopram with Exclusion: analysis HAMD-17 scores (observed cases) venlafaxine XR in History of mania or bipolar Rx1: Escitalopram. Initial Rx1 Rx2 NS primary care disorder, schizophrenia or dose 10 mg/day. At week Baseline 19.9 20.4 patients with any psychotic disorder; 2 or 4, dose could be Week 8 5.5 6.4 Major Depressive currently suffering from increased to 20 mg/day; N Disorder. obsessive compulsive = 146 Rx1 group achieved sustained disorder; eating disorders, response significantly faster (4.6 days Funding: mental retardation; Rx2: Venlafaxine XR. faster) than Rx2 (p<0.05). p<0.05 Sponsored by H. development or cognitive Initial dose 75 mg/day. At Lundbeck A/S. disorder; MADRS score ≥ 5 week 2 or 4, dose could Rx1 group achieved sustained on item 10 (suicidal be increased to 150 remission significantly faster (6.6 days thoughts); alcohol or drug mg/day; N = 142 faster) than Rx2 (p<0.001). p<0.001 abuse problems past one year; treatment with Rx2 group had significantly more antipsychotics, nausea, constipation, and increased antidepressants, sweating (p < 0.05). <0.05 psychotropics, serotonin receptor agonists, lithium, Rx2 group had significantly more carbamazepine, valproate, or discontinuation symptoms (p < 0.01). <0.01 alpromide; ECT; treatment with behavior therapy or No difference in overall discontinuation psychotherapy; pregnant or rates (14.4% vs. 13.3%) breast feeding.

Table 1.13 Intervention & Limitations / dose p Study Inclusion & Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Rapaport, et Inclusion: 60+ Study restricted to Participants 12 weeks Primary outcome HAMD total score change from baseline in al.(2003) Efficacy Elderly adults with DSM-IV Major elderly outpatients randomized into one of measure was Intention-to-Treat, LOCF population: of controlled- Depressive Disorder; HAMD-17 score (not those in three groups (flexible change in HAMD release ≥18 at both screening and baseline nursing homes, dose, double-blind total score from Rx1 Rx2 Rx3 paroxetine in the visits. etc.) study) baseline to Baseline 22.1 22.3 22.1 treatment of late- endpoint. Endpoint 10.0 10.0 12.6 life depression. Exclusion: Excluded patients Rx1: Paroxetine CR up Change -12.1 -12.3 -9.5 HAMD total score decreased by 25% with severe or to 50 mg/day, N = 104 Funding: or more between screening and unstable medical Adjusted difference between Rx1 and Rx3 GlaxoSmithKline, baseline; concomitant therapy with illness. Rx2: Paroxetine IR up = -2.8 (95% confidence interval = -4.47 to Research psychoactive medication other than to 40 mg/day -0.73, p=0.007). p=0.007 Triangle Park, NC chloral hydrate; diagnosis of other axis I disorder; history of brief Rx3: Placebo Adjusted difference between Rx2 and Rx3 depressive episodes previousing ≤8 = -2.8 (95% confidence interval = -4.65 to 0.03 weeks with spontaneous remission; -0.99, p=0.03). neurological disorders contributing to secondary depression; dementia; Response rates (score of 1 or 2 on CGI-I): MMSE score ≤24; serious medical Rx1: 72% (p<0.002 vs. Rx3) <0.002 conditions contraindicative to Rx2: 65% (p=0.06 vs. Rx3) 0.06 paroxetine; history of seizure Rx3: 52% disorders; concomitant treatment with warfarin, phenytoin, cimetidine, Remission rates (HAMD ≤7): sumatribtan, type 1C antiarrhythmic Rx1: 43% (p<0.009 vs. Rx3) <0.009 agents, or quinidine; history of Rx2: 44% (p=0.01 vs. Rx3) 0.01 substance abuse or dependence, Rx3: 26% ECT within 3 months; unresolved or abnormal ECG findings; suicidal or Post-hoc analysis revealed that patients homicidal tendencies. with chronic depression (duration > 2 years) responded as well as patients with short-term depression.

Withdrawal due to adverse events: Rx1: 12.5% Rx2: 16.0% Rx3: 8.3%

Table 1.14 Intervention and Inclusion & Exclusion Limitations / dose p Study Criteria Age Biases N and Final N Duration Outcome Results NNT value

Sauer, Uppertz- Inclusion: 18-65 Noninferiority study. After a one-week wash- 6 weeks Primary outcome Significant noninferiority of venlafaxine, Helmhold & Adult outpatients with ICD-10 out period, participants measure was as reflected by change in HAMD scores Dierkes (2003) Major Depression of moderate No placebo control. were randomized into change in HAMD- (Intention-to-Treat analysis): Efficacy and severity; HAMD-21 score 20-26 21 score. safety of at first screening; depressive Study conducted in Rx1: Venlafaxine ER Rx1 Rx2 0.0042 venlafaxine ER symptoms present for minimum Germany, where 75mg, N = 79 Baseline 23.6 23.6 vs. amitriptyline of 14 days prior to study. antidepressants are Endpoint 13.1 13.3 ER in patients prescribed at Rx2: Amitriptyline ER: 2 Change -10.5 -10.4 with Major Exclusion: generally lower mg on day one, 50 mg on Depression of Hypersensitivity to or previous doses. day two, 75 mg from day Similar results found in ATP (According moderate severity unsuccessful treatment with three onwards, N = 77 to Protocol) analysis: venlafaxine or amitriptyline; Industry funded Rx1 Rx2 0.01 Funding: bipolar or psychotic disorders, In cases of insufficient Baseline 23.6 23.6 Study granted by history of convulsive disorders, response, doses were Endpoint 13.0 12.6 Wyeth Pharma hypertension, suicidality, HAMD increased to 75 mg from Change -10.6 -11.0 GmbH, Germany score decrease ≥ 4 between day 15 onwards. screening and baseline; onset of Frequency of adverse events: 0.11 additional psychotherapy; Rx1: 70.9% pregnancy or lactation, treatment Rx2: 81.8% with sumatriptan or antipsychotic p=0.11 medication, ECT within 30 days prior, treatment with fluoxetine Frequency of adverse drug reactions: 0.04 within 30 days prior, treatment Rx1: 55.7% with MAO inhibitors within 14 Rx2: 71.4 days prior, clinically relevant p=0.04 findings concerning physical exam, ECG or laboratory parameters

Table 1.15 Intervention and Inclusion & Limitations / dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Kool (2003) Inclusion: 18-60 Small number of Patients randomized into 24 weeks Outcome measures Combined therapy was more effective than 0.04 Efficacy of Adults with DSM-III-R subjects – risk of one of two groups: were CGI-I, CGI-S, pharmacotherapy alone for depressed patients combined therapy Major Depression (with Type II error. HAMD-17, QLDS, with personality disorders. and or without dysthymia; Rx1: Pharmacotherapy and SCL-90. pharmacotherapy with or without Specialty mental with three tiered protocol Combined therapy was not more effective than 0.74 for depressed personality disorder); health setting -- ? (steps2 and 3 used if pharmacotherapy alone for depressed patients patients with or HAMD-17 ≥ 14. applicability to steps 1 and 2 proved without personality disorders. without primary care ineffective): personality Exclusion: settings. 1) fluoxetine 20 mg/day Change in HAMD scores: disorders. Patient considered “too 2) amitriptyline 100-150 Baseline Endpoint ill” or “too suicidal” to mg/day Rx1 Funding: participate in a clinical 3) moclobemide 300-600 with PD 20.75 14.89 Supported by an trial; drug abuse or mg/day Rx2 unrestricted psycho-organic, N = 56 with PD 20.12 11.10 educational grant psychotic, or dissociative Rx1 from Eli Lilly disorder; patient not Rx2: Combined therapy: w/o PD 21.20 12.10 Nederland. considered reliable pharmacotherapy as Rx2 enough to participate in a described above plus 16 w/o PD 19.70 11.09 clinical trial. sessions of short psychodynamic supportive psychotherapy (SPSP) starting two weeks after the initiation of medication. N = 72

Table 1.16 Intervention and Inclusion & Limitations / dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Wade, et al. Inclusion: 18+ No placebo control. Participants randomized 24 weeks Primary outcome There was no statistically significant difference 0.15 (2003) A Male and female adults, into one of two groups: measure was change in HAMD improvement at 24 weeks. randomized, aged 18 and over; DSM- No washout period. in HAMD-17 score Rx1: -18.2 double-blind, 24- IV criteria for single or Rx1: Mirtazipine 30 from baseline. Rx2: -16.6 week study recurrent depressive High discontinuation mg/day (between weeks comparing the episode, HAMD-17 score rates overall (>50% 5-24 dosage could be At weeks 2, and 4 there was a statistically efficacy and >18. each group). increased to 45 mg/day) N significant difference in HAMD improvement, in tolerability of = 99 favor of mirtazapine: mirtazapine and Exclusion: Industry funded paroxetine in Schizophrenia or bipolar Rx2: Paroxetine 20 Week 2 depressed affective disorder, mg/day (between weeks Difference -2.0 (95% CI: -3.5 to -0.4; p=0.012) patients in suicidality, abuse of illicit 5-24 dosage could be Week 4 primary care. drugs, alcohol increased to 30 mg/day), Difference -2.0 (95% CI: -3.8 to -0.2; p=0.030) dependence; recent N = 98 Funding: treatment with other Overall adverse effects: Rx1: 79%, Rx2: 85%. Study funded by psychotropic drugs, a clinical research hypersensitivity to Tolerability/adverse events grant from paroxetine or mirtazipine Rx1 statistically significantly higher incidence of 0.012 Organon (or use for current fatigue. Laboratories Ltd., depressive episode); Dambridge fluoxetine within 5 Rx2 group reported statistically significantly Science Park, weeks, use of other more sweating (p=0.010), headache (p=0.008) Cambridge UK. antidepressants within 2 and nausea (p<0.001). weeks of study; clinically meaningful renal, HAMD response rates: hepatic, respiratory, Rx1: 87% cardiovascular or Rx2: 78% cerebrovascular disease; pregnancy or lactation; HAMD remission rates: investigator’s Rx1: 61% assessment of Rx2: 42% unsuitability for trial.

Table 1.17 Intervention and Inclusion & Limitations / dose – N and Final p Study Exclusion Criteria Age Biases N Duration Outcome Results NNT value

Montgomery Inclusion: 18-65 Small number of After 4-14 day washout 28-56 days Primary outcome In three of the four trials, the reboxetine group <0.001 (2003) The Adult patients with DSM- studies analyzed. period, patients were measure was mean had a significantly greater decrease in HAMD antidepressant III or DSM-IV criteria for randomized into one of change in HAMD score when compared with placebo. efficacy of Major Depressive The four studies were two groups: score from baseline reboxetine in Disorder of at least one not similar in terms of to previous follow-up In three of the four trials, antidepressant <0.05 patients with month’s duration and duration or study Rx1: Reboxetine – evaluation, in each efficacy occurred significantly faster (at two severe baseline severity score ≥ population (n). initiated at lower doses, of the four trials. weeks) in the reboxetine group when compared depression 20 on HAMD-21. but maintained at 8-10 with the placebo group. One of the four mg/day divided into two (analysis of 4 Exclusion: studies (Versiani et al, daily doses In three of the four trials, the responder rate <0.05 - RCTs) Pregnancy or 2000) had a much was significantly higher in the reboxetine group <0.001 breastfeeding, higher baseline mean Rx2: placebo (56-74%) compared with placebo (20-52%). Funding: hypersensitivity to HAMD score – 35.4 Data reported psychotropic vs. 26.4, 27.0, and supported by medications, recent 27.2). grants from history of substance Pharmacia abuse; other medical or Patients unresponsive Corporation, psychiatric conditions; to previous Peapack, NJ. history of resistance to antidepressant antidepressant treatment were medications. excluded.

Remission rates not reported

All studies included were funded by Pharmacia, the manufacturer of reboxetine; a systematic review was not performed (unpublished studies may not have been included).

Table 1.18

Inclusion & Limitations / Intervention and dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Gasto, et al. Inclusion: 65+ Single blind study After a two-week washout 6 months Primary outcome Intention-to-treat analysis (N = 61: Rx1 N (2003) Single- In- and outpatients with (psychiatrist only) period, participants were measures were = 31, Rx2 N = 30) blind comparison DSM-IV Major randomized into one of two scores on HAMD-17 of venlafaxine Depression, with or No placebo control. groups: and Newcastle Remission rates: 0.84 NS and nortriptyline without endogenous or Scale. Rx1: 70.1% in elderly Major psychotic features; Elderly patients only. Rx1: Venlafaxine – Rx2: 70% Depression baseline HAMD-17 ≥21; Starting dose: 75 mg/d symptoms present for at Day 4: 150 mg/d Efficacy was not dependent on clinical 0.94 – Funding: least one month. Day 8: 225 mg/day severity of the depressive episode. 1.00 NS None reported. Clinician option to increase to Treatment groups were similar when sub- Exclusion: 300 mg/day at 2-week analyses were performed evaluating the Uncontrolled medical evaluation. following categories: endogenous, illness; manic or hypo N = 34 nonendogenous, psychotic, nonpsychotic, manic episode, history of severe inhibition, mild inhibition. nonaffective psychosis, Rx2: Nortriptyline – substance dependence; Starting dose: 12.5 mg/d Both drugs were similarly tolerated. Side ECT therapy within 6 Day 4: 25 mg/d effects were frequent (Rx1 = 73.5%, Rx2 months of recruitment. Day 8: 50 mg/day =82.3%) but mild to moderate in intensity. Clinician option to increase to 300 mg/day at 2-week On the autonomic side-effects subscale, evaluation. Rx1 scored lower than Rx2 (2.03 and 2.91 0.0001 Plasma concentrations were respectively), suggesting a more benign assessed after one week and side-effect profile for venlafaxine. doses were adjusted to achieve a plasma concentration between 80 and 100 mg/ml Maximum dose: 100mg/d N = 34

Table 1.19 Inclusion & Exclusion Limitations Intervention and dose Study Criteria / Biases N and Final N Outcome Results

Hansen, et al. Efficacy trials, N = 46 Limited Qualitative analysis of Primary Head-to-head comparison trials (2005) Efficacy Head-to-head quantitative studies outcome Efficacy Overall, trials reported similar outcomes among the six SSRIs. Differences in treatment effects and safety of comparison of one analyses due measures for between some trials that found a significant and those that didn’t could be attributed to small sample sizes second- antidepressant with to inadequate Quantitative analysis when head-to-head and publication bias in favor of the sponsoring pharmaceutical company’s antidepressant. generation another; conducted in evidence. more than three head-to- comparison Trials comparing SSRIs with other second generation antidepressants showed similar efficacy. antidepressants Primary Care settings; head trials compared the trials were in the treatment ≥ 3 month duration of Many trials same treatments (primary efficacy, speed Speed of response Overall, the trials reported no difference among SSRIs. Evidence of a faster response of Major follow-up; minimal sponsored by outcome measure of response, to citalopram, fluvoxamine, and paroxetine than to fluoxetine is based on results of one trial or is Depressive inclusion and pharmaceutical treatment response). quality of life inconsistent with other evidence. Trials comparing SSRIs with other second generation antidepressants Disorder. exclusion criteria (to companies; and showed an average speed of response of 4-6 weeks, with no statistically significant differences among represent general possible If treatment effects differed tolerability/adve treatments. Evidence in some trials of a faster response rate with venlafaxine is equivocal. (Review) population); assessed publication among studies, potential rse effects. health outcomes biases. reasons were assessed. Quality of life Overall, trials showed no significant difference among SSRIs in their ability to improve Funding: rather than immediate Primary health-related quality of life. One trial did report better sleep quality with fluovoxamine than with fluoxetine. Dr. Gaynes outcomes; adequate Heterogeneity tested for outcome Trials comparing SSRIs with other second generation antidepressants reported no differences in overall supported in sample size to treatment effects in meta- measure for quality of life. part by a determine a minimally analyses. meta-analyses National important difference was responder Tolerability/adverse effects Overall, incidence of adverse effects was similar among antidepressants. Institute of (from a patient’s Mean incidence and 95% rate. Quality of reporting and methods used to report adverse effects differed among studies Mental Health perspective) on a confidence intervals K23 Career health-related quality calculated for specific Meta-analyses Development of life instrument. adverse events (significant Fluoxetine vs. paroxetine Award, the variance, should be Responder rate did not differ significantly between fluoxetine and paroxetine Robert Wood Safety and tolerability, interpreted with caution) (relative benefit 1.09, CI: 0.97 to 1.21). Johnson N = 21 Foundation, and Head-to-head trials; Fluoxetine with sertraline the Agency for placebo-controlled; Pooled results showed a small treatment effect of sertraline compared with fluoxetine Healthcare observation studies (relative benefit, 1.10, CI: 1.01 to 1.22) although no individual trial showed significant differences. Research and with large samples Quality. (>100) previousing at Venlafaxine vs. fluoxetine least one year. Pooled data from 6 studies showed that venlafaxine yielded more responders than fluoxetine (57.6% vs. 51.1%, ARR = 6.5%, NNT = 15; RR = 1.12, CI: 1.02-1.23). Most other individual studies comparisons for venlafxaine vs. other SSRIs did not show a difference, pooled analysis for venlafaxine vs. all SSRIs not performed.

Table 1.20 Intervention and Inclusion & Limitations / dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Arroll, et al. Inclusion 18+ Larger number of Three groupings of N/A Primary outcome Pooled efficacy data showed both TCAs and (2005) Efficacy Randomized, controlled (primar studies comparing studies, total N = 15: measure was SSRIs were significantly more effective than and tolerability of trials using TCAs and/or ily) TCAs with placebo efficacy of TCAs and placebo: tricyclic SSRIs using primary than comparing TCAs vs. placebo, N = 10 SSRIs in comparison antidepressants care patients; study SSRIs with placebo. with placebo. TCAs vs. placebo 4 and SSRIs population of adults with SSRIs vs. placebo, N = 3 Relative risk 1.26 (95% CI: 1.12 – 1.42) compared with diagnosis of Major Studies lacked NNT = 4, NNH (withdrawal)= 5-11. placebo for Depression. consistency in TCAs and SSRIs vs. 6 treatment of patients’ severity of placebo, N = 2 SSRIs vs. placebo: depression in Exclusion: depression. Relative risk 1.37 (95% CI: 1.21 – 1.55) primary care: a Studies using NNT = 6, NNH (withdrawal)=21-94. meta-analysis predominantly children or the elderly. Both low dose and high dose TCAs were Funding: effective. Funding Body Chief Scientist Office, Scotland.

Table 1.21 Study, Treatment Groups Size & Total n Intervention Description Study Population Results Comments

Detke, M. For efficacy analysis Men and women at least 18 years of age Least square mean change Treatment-emergent adverse events Duloxetine in a once 2002 (RCT, double-blind) from baseline to previous (safety measure) daily dose of 60 mg/day Rx1: Duloxetine, Adult patients with DSM-IV MDD baseline observation using HAM-D- Nausea was significantly superior Follow-up: 9 weeks 60 mg/day score of ≥ 15 on the HAM-D-17 (17-item 17 scale (primary efficacy Rx1: 46.3% of patients to placebo in reducing (n = 121) Hamilton Rating Scale for Depression) measure) Rx2: 9.0% of patients HAM-D-17 total scores, Initial n: 245 p < 0.001 (in favor of placebo) starting at week 2, but is Final n: 225 (based on safety Rx2: Placebo Baseline score of ≥ 4 on the CGI-S Rx1: -10.91 associated with a analysis numbers) (n = 115) (Clinical Global Impressions-Severity) Rx2: -6.05 Dry mouth significantly increased p < 0.001 (in favor of Rx1: 27.6% risk of side effects. For safety analysis duloxetine) Rx2: 6.6% p < 0.001 Rx1: Duloxetine, Estimated probability of 60 mg/day remission for duloxetine Somnolence (n = 123) patients = 44% vs. 16% for Rx1: 21.1% placebo-treated patients Rx2: 4.9% Rx2: Placebo p < 0.001 (n = 122) The following adverse effects were also statistically significant: dizziness, diarrhea, insomnia, and constipation

Table 1.22 Study, Treatment Groups Size & Total n Intervention Description Study Population Results Comments

Goldstein, D. Rx1: duloxetine, titrated in the first Male and female outpatients Least square mean change Treatment-emergent adverse events Duloxetine is statistically 2002 (RCT, double-blind) three weeks from 40 mg ages 18 to 65 with DSM-IV from baseline to previous visit (safety measure) superior to placebo in (20 mg b.i.d.) to 120 mg/day Major Depressive Disorder using HAM-D-17 scale Insomnia reducing the symptoms of Follow-up: 8 weeks (60 mg b.i.d.) (n = 70) (primary efficacy measure) Rx1: 20.0% of patients MDD. Clinical Global Impressions Rx2: 7.1% of patients Initial n: 173 Rx2: placebo (n = 70) (CGI)-Severity of Illness Rx1: -9.73 Rx3: 9.1% of patients Study was not designed to score of at least moderate Rx2: -6.61 p = 0.046 in favor of placebo (duloxetine vs. be a comparison of Final n: 167 Rx3: fluoxetine, severity (≥ 4) Rx3: -7.75 placebo) duloxetine and fluoxetine. 20 mg q.d. (n = 33), was used as an p = 0.009 (duloxetine vs. internal control 17-item Hamilton Rating placebo) in favor of Duloxetine treated patients exhibited a small but Fluoxetine was included Scale for Depression (HAM- duloxetine statistically significant reduction in body weight as an internal control to be D-17) total score of at least relative to placebo sure patients were 15 Estimated probability of (0.59 kg) p = 0.005 antidepressant remission for duloxetine- responsive. treated patients was 56% vs. The mean increase in standing diastolic blood 32% for placebo-treated pressure for duloxetine-treated patients was 2.80 Clinical significance of patients, mm Hg greater than for placebo-treated patients changes in BP and weight p = 0.22 (p = 0.041) uncertain.

The following adverse effects were not statistically significant: dry mouth, headache, somnolence, dizziness, diarrhea, nausea, and constipation

Table 1.23 Study, Treatment Groups Size & Total n Intervention Description Study Population Results Comments

Wade, A. Rx1: escitalopram (SSRI) Patients were aged between Adjusted mean change in MADRS total Tolerability Escitalopram 10 mg/day had a 2002 (RCT, double -blind) 10 mg/day 18 and 65 years, 3:1 ratio of score from baseline to week 8 Nausea (% of patients) statistically significantly better (n = 191) women to men Rx1: 8.9% antidepressant effect than Follow-up: 8 weeks, following > 97% Caucasian Rx1: 16.3 Rx2: 3.7% placebo as early as week one, an initial 1-week single-blind, Rx2: placebo p < 0.05 (in favor of placebo) and was safe and well tolerated. placebo period (n = 189) Patients fulfilled DSM-IV Rx2: 13.6 This difference disappeared within criteria for MDD the first two weeks of double-blind The proportion of escitalopram– Initial n: 380 p = 0.002 (in favor of escitalopram) treatment treated patients in complete Had a baseline Montgomery- remission was also statistically Final n:320 Asberg Depression Rating Headache (% of patients) significantly higher than that of Scale (MADRS) total score ≥ Rx1: 12% placebo-treated patients at week 22 and ≤ 40 Rx2: 10.1% eight. (p < 0.01) Not statistically significant

Table 1.24 Study, Treatment Groups Size & Total n Intervention Description Study Population Results Comments

Moncrieff, J. Randomized and quasi Participants of either sex (Individual studies) (Combined analysis) Majority of trials found only small 1998 (meta- randomized trials of all age groups with Change in mood Change in mood differences between analysis) primary diagnosis of Daneman, 1961 All nine trials, using the more conservative antidepressants and active Double-blinded depressive disorder SMD = 1.1 (0.8 to 1.4) estimate from Weintraub, 1963 (rating by placebos hospital director) # studies found: 12 Drugs used were all TCAs. Inpatients and outpatients Uhlenhuth, 1963 SMD = 0.39 (0.24 to 0.54) Unblinding effects may inflate the SMD (unadjusted) = 0.60 Heterogeneity p < 0.001 efficacy of antidepressants in trials # studies included: All trials used active placebos Specialty behavioral (0.02 to 1.2) using inert placebos. 9 containing atropine health settings SMD (adjusted for baseline values) = 0.35 (- Eight trials, excluding Daneman, 1961 (due to 0.25 to 0.96) high degree of heterogeneity) Meta-analysis with small number SMD = 0.17 (0.00 to 0.34) of trials Weintraub, 1963 Heterogeneity p = 0.29 Short duration of trials (minimum SMD (for hospital director) = 0.14 three weeks, maximum 12 weeks) (-0.34 to 0.62) Eight trials, excluding Daneman, 1961 and SMD (for ward doctor) = 0.63 using the higher estimate from Weintraub, Studies old (0.15 to 1.11) 1963 (rating by ward doctor) SMD = 0.23 (0.06 to 0.40) Variety of depression instruments Wilson, 1963 used SMD = -0.26 (-1.10 to 0.58) Seven trials, excluding Daneman, 1961 and Murphy, 1984 (participants received cognitive Limited to TCAs-extrapolation to Hollister, 1964 therapy as well as medication) other antidepressants may not SMD = 0.19 (-0.24 to 0.63) SMD = 0.21 (0.03 to 0.38) necessarily be true

Freidman, 1966 Fixed effect model SMD = 0.13 (-0.37 to 0.64)

Hussain, 1970 SMD = 0.79 (0.09 to 1.5)

Friedman, 1975 SMD = 0.14 (-0.14 to 0.42)

Murphy, 1984 SMD = -0.36 (-1.0 to 0.28)

Table 1.25 Author & Last Updated & Methodology & Characteristics of Study Results Title Search Database Study Characteristics Participants Heterogeneity (95% CI)

Wilson, K. Most recent Update Number of studies included: Sample: Other variables associated with the aging process Efficacy: March 2001 17 trials were included Depressive disorders: (such as physical ill health) are likely to influence Seventeen trials 2002 Setting: Not stated. n = 1,326 the outcome of trials. The effects of these aspects contributed data to the Databases: Major Depressive Disorder. of clinical heterogeneity were examined and trials analyses comparing the Cochrane Collaboration Study Inclusion / Exclusion: combined if appropriate. efficacy of Depression The review included all randomized, Inclusion Criteria: antidepressant treatment Anxiety and Neurosis placebo controlled trials using Patients over 60 with depression. Where possible, the influence of patient and placebo. Review Group antidepressant drugs in the treatment of characteristics, for example inpatient vs. (CCDAN) depression in subjects described as Exclusion Criteria: Not stated. outpatient, subtypes of depression, under 75 vs. Analyses of efficacy was Reference lists of related elderly, geriatric or senile or in trials over 75 was examined. The effect of the trial based on 245 patients reviews where all subjects are over the age of Design of Trials: length was examined. If enough studies were treated with TCAs (223 References of located 60. RCT identified, the year of publication and country of with placebo), studies. publication was examined. A funnel graph to test 365 patients treated with Contact was made with Trials that included subjects under the Duration of Trial: for publication bias was also used. In addition, a SSRIs (372 with authors working in the age of 60 were excluded unless data Not stated. formal test for statistical heterogeneity, the natural placebo) and 58 patients field. concerning subjects over the age of 60, approximate chi-square test was conducted. treated with MAOIs or those described as elderly, geriatric Method of abstraction: (63 with placebo). Search Terms: or senile, were randomized and Three reviewers independently assessed the The standardized effect size for the three groups Electronic databases analyzed separately. relevance of each trial, blind to decisions respectively were: were searched using made by each other. TCAs: OR = 0.32 (0.21 to 0.47), optimally sensitive Funding Source: search terms (exact Wirral and West Cheshire Community Each trial was assessed against pre-set SSRIs: OR = 0.51 (0.36 to 0.72), terms not stated). Trust UK criteria and rated on a scoring sheet. In cases of disagreement open discussion was MAOIs: OR = 0.17 (0.07 to 0.39). Drug Comparisons: undertaken and decision reached by TCAs with placebo consensus. Reasons for exclusion and/or Adverse SSRIs with placebo inclusion were recorded. Two reviewers are Dropout Rates: Effects: MAOIs with placebo acknowledged expert in the field, the other Not reported. Not reported. reviewer wasn’t. Reviewers were blind to Dosages: authorship of trials, journals and institutions Statistical advice was sought through the Not stated from which authors come. Blindness was Cochrane Depression, Anxiety and Neurosis tested through reviewers’ 'best guessing' Review Group and through the Cochrane Stage of depression: authorship, journal and institution. Statistical Support Group in Liverpool. Not stated.

Table 1.26: Effects of Specific Psychological Treatments for Depressive Disorders

INTERVENTION EVIDENCE BENEFITS HARMS DISADVANTAGES 1 SR (48 RCTs of psychological therapies [2,765 Requires extensive 79% of people receiving placebo were more people, mean age 39.3 y] mainly outpatients in training. Limited symptomatic than the average person receiving secondary care; therefore, probably with mild to No availability. RCTs Cognitive CT (p < 0.0001). 65% of people receiving CT moderate depression; people with psychotic or harms in primary care therapy were less symptomatic than the average person bipolar symptoms were excluded); 20 RCTs reported suggest limited treated with antidepressant drugs compared CT with waiting list or placebo and 17 acceptability to (p < 0.0001). compared it with drug treatment. some people. No SR. 1 large RCT (people with mild to Rates of recovery from depression: interpersonal moderate depression, mean age 35 y) compared No Requires extensive Interpersonal psychotherapy (43%; NNT = 5, 95% CI: 3 to interpersonal psychotherapy vs. either drug harms training. Limited psychotherapy 19), imipramine (42%; NNT = 5, 95% CI: 3 to treatment, CT or placebo plus clinical reported availability. 22), placebo clinical management (21%). management for 16 weeks. No SR. 1 large RCT (452 people aged 18 to 65 y PS vs. control significantly increased the with mild to moderate depression or adjustment proportion of people who were not depressed at Problem- No Requires extensive disorders) compared PS, group treatment, and 6 mo., but no significant difference at 1 y. solving harms training. Limited control. 1 RCT (91 people aged 18 to 64 y with PS vs. placebo significantly improved symptoms therapy reported availability. mild to moderate depression) compared problem- at 12 weeks, and no significant difference in solving, placebo, and amitriptyline. symptoms with PS vs. amitriptyline. Counseling vs. standard care significantly 1 SR (7 RCTs, 772 people aged over 18 y with improved symptoms in the short term (1 to 6 No Requires extensive Nondirective recent onset psychological problems including mo.; WMD -2.03, 95% CI: -3.82 to -0.24), but harms training. Limited counseling depression in UK primary care) compared no significant difference in the long term reported availability. counseling vs. standard physician care. (> 6 mo.; WMD -0.03, 95% CI: -0.39 to +0.32). CT: cognitive therapy, mo.: month, PS: problem-solving, SR: systematic review, y: year Clinical Evidence, November 2003(70)

Table 1.27 Study, Treatment Groups Size & Total n Intervention Description Study Population Results Comments

Casacalenda, N. Rx1: Medication Adults Full remission (%) Intention-to-treat analyses indicated that 2002 (meta-analysis) (n = 261); five studies used tricyclics and (based on intention-to-treat analysis of the main analysis pharmochotherapy and psychotherapy were one used phenelzine All were diagnosed as having of the studies) significantly more efficacious than control Follow-up: 10 to 34 nonpsychotic Major Depression conditions but were not significantly different weeks (median = 16 Rx2: Psychotherapy Rx1: 46.4% from each other, when treating mildly to weeks) (n = 352); three studies used cognitive moderately depressed patients behavior therapy, three used interpersonal Rx2: 46.3% therapy, one used problem-solving Heterogeneity not stated. # of studies found: 6 (six studies total, one study used both CBT Rx3: 24.4% and IPT) # of studies included: 6 p < 0.0001 (favoring treatment groups) RX3: Placebo (n = 270) Intent- to treat analysis Definition of remission: All studies were randomized, control trials. Definition varied by study. Raskin Depression Scale score ≤ 5 Hamilton depression scale score ≤ 6 Hamilton depression scale score ≤ 7

Table 1.28 Study, Treatment Groups Size & Intervention Total n Description Study Population Results Comments

Thase, E. Rx1: venlafaxine (n = 851), Patients were at least 18 years old Remission rates (Hamilton Rating Drop-outs due to side Absolute remission rates were 2001 (meta-analysis, Scale for Depression, HRSD total effects significantly higher (10%) with nonsystematic review) Dose range: Met the DSM-III-R criteria for Major score of ≤ 7) venlafaxine (SNRI) than with an venlafaxine IR, 75 to 375 mg/day; Depressive Disorder and DSM-IV Rx1: 45% (Rx1 vs. Rx3) SSRI Follow-up : venlafaxine XR, 75 to 225 mg/day criteria for MDD for at least one month Rx2: 35% p = 0.001 (significant) 6 to 8 weeks Rx3: 25% Only four of eight trials were Rx2: SSRIs Minimum score of 20 on HRSD (Rx2 vs. Rx3) placebo controlled (fluoxetine 20 to 80 mg/day, paroxetine 20 to 40 (Hamilton Rating Scale for (NNT = 10) favoring venlafaxine p = 0.001 (significant) # of studies found: 8 mg/day, fluvoxamine 100 to 200 mg/day) (n = 748) Depression) or 25 on MADRS Rx1 vs. Rx3 = 2.2 All trials reviewed were funded (Montgomery-Asberg Depression Rx2 vs. Rx3 = 1.4 (Rx1 vs. Rx2) by the manufacturer of #of studies included: 8 Rx3: Placebo Rating Scale) p = 0.185) venlafaxine. (four studies n = 446) Testing for homogeneity of the (not significant) odds ratio revealed no significant SSRI remission rate lower than Eight randomized, double-blind studies difference (p = 0.28) seen in other trials, suggesting possible publication bias (nonsystematic review).

Table 1.29 Study, Total n Treatment Groups Size & Drug Study Population Results Comments

Mulsant, H. Outpatients Age 60 and older with MDD Hamilton Rating Scale for Depression for Efficacy of nortriptyline and paroxetine did not differ 2001 (RCT, double-blind) Rx1: Nortriptyline, 25 mg in the evening, intention-to treat groups significantly in older patients with MDD. placebo pills in the morning 71.6% female Rx1: 9.8 ± 5.2 Follow-up: 12 weeks Rx2: 11.5 ± 7.1 Dropouts attributed to a side effect were significantly higher Rx2: Paroxetine, 10 mg in the morning initially 86.2% white p = 0.16 in patients treated with nortriptyline. No difference was Initial n: 116 and increased to 20 mg after one week, (not statistically significant) noted in overall frequency of side effects or dropouts for all placebo pills in the evening 17-item Hamilton Rating reasons. Final n: 64 Scale for Depression (HAM- Discontinuation: Inpatients D) score of 15 or above Patients were twice as likely to discontinue Overall reasons for dropout included items of questionable Rx1: Nortriptyline, 50 mg in the evening, nortriptyline (33%) as paroxetine (16%) due clinical relevance for initial decision making when deciding placebo pills in the morning Mini-Mental State Exam to a significant side effect (p = 0.04), but the between two medications (i.e., transportation issues). (MMSE) score of 15 or overall discontinuation rates did not differ Separate analysis of dropouts due to patient perceived lack Rx2: Paroxetine, 20 mg in the morning, above significantly, p = 0.30. of efficacy was not presented. placebo pills in the evening UKU side effects total score for intention-to- Study results based on both out patients and inpatients Rx1: 54 treat groups outcomes. No separate statistical analysis given for Rx2: 62 outpatients only. Rx1: 12 ± 6 Rx2: 12 ± 7 p = 0.61 (not statistically significant)

2. Hypericum (St. John’s Wort) For Treatment of MDD

Problem Formulation 2

Clinical Question: Should Hypericum (St. John’s Wort) be used for treatment of adults with MDD? Intended Use of To assist primary care physicians and other health care professionals the Guideline: in treating adults with Major Depression. Population: All adults (age 19 and older) with Major Depression Health Problem: MDD Health Intervention:  Hypericum (St. John’s Wort) vs:  Prescription antidepressants (SSRI, SNRI, TCA, NRI, or DA)  No treatment  Placebo Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics Health Outcomes  Change in symptoms  Office/UCC/ER visits (associated with the  Quality of life  Hospitalizations intervention):  Missed school/work days  Mortality Side Effects  Sexual problems  Serotonin syndrome Associated With  Drowsiness  Elevated blood pressure the Intervention:  Headache  Constipation  Nausea  Diarrhea  Insomnia  Abdominal pain  Agitation/nervousness  Dizziness  Dry mouth  Blurred vision  Seizures  Weight gain  Photosensitivity  GI bleeding  Bleeding  Falls

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* ((((depression/drug therapy[MESH] Randomized, 10/2001 2/20 OR depression/therapy[MESH]) OR controlled trial, to ("depressive disorder/drug All Adult: 19+ 9/2007 therapy"[MESH] OR "depressive years English, disorder/therapy"[MESH])) OR Human ("dysthymic disorder/drug therapy"[MESH] OR "dysthymic disorder/therapy"[MESH])) AND "hypericum"[MeSH Terms]) ("depression/drug therapy"[MESH] Meta-analysis, 4/03 0/0 OR "depression/therapy"[MESH] OR All Adult: 19+ to "Major Depressive Disorder"[All years, English, 10/2007 Fields]) AND ("hypericum" [MeSH Human Terms] OR St. John's wort) Controlled 4/03 0/9 Clinical Trial to OR Comparative 10/2007 Study, All Adult: 19+ years, English, Human Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 1/131 Group Reviews Clinical Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs PubMed ("depression/drug therapy"[MESH] Randomized, 01/01/03 1/3 OR "depression/therapy"[MESH] OR controlled trials, - "Major Depressive Disorder"[All All adults: 19+ 08/01/05 Fields]) AND ("hypericum"[MeSH years, English, Terms] OR (("hypericum"[TIAB] Human NOT Medline[SB]) OR "hypericum"[MeSH Terms] OR St. John's wort[Text Word])) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] Systematic 03/05/03 0/295 Cochrane Depression reviews Clinical Systematic 03/05/03 1/80 Depression Evidence reviews & RCTs © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 198 National Adult Depression Clincial Practice Guideline

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed Search #1 update on AHRQ Randomized, 01/01/98 4/4 (((((((((((depression/drug controlled trials, - therapy[MESH] OR All adults: 19+ 03/2001 depression/therapy[MESH]) OR years, English, ("depressive disorder/drug Human therapy"[MESH]OR "depressive disorder/therapy"[MESH])) OR ("dysthymic disorder/drug therapy"[MESH] OR "dysthymic disorder/therapy"[MESH])) AND ("Serotonin Uptake Inhibitors"[MESH] OR "Antidepressive Agents, Tricyclic"[MESH])) AND notpubref[sb]) ((((((((((depression/drug Randomized, 03/2001 1/6 therapy[MESH] OR controlled trials, - depression/therapy[MESH]) OR All adults: 19+ 10/2001 ("depressive disorder/drug years, English, therapy"[MESH] OR "depressive Human disorder/therapy"[MESH])) OR ("dysthymic disorder/drug therapy"[MESH] OR "dysthymic disorder/therapy"[MESH])) AND "hypericum"[MeSH Terms]) AND notpubref[sb]) ("depression/drug therapy"[MESH] Meta-analysis, 01/01/01 0/0 OR "depression/therapy"[MESH] OR All Adult: 19+ - "Major Depressive Disorder"[All years English, 04/01/03 Fields]) AND ("hypericum" [MeSH Human Terms] OR St. John's wort) Controlled 01/01/01 3/3 Trials, All - Adult: 19+ years 04/01/03 English, Human

Evidence Tables

Table 2.1: Effects of Treatment with Hypericum for Major Depression (RCTs) Mean Mean ±SD Mean ±SD ±SD Age % Follow-up Follow-up Baseline Follow-up Effect Study * † Name Tx (N) (yr) Female Rate (%) Time HAMD HAMD Difference p Quality Biases <0.0001 Hypericum 612 48.3 ±12.7 79.4 73 24 weeks 22.0±1.1 5.7 ±4.8 1.3 noninferiority 5 N Gastpar et al., (123) test 2005 Sertraline 50 49.5 ±13.8 69.4 77 22.1±1.1 7.1 ±6.3 (118) Hypericum 900 50.8 ±12.1 65.6 79 6 weeks 21.9±1.2 10.3 ±6.4 vs C: 0.1 Noninferior 5 N (131) Gastpar et al., Citalopram 20 2006 49.3 ±10.7 64.6 82 21.8±1.2 10.3 ±6.4 vs P: 2.6 <0.0001 (127) Placebo (130) 49.4 ±12.7 73.1 81 22.0±1.2 13.0 ±6.9 vs P: 2.5 <0.0001 Hypericum 600 46.3 ±11.5 67 90.2 6 weeks 22.8±3.3 11.2 ±7.0 vs P: 5.6 <0.001 5 N (123) Kasper et al., Hypericum 2006 46.1 ±10.7 82 85.0 22.6±3.8 11.8 ±8.3 vs H12 :0.8 NS 1200 (127) Placebo (82) 46.6 ±11.8 56 90.2 23.6±4.2 17.6 ±8.8 vs P: 4.8 <0.001 Comments: Support from pharmaceutical manufacturers Hypericum 900 37.4 ±11.7 53 60 12 weeks 19.6±3.5 10.2 ±6.6 vs P: 2.1 0.096 3 1 (45) Fava et al., Fluoxetine 20 2005 36.7 ±9.6 53 51 19.6±3.1 13.3 ±7.3 vs F: 3.1 <0.05 (47) Placebo (43) 37.8 ±12.0 65 49 19.9±2.9 12.6 ±6.4 vs P: - 1 NS Comments: Support from pharmaceutical manufacturers HAMD = Hamilton Depression Scale; NS, not significant

* Study quality measured by Jadad trials scoring system (1 to 5 = low to high).

† Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, power); 4: study procedure biases.

Table 2.2 Intervention and Inclusion & dose p Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value

Gelenberg (2004), Men and women with 18+ Naturalistic, follow-up Patients who did not 24 weeks Phase 2 changes in Significant time effect for Phase 1 < 0.001 The effectiveness DSM-IV Major Depressive design. respond to hypericum (N = HAM-D scores nonresponders over the 24 weeks of of St. John's wort Disorder from tertiary care 43) or placebo (N = 55) in between Phase 2 treatment, indicating that in Major clinics in academic Few patients who Phase 1 treated with nonresponders who nonresponders in the initial trial were Depressive medical centers. continued on St. John's antidepressants for 24 received hypericum not treatment resistant (nonresponders Disorder: A wort. weeks (Phase 2). extract and those who in phase 1 did respond in phase 2). naturalistic Phase received placebo in 2 follow-up in Sample limited to Phase 1. HAM-D scores of Phase 1 which outpatients in a tertiary nonresponders in Phase 2: nonresponders care academic center not were provided necessarily interested in Baseline Endpoint alternate herbal treatment – limited Hypericum 18.3 7.9 medication. generalizability. Placebo 18.1 8.8 0.8 Small sample. No significant effect of prior Phase 1 treatment (hypericum or placebo) Nonresponders not group. blinded (open label).

Table 2.3 Intervention and Inclusion & dose p Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value

Uebelhack (2004). Inclusion: 18-70 Adequacy of blinding not After a 7-day placebo run- 6 weeks Change in total HAM- Significant improvement in HAM-D < 0.001 Efficacy and Outpatients with moderate assessed. in period, 140 patients D score from baseline score in hypericum group when tolerability of depression disorder, a were randomized into one to end of study. compared with placebo group: Hypericum extract total HAM-D score of 20- Remission rates not of two groups: STW 3-VI in 24 at baseline. assessed. Baseline Endpoint patients with Rx1: Intervention (N = Hypericum 22.8 11.8 moderate Exclusion: 70): Hypericum extract Placebo 22.6 19.2 depression: a Suicidal patients; those 900mg once daily for six double-blind, with resistant depression. weeks. Hypericum group showed significant < 0.001 randomized, improvement in BfS score when placebo-controlled Rx2: Control (N = 70): compared with placebo group: clinical trial. Placebo once daily for six weeks. Baseline Endpoint Hypericum 38.8 20.7 Placebo 38.0 31.1 Primary outcome was change in HAM-D score, 58.6% of Hypericum group assessed secondary measure was as responders at end of study, responder rate (% of compared with 5.7% in placebo group. patients with >50% decrease from baseline 23 adverse events reported by HAM-D score).. patients, none considered serious, and two cases suggested a connection to the study medication.

Table 2.4 Intervention and Inclusion & Limitations / dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Szegedi (2005), Inclusion: 18-70 Placebo control not After 3-7 day placebo run 6 weeks Change in HAM-D HAM-D scores decreased for both Acute treatment of Caucasian male and used because of in period, participants score from baseline to groups. moderate to female adult outpatients “ethical reasons” were randomized into one day 42. severe depression with moderate to severe (studying patients with of two groups: ITT Analysis: with hypericum MDD and total HAM-D moderate to severe Baseline Endpoint extract WS 5570 score ≥ 22 depression) Rx1: Hypericum (N = Hypericum 25.5 11.1 (St. John's wort): 122): 900mg hypericum Paroxetine 25.5 14.1 randomised Exclusion: Patients at high risk of extract three times per controlled double- Decrease in total suicide excluded. day for six weeks. Per-Protocol Analysis: blind noninferiority depression score of ≥ Baseline Endpoint trial versus 25% during run-in; Rx2: Paroxetine (N = Hypericum 25.5 10.9 paroxetine. diagnoses of 122): 20mg paroxetine Paroxetine 25.5 13.5 schizophrenia, acute once per day for six anxiety, adjustment weeks. Authors conclude from these findings disorder, other depressive that hypericum is not inferior to disorders, organic mental If participant showed no paroxetine. disorder, or substance response after two weeks, abuse; suicidality or dosage was increased: to More patients in hypericum group 0.02 previous suicide attempt. 1800mg hypericum or (50%) than in paroxetine group (35%) 40mg paroxetine. showed remission.

Incidence of adverse effects: Hypericum: 0.035 Paroxetine: 0.060

Table 2.5 Intervention and Inclusion & dose p Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value

Bjerkenstedt Inclusion: 18-70 Fixed doses - dosing was After a 3-7 day run-in 6 weeks Change in HAM-D Similar improvements among (2004) Hypericum Caucasian males and not increased for non- or period, 163 subjects were scores from baseline treatment groups on HAM-D. extract LI 160 and females with mild to partial response, as it randomized into one of to week 4. fluoxetine in mild moderate depression (as might be in clinical three groups: The only statistically significant finding to moderate defined by the DSM-IV) setting. was remission rate (HAM-D total score depression: a with a total HAM-D score Rx1: Hypericum (N = 54): < 8): randomized, ≥ 21. Short duration - only four 300mg tid for six weeks Hypericum (24%) vs. placebo (7%) 0.02 placebo-controlled weeks - due to ERC Fluoxetine (28%) vs. placebo (7%) 0.005 multi-center study Exclusion: restriction. Rx2: Fluoxetine (N = 54): in outpatients. Psychiatric disorders; 20mg per day for six MAO-I treatment within 14 Poor estimation of weeks Hypericum better tolerated than days prior to entry; history compliance. fluoxetine of treatment-resistant Rx3: Placebo (N = 55): Number of adverse events: MDD, risk of suicide, No statistical test done for six weeks. Per ERC Hypericum (38) vs. fluoxetine (52) 0.04 history of seizure disorder, on fluoxetine vs. requirement, placebo Hypericum (38) vs. placebo (27) 0.84 alcohol or substance hypericum. patients randomly Fluoxetine (52) vs. placebo (27) 0.01 abuse; unstable medical switched to hypericum or illness, impaired renal Dropout rates not fluoxetine after four function, pregnancy, reported. weeks, until end of study. known intolerance to study medications; substantial placebo response; treatment with trial drug prior to study.

Table 2.6 Study, Treatment Groups Study Population Results Comments Total n Size & Drug Hypericum Rx1: hypericum At least 18 years old with current HAM-D total score (week 8 – week 1) Adverse Events They found no evidence Depression Trial (900 – 1,500 mg/dl) diagnosis of Major Depression Rx1: -8.68 Diarrhea that hypericum is more Study Group (n = 113) Rx2: -10.53 (Rx1 vs. Rx3) p = 0.81 effective than placebo in 2002 (RCT, Minimum total score of 20 on the Rx3: -9.20 (not significant) treating moderately double-blind) Rx2: sertraline 17-item Hamilton Depression (Rx1 vs. Rx3) p = 0.59 (Rx2 vs. Rx3) p = 0.003 (significant) severe Major (50 – 100 mg/d) (HAM-D) scale (not significant) Depression. Follow-up: 8 (n = 111) (Rx2 vs. Rx3) p = 0.18 Nausea weeks (not significant) (Rx1 vs. Rx3) p = 0.78 The principal comparison Rx3: placebo (n = 116) (not significant) was between the Initial n: 340 Full response rate (%) (Rx2 vs. Rx3) p = 0.02 (significant) hypericum and placebo Final n: 245 One week run-in period Rx1: 23.9 groups. Sertraline Rx2: 24.8 Anorgasmia served as an active Rx3: 31.9 (Rx1 vs. Rx3) p = 0.04 (significant) comparator to evaluate (Rx2 vs. Rx3) p = 0.002 (significant) the study’s sensitivity. (Rx1 vs. Rx3) p = 0.21 (not significant) (Rx2 vs. Rx3) p = 0.26 (not significant)

Full response is indicated with a HAM-D score of eight or less and a Clinical Global Impressions Improvement (CGI-I) score of one or two.

Table 2.7 Study, Treatment Groups Size Study Population Results Comments Total n & Drug

Kalb, R. Rx1: hypericum extract WS Male and female outpatients aged Change (decrease) in HAM-D score (%) The study concludes that the 2001, (RCT, double-blind) 5572 between 18 and 65 years with standardized Hypericum extract (3 x 300 mg/day) (n = 37) diagnosis of mild or moderate MDD Rx1: 54.8% (19.7 ± 3.4 to 8.9 ± 4.3 points, WS 5572 has superior efficacy Follow-up = 6 weeks with single or recurrent episodes overall change -10.8 points) compared with placebo and very Rx2: placebo (n = 35) according to DSM-IV criteria Rx2: 29.2% (20.1 ± 2.6 to 14.4 ± 6.8 points, good tolerability in the acute Initial n: 72 overall change -5.7 points) treatment of mildly to moderately Total score for the Hamilton Rating Difference 5.1 points, p < 0.001 depressed patients. Final n: 64 Scale for Depression (HAMD, 17 – (in favor of hypericum) item version) ≥ 16 at study entry and High placebo response rate. during a subsequent baseline % of patients showing at least a 50% reduction in HAM-D scores: investigation (3 to 7 days later). Study may be underpowered to Rx1: 62.2% [95% CI: 46.5 to 77.8] detect differences in 50% reduction Rx2: 42.9% [95% CI: 26.5 to 59.3] in HAM-D scores. p = 0.10

% of patients showing at least a 60% reduction in HAM-D scores:

Rx1: 51.4% [95% CI: 35.2 to 67.5] Rx2: 17.1% [95% CI: 4.7 to 29.6] p = 0.002

Table 2.8 Study, Treatment Groups Size & Drug Study Population Results Comments Total n

Behnke, K. Rx1: hypericum 18 to 73 years of age with mild to Change (decrease) in HAM-D score (%) The study concludes that 2002 (RCT, double-blind) (150 mg twice daily) (n = 35) moderate depression Rx1: 50% Hypericum perforatum is Rx2: 58% therapeutically equivalent to Follow-up = 6 weeks Rx2: fluoxetine Hamilton Rating Scale for The decrease was highly significant fluoxetine and therefore a (20 mg twice daily) Depression of between 16 and 24 (p < 0.001) in both groups but not significantly different (p = 0.23) between rational alternative to Initial n: 70 (n = 35) groups synthetic antidepressants.

Final n: 61 No placebo control group No placebo control group

3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, or Plan

Problem Formulation 3

Clinical Question: Which antidepressants should be avoided for treatment of patients with MDD expressing suicidal ideation, intent, or plan? To assist primary care physicians and other health care professionals Intended Use of in treating adults with Major Depression who are expressing suicidal the Guideline: ideation, intent, or plan. Population: All adult (age 19 and older) patients with Major Depression treated with antidepressant medication who are expressing suicidal ideation, intent, or plan Suicide ideation, intent, or plan in primary care patients taking Health Problem: antidepressants

Health Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs) Intervention: KP primary care physicians, physician assistants, nurse practitioners, Practitioners: pharmacists, and health educators

Setting: Outpatient office visit, emergency department, urgent care clinics

Health Outcomes  Hospitalizations (associated with the  Attempted suicide intervention):

Side Effects  Suicide by overdose Associated With  Suicide (all cause) the Intervention:

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed (((("depression/drug effects"[MESH] Only items with 8/2005 0/411 OR "depression/drug abstracts, to therapy"[MESH]) OR Humans, 9/2007 "depression/therapy"[MESH]) OR Randomized "antidepressive Controlled Trial, agents/poisoning"[MeSH] OR "Major English, All Depressive Disorder"[All Fields]) Adult: 19+ years AND (("suicide"[MeSH Terms] OR suicide[Text word]) OR "suicide, attempted"[MeSH])) Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Cochrane Group Reviews Clinical Systematic January N/A Evidence, Chapter: Depressive Disorders Reviews and 2006 Issue 14 RCTs PubMed (((("depression/drug effects"[MESH] All Adult: 19+ 01/01/03 1/187 OR "depression/drug years, - therapy"[MESH]) OR Publication Date 08/01/05 "depression/therapy"[MESH]) OR from 2003/01/01 "antidepressive to 2005/08/01, agents/poisoning"[MeSH] OR "Major English, Humans Depressive Disorder" [All Fields])AND (("suicide"[MeSH Terms] OR suicide[Text word]) OR "suicide, attempted"[MeSH])) AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "3000"[PDAT]) AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT])

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Systematic 06/05/03 0/80 Cochrane Suicide reviews Systematic 06/05/03 1/6 Clinical Suicide reviews and Evidence RCTs PubMed (((((((((((depression/drug therapy Randomized, 1998 0/222 [MESH] OR depression/therapy controlled trials, - [MESH]) OR ("depressive disorder/ All adults 19+ 03/2001 drug therapy"[MESH] OR "depressive years, English disorder/therapy" [MESH])) OR ("dysthymic disorder/drug therapy"[MESH] OR "dysthymic disorder/therapy"[MESH])) AND ("Serotonin Uptake Inhibitors"[MESH] OR "Antidepressive Agents, Tricyclic"[MESH])) AND notpubref[sb]) PubMed (((((((("depression/drug All Adult: 19+ 01/01/01 1/67 effects"[MESH] OR "depression/drug years English, - therapy"[MESH]) OR Human 04/01/03 "depression/therapy"[MESH]) OR "antidepressive agents/poisoning" [MeSH] OR "Major Depressive Disorder"[All Fields]) AND (("suicide"[MeSH Terms] OR suicide[Text word]) OR "suicide, attempted"[MeSH]))

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed.

Buckley(112) did not show up in our search results due to the way PubMed indexing is done.

Other Information Source:  Evidence report on the Treatment of Depression - Newer Pharmacotherapies. AHRQ(169)

Evidence Tables

Table 3.1 Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT p value

Yerevanian, et al. Inclusion: 43 Treatment Patient charts (N = 521) N/A Number of the following Rate of suicidal behavior < 0.0001 (2004) In clinical care with senior (mean) adherence not part were followed and events during periods of significantly higher in Antidepressants author from 1978-2002; of methodology. reviewed. active treatment or discontinuation vs. active and suicidal DSM-IV criteria for Major discontinuation with treatment period (p <0.00001) behavior in Depression and/or SSRIs or TCAs. unipolar dysthymia; minimum 6 Rate of suicidal behavior < 0.0001 depression month follow-up by senior 1) completed suicide, 2) significantly higher in author; antidepressant suicide attempts, or discontinuation vs. active monotherapy; charts 3)hospitalization for treatment period with TCAs contained specific serious suicidal thought (p <0.00001) <0.0001 information about suicidal or intent behavior. Rate of suicidal behavior significantly higher in Exclusion: discontinuation vs. active Multiple antidepressant, treatment period with SSRIs mood stabilization, or (p <.00001) <0.0001 antipsychotic regimens; alcohol and substance Rate of suicidal behavior similar for abuse. active TCA vs. active SSRI treatment (p =0.046) 0.046

Table 3.2 Intervention and Inclusion & dose Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT p value Martinez, et al. Patients (N = 146,095) ≤ 90 Outcome under study might Clinical records (N = N/A Risk of nonfatal self- 1968 cases of self-harm (2005) from Primary Care in in itself be the reason one 146,095) from the harm and suicide 69 suicides Antidepressant the UK with a new drug was prescribed over General Practice between users of treatment and diagnosis of another. Research Database were SSRIs and users of Adjusted odds ratio of nonfatal NS the risk of fatal depression who were acquired and reviewed. TCAs. self-harm in people prescribed and nonfatal prescribed No consistent monitoring of SSRIs vs. TCAs was 0.99 (95% CI: self-harm in first antidepressants for adherence to medication. 0.86 - 1.14) episode the first time between depression: 1995 and 2001. Large number of hypothesis Adjusted odds ratio of suicide in NS nested case tests could have led to people prescribed SSRIs vs. TCAs control study. change findings of was 0.57 (95% CI: 0.26 - 1.25) associations. No evidence risk of nonfatal self- 0.35 No comparison between harm varied among different those prescribed SSRIs and SSRIs. those with equivalent morbidity not receiving No evidence risk of nonfatal self- 0.69 treatment (i.e. no control). harm varied among different TCAs.

No age-related differences in nonfatal self harm between patients prescribed SSRIs and TCAs.

Table 3.3 Inclusion & Exclusion Limitations / Intervention and dose p Study Criteria Age Biases N and Final N Duration Outcome Results NNT value Fergusson, et All RCTs (N = 702) Underreporting of Three separate meta-analyses Number of fatal Significant increase in odds of suicide 684 0.02 al. (2005) comparing SSRI suicide attempts in were conducted to evaluate the and nonfatal attempts for patients receiving SSRIs (NNT to Association with placebo or RCTs. association between suicide suicide compared with placebo (odds ratio harm) between active non-SSRI attempts and the sue of SSRIs: attempts. 2.28, CI: 1.14 to 4.55). suicide control. Treatment High rates of losses to attempts and condition not limited follow-up. 1) SSRIs compared with No difference in odds of suicide selective to Major placebo attempts in patients receiving SSRIs serotonin Depression. Small trial sizes and compared with TCAs (odds ratio 0.88, reuptake durations. 2) SSRIs compared with TCAs CI: 0.54-1.42). inhibitors: 239 systematic Some trials restricted 3) SSRIs compared with other Increase in odds of suicide attempts (NNT to review of eligibility to patients active forms of treatment. when comparing SSRIs with harm) randomised who previously therapeutic interventions other than controlled trials. tolerated SSRIs well. TCAs (odds ratio 1.94, 1.06 to 3.57).

Some trials did not have a sufficient washout period.

Did not compare TCAs with placebo, or other active treatment with placebo.

Table 3.4 Inclusion & Intervention and Exclusion dose p Study Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value Gibbons, et al. Suicides in all US 5+ Medication estimates based Analysis of relationship N/A Primary outcome Overall relationship between all (2005) The counties between on outpatient use. between antidepressant measure was number of prescribed antidepressant drugs and relationship 1996-1998; pharmacy prescription suicides for given suicide rate was not statistically between adjusted for sex, Uncontrolled variability in volumes and overall population size. significant (p = 0.14). 0.14 antidepressant race, age and suicide rate data (definition of suicide rate. medication use income. suicide, qualifications of For individual classes of and rate of medical examiner, extent of antidepressants, there was a suicide. case investigation, relationship significant positive association between prescription rates and between TCAs and suicide rate < 0.001 actual taking of medication, (p < 0.001). quality of data) Combination of SSRI and non-SSRI Possible selection bias or non-TCA prescriptions had a < 0.001 (different classes of significant negative association with antidepressants may have suicide rate (p < 0.001). been selectively prescribed to different patient groups).

No data on cause of suicide.

4. Second-Line Treatement of MDD

Problem Formulation 4

Clinical Question: What strategies should be used in adults with MDD whose symptoms do not resolve after the first-line treatment?

Intended Use of To assist primary care physicians and other health care professionals in the Guideline: treating adults with Major Depression. Population: All adult (age 19 and older) with Major Depression who are unresponsive to first-line treatment Health Problem: MDD Health  Change antidepressant medication Intervention:  Increase existing antidepressant dose  Switch to psychotherapy  Add psychotherapy  Add another antidepressant to existing antidepressant  Add an augmenting agent to the existing antidepressant (lithium, beta-blocker, buspirone, Cytomel, carbamazepine, valproic acid, methylphenidate, ethyl-eicosapentaenoate (E-EPA), folate, inositol, atypical antipsychotic, risperidone, aripiprazole  rTMS  Vagus nerve stimulation Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics Health Outcomes  Change in symptoms  Office/UCC/ER visits (associated with  Quality of life  Hospitalizations the intervention):  Missed school/work days  Mortality  Sexual problems Side Effects  Constipation  Drowsiness Associated With  Diarrhea  Headache the Intervention:  Abdominal pain  Nausea  Dizziness  Insomnia  Blurred vision  Agitation/nervousness  Weight gain  Dry mouth  GI bleeding  Seizures  Falls  Elevated blood pressure

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items 8/2005 0/129 Depressive Disorder"[All Fields] AND with to (“systematic"[All Fields] OR “systematic abstracts, 9/2007 review"[All Fields] OR “meta- Humans, analysis"[All Fields])) English, All Adult: 19+ years Cochrane Depression N/A 2005 0/134 Systematic to Reviews 2007 PubMed ((("depression/drug effects"[MESH] OR Randomized 8/2005 5/271 "depression/drug therapy"[MESH]) OR controlled to "depression/therapy"[MESH]) OR "Major trials, only 9/2007 Depressive Disorder"[All Fields]) AND items with ((((("Antidepressive Agents/adverse abstracts, effects"[MESH] OR "Antidepressive Humans, Agents/therapeutic use"[MESH]) OR English, All “apiprazole” [text word] OR “atypical Adult: 19+ antipsychotic”[text word] OR years "carbamazepine"[MESH terms] OR "valproic acid"[MESH terms] OR "buspirone"[MESH terms] OR "triiodothyronine"[MESH terms] OR Cytomel[text word] OR "adrenergic beta- antagonists "[MESH terms] OR beta blocker[text word] OR "methylphenidate"[MESH terms] OR "psychotherapy"[MESH terms]) OR (cognitive[All Fields] AND "behavior therapy"[MESH Terms])) OR "interpersonal therapy"[All Fields]) OR ("Problem-solving"[MESH Terms] AND "therapy"[MESH Subheading])))

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* National Depression Systematic Decembe N/A Institute Review, r 6, 2004 for Meta- Clinical analyses and Excellence RCTs (NICE) Cochrane Depression, Anxiety and Neurosis Group Systematic Q4, 2005 3/131 Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs PubMed (((("depression/drug effects"[MESH] OR Randomized, 01/01/05 6/239 "depression/drug therapy"[MESH]) OR controlled - "depression/ therapy" [MESH]) OR trials 08/01/05 "Major Depressive Disorder"[All Fields]) AND ((((("Antidepressive Agents/adverse effects"[MESH] OR "Antidepressive Agents/therapeutic use"[MESH]) OR "carbamazepine"[meSH terms] OR "valproic acid"[meSH terms] OR "buspirone"[meSH terms] OR "triiodothyronine "[meSH terms] OR Cytomel[text word] OR "adrenergic beta- antagonists "[meSH terms] OR beta blocker[text word] OR "methylphenidate"[meSH terms] OR "psychotherapy"[MESH]) OR (cognitive[All Fields] AND "behavior therapy"[MeSH Terms])) OR "interpersonal therapy"[All Fields]) OR ("Problem-solving"[MeSH Terms] AND "therapy"[MeSH Subheading]))) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT]) Systematic 03/05/03 0/295 Cochrane Depression reviews

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Systematic 03/05/03 1/80 Clinical Depression reviews and Evidence RCTs PubMed (((("depression/drug effects"[MESH] OR Meta-analysis, 01/01/80 0/12 "depression/drug therapy"[MESH]) OR All Adult: 19+ - "depression/therapy"[MESH]) OR "Major years English, 12/31/00 Depressive Disorder"[All Fields]) AND Human ((((("Antidepressive Agents/adverse effects"[MESH] OR "Antidepressive Controlled 01/01/80 0/576 Agents/therapeutic use"[MESH]) OR Trials, All - "carbamazepine" [meSH terms] OR "valproic Adult: 19+ 12/31/00 acid" [meSH terms] OR "buspirone" [meSH years English, terms] OR "triiodothyronine " [MESH terms] Human OR Cytomel [text word] OR "adrenergic beta- antagonists " [MESH terms] OR beta blocker [text word] OR "methylphenidate" [MESH terms]OR "psychotherapy"[MESH]) OR (cognitive[All Fields] AND "behavior therapy"[MESH Terms])) OR "interpersonal therapy"[All Fields]) OR ("Problem- solving"[MESH Terms] AND "therapy"[MESH Subheading]))) PubMed /therapeutic use"[MESH]) OR "carbamazepine" Meta-analysis, 01/01/01 0/5 [meSH terms] OR "valproic acid" [meSH terms] All Adult: 19+ - OR "buspirone" [meSH terms] OR years English, 04/01/03 "triiodothyronine " [meSH terms] OR Cytomel Human [text word] OR "adrenergic beta-antagonists " [meSH terms] OR beta blocker [text word] OR Controlled 01/01/01 3/129 "methylphenidate" [meSH terms]OR Trials, All - "psychotherapy"[MESH]) OR (cognitive[All Adult: 19+ 04/01/03 Fields] AND "behavior therapy"[MeSH Terms])) years English, OR "interpersonal therapy"[All Fields]) OR ("Problem-solving"[MeSH Terms] AND Human "therapy"[MeSH Subheading])))

The rationale statement from the November 2005 KP Inter-regional New Technologies evidence- based review on vagus nerve stimulation was incorporated into these guidelines.

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. The Peet(136) study did not show up in the search results due to the way PubMed indexing is done. The GDT decided to include this study, since it met the inclusion criteria. The Perez(138) study did not show up in the search results because pindolol was indexed as serotonin receptor antagonist rather than as a beta-blocker or an adrenergic beta- antagonist.

Evidence Tables

Table 4.1: RCTs of Second-Line Treatments for Depression Augmentation Switch to with Cognitive Augmentation Cognitive Switch to New Mean Follow Follow Therapy with Medication Therapy Medication ±SD Age (yr) % -up -up % % % % Study Name N Female Rate Time Remissions N Remissions N Remissions N Remissions N p Quality† Biases* AUG 40.0±12.8 Thase, 65.4 14 SW 42.2±13.7 NR 23.1 15 33.3 39 25.0 9 27.9 24 NS 1 3, 4 2007 61.5 weeks N Cognitive therapy not independently validated. No placebo control group included. Mean Follow Follow Bupropion-SR Sertraline Venflaxine-XR ±SD Age (yr) % -up -up % % % Study Name N Female Rate Time Remissions N Remissions N Remissions N p Quality† Biases* Rush, 41.8±12.8 14 58.7 NR 21.3 51 17.6 42 24.8 62 NS 1 4 2006 727 weeks Adverse effects were similar among treatment groups. No placebo control group included. Mean Follow Follow Bupropion-SR Buspirone ±SD Age (yr) % -up -up Study Name N Female Rate Time % Remissions N % Remissions N p Quality† Biases* Trivedi, 41.1 ± 12.7 6 58.8 NR 29.7 83 30.1 86 NS 1 4 2006 565 weeks Adverse effect burden was similar among treatment groups; however, fewer participants taking citalopram plus sustained-release bupropion stopped treatment because of intolerance than did those taking citalopram plus buspirone (12.5 percent vs. 20.6 percent; ÷ 2 = 6.86; p<0.001). No placebo control group included. Mean Follow Follow Risperidone Placebo ±SD Age (yr) % -up -up Study Name N Female Rate Time % Remissions N % Remissions N p Quality† Biases* Mahmoud, Risperidone 137 70.8 6 0.0 81% 25.4 26 10.7 12 4 1 2007 Placebo 131 76.3 weeks 04 Adverse effects were similar among treatment groups. Funded by manufacturer of risperidone. AUG, augmentation; NR, not reported; NS, not significant; SW, switch †Study quality measured by Jadad scoring system (1 to 5 = low to high *Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization)

Table 4.2: Meta-analyses of Augmentation with Atypical Antipsychotic Medications Studies Study Population Total N Group Size & Drug Results Comments Papakostos GI 2007 All patients diagnosed with treatment- Remission: Discontinuation due to adverse effects:RR = 3.38 Authors’ conclusions: These results support the utility of (meta-analysis) resistant depression RR = 1.75 (95% CI, 1.36– 2.24; (95% CI, 1.98-–3.38; p<0. 0001) for active augmenting therapy for treatment-resistant depression with p<. 0001) for active treatment treatment versus placebo atypical antipsychotic. # studies found: 137 All trials compared adjunctive treatment versus placebo # studies included: 10 with atypical antipsychotics against No difference noted in overall rate of Biases, etc.: Studies involved only olanzapine, quetiapine, placebo treatment. Pooled remission: discontinuation: and risperidone. Total N = 1500 Active treatment: 47.4% RR = 1.18 (95% CI, 0.93–1.49; p =0.929) 4 trials from published medical literature Placebo: 22.3% Higher discontinuation rate due to side effects with Heterogeneity: heterogeneity 6 reports from scientific meetings active treatment: addressed by use of random- Pooled response: RR = 3.38 (95% CI, 1.98–5.76; p<0.001) effects model 5 reports of olanzapine Active treatment: 57.2% 3 reports of quetiapine Placebo: 35.4% 2 reports of risperidone

Table 4.3: RCTs of Augmentation with Atypical Antipsychotic Medications Follow Placebo Apiprazole Mean ± SD Age (yr) Follow- -up % % Study Name N % Female up Rate Time Remissions N Remissions N p Quality† Biases* Berman, Placebo 44.2±10.9 64.2 90.9 6 weeks 15.7 27 26.0 47 <0. 05 5 None 2007 176 Apiprazole 46.5±10.6 61.5 87.9 182 81.9% of active-treatment patients reported adverse effects.

†Study quality measured by Jadad scoring system (1 to 5 = low to high *Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization)

Table 4.4: RCTs of Third-Line Treatments for Depression Mean ± SD Age (yr) Follow- Follow- Mirtazapine Nortriptyline Study Name N % Female up Rate up Time % Remissions N % Remissions N p Quality† Biases* Fava, 44.9±11.9 46.8 NR 14 12.3 14 19.8 24 NS 1 3,4 2006 235 weeks Adverse effects were similar among treatment groups. No placebo control group included. Mean ± SD Age (yr) Follow- Follow- Lithium Triiodothyronine Study Name N % Female up Rate up Time % Remissions N % Remissions N p Quality† Biases* Nierenberg, 42.0±2.0 58.5 NR 9.6 weeks 15.9 11 24.7 18 NS 1 3, 4 2006 142 Fewer side effects were seen with triiodothyronine. No placebo control group included. NR, not reported; NS, not significant †Study quality measured by Jadad scoring system *Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization)

Table 4.5

Inclusion & Exclusion Intervention and dose p Study Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value

Schatzberg Inclusion: 18-75 No placebo control; no 681 patients randomized into 24 weeks HAM-D score of Both groups improved from (2005) Adult outpatients in a current nonresponder control acute phase of nefazodone (N nonresponders to baseline of crossover to Major Depressive Disorder group continuing in = 226), CBASP (N = 228) or nefazodone or CBASP endpoint. Medication episode and scoring 20+ on previous (initial) therapy. combination therapy (N = 227). 12 weeks after they (Nefazodone) or the HAM-D switched to the other In the intention-to-treat psychotherapy Treatments only switched After 12 weeks, nonresponders treatment. analysis, patients who (CBASP) is Exclusion: for nonresponders able to of nefazodone (N = 73) were switched from nefazodone effective when the Organic mental syndromes, complete acute trial. switched to CBASP and to CBASP showed 0.03 other is not psychotic disorders, panic nonresponders of CBASP (N = significantly greater disorder, PTSD, substance Excluded patients with 83) were switched to improvement than those abuse, eating disorders, greater levels of comorbid nefazodone. who had switched from suicidality, medical conditions. CBASP to nefazodone. contraindications to antidepressants, unstable Nonresponders who In the completer analysis, general medical disorders, entered crossover trial there was no significant nonresponse to nefazodone, may not have been between-group difference. recent treatment with comparable since they benzodiazepines, fluoxetine, were not initially MAO-I, ECT, neuroleptics; randomized. psychotherapy outside trial

Table 4.6

Inclusion & Limitations / Intervention and dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Parker, Brotchie, & Inclusion: Mean Small number of Patients (N = 20) randomized into 2 weeks HAM-D scores at 2 Nonsignificant HAM-D improvement: 0.06 Parker (2005) Is Male and female age subjects. one of two groups: weeks. Endpoint combination outpatients with a first or 49 Baseline (Day 14) olanzapine and new episode of DSM-IV Rx1: antidepressant plus Rx1 20.5 8.4 antidepressant nonpsychotic Major olanzapine (N = 10) Rx2 23.6 13.5 medication Depression. associated with a Rx2: antidepressant plus placebo Four nonresponders of antidepressant more rapid Exclusion: (N = 10) [After two weeks, Rx2 plus placebo who were given olanzapine response trajectory Antidepressant in nonresponders (N = 4) were given at 2 weeks, showed distinctive than preceding two weeks, late olanzapine augmentation.] improvement from baseline at day 21. antidepressant ECT in previous one Endpoint alone? month. Baseline (Day 21) Rx2 25.2 3.0 Table 4.7

Inclusion & Limitations / Intervention and dose p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Perry, et al. Inclusion: 18-75 Type II error. Patients initially received at least 20 3 weeks Primary outcome No significant differences in (2004) Pindolol Male and female mg fluoxetine, 20mg paroxetine, or measure was change antidepressant response augmentation in outpatients with Major Inconsistent dosing in 50mg sertraline per day for a in HAM-D score from between the two groups: depressed Depression (per DSM IV acute phase. minimum of 6 weeks prior to study. baseline to the end of patients resistant criteria) and minimum week 3. Partial response rates for to selective HAM-D baseline score of Confounding patient Forty-two patients who failed to pindolol (19%) and control (24%) serotonin 25. characteristics. respond sufficiently to acute trial of were comparable at three weeks. reuptake SSRIs were continued on SSRI inhibitors: a Exclusion: treatment and randomly assigned to Pindolol and control groups double-blind, RCT Neuroleptics, psychosis, one of the following groups for 3 demonstrated mean decreases in substance abuse, weeks: HAM-D scores of 6.5 and 9.7, pregnancy, respectively, at three weeks. contraindications to beta Rx1 blockers, reactive airway pindolol 2.5mg tid (N = 21) disease, diabetes, significant medical illness. Rx2 placebo tid (N = 17)

Table 4.8 Intervention and Inclusion & dose p Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value

Kauffmann (2004) Inclusion: 18+ Small number of subjects. Patients randomly 10 days Primary outcome Mean HAM-D score for Rx1 decreased < 0.02 Slow right Eleven females, one male assigned to one of two measure was HAM-D significantly from 21.86 to prefrontal (mean age 52) with Major Short duration (10 days). groups: score after 10 days. 11.29.(p<.02) transcranial Depression (per DSM-IV magnetic criteria) who failed to Limited evidence. Rx1: Mean HAM-D score for Rx2 group > 0.09 stimulation as a respond to at least two Right transcranial decreased from 18.20 to 11.80 (not treatment for standard antidepressants Effectiveness of blinding magnetic stimulation significant). (p>.09) medication- given at adequate doses not assessed. (rTMS), N = 7 resistant for at least 8 weeks. On follow-up, Rx1 relapsed after 2-3 depression: a Control group stimulation Rx2: months, whereas Rx2 relapsed after 2 double-blind, Exclusion: similar to treatment group "sham" rTMS, N = 5 weeks. placebo- Pre-existing neurological stimulation. controlled study and/or cardiac diseases. Unadjusted differences in baseline HAM-D scores: Active group 21.9, control group 18.2.

Group x time interaction not assessed.

Table 4.9 Intervention and Inclusion & dose p Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value

Rumi (2005) Inclusion: Mean Efficacy of blinding not Seven days prior to 4 weeks Primary outcome Overall response ratio (HAM-D < 0.001 Transcranial Outpatient adults with age 39 assessed. treatment, all patients (N = measures were HAM-D decrease ≥ 50%) was significantly magnetic severe nonpsychotic 46) were started on and MADRS scores, CGI higher in rTMS group than in sham stimulation Major Depressive Disorder Short-term study. amitriptyline which were changes, and VAS at group (95% and 46% respectively). accelerates the (DSM-IV) and minimum maintained during the 4- four weeks. antidepressant baseline score of at least Longer-term difference in week trial. Remission (HAM-D ≤ 7) was < 0.002 effect of 22 on HAM-D response and remission significantly higher in rTMS group than amitriptyline in rates not assessed. Patients (N = 46) were in sham group (54% and 12% severe Exclusion: randomized into one of respectively). depression: a Neurological conditions, two groups: double-blind, personality disorders, Similar findings were observed for placebo-controlled suicide risk, severe Rx1: MADRS and CGI scales, and study. uncontrolled organic rTMS (N = 22) - 5 subjective assessments through VAS. disease, substance abuse, sessions a week for four abnormal lab tests, weeks. Neck pain and burning, and burning in pacemaker, history of scalp was significantly predominant in seizure, major head Rx2: rTMS group. trauma, risk factors for sham rTMS (N = 24) - 5 TMS procedure. sessions a week for four The need for clonazepam was < 0.001 weeks. significantly smaller in rTMS group than in sham group (p<0.001). Clonazepam was allowed for sedative purposes; its use was monitored throughout the trial.

Table 4.10 Study, Total n Treatment Groups Size & Drug Study Population Results Comments

Hirschfeld, M. Rx1: nefazodone at 200 mg/day (in 2 Patients met criteria for either chronic HAM-D score analysis (numbers obtained from initial Keller There was greater improvement in 2002 (RCT, open-label divided doses) during the first week and Major Depressive Disorder, current Major study) psychosocial functioning and trial) increased to 300 mg/day during week two, Depressive Disorder superimposed on p = 0.68 (Rx1 vs. Rx2) (no difference) general health when combined dose adjustments were made thereafter in antecedent dysthymic disorder, or p ≤ 0.001 (Rx1 vs. Rx3) (in favor of combined treatment) treatment was used. Follow-up: 12 weeks weekly increments of 100 mg/day up to 600 recurrent MDD with incomplete p ≤ 0.001 (Rx2 vs. Rx3) (in favor of combined treatment) mg/day. interepisode recovery (by definition, Combined treatment was Initial n: 681 these patients would have failed first-line SF-36 general health without HAM-D statistically superior to Rx2: Cognitive Behavioral Analysis System treatment). p = 0.22 (Rx2 vs. Rx1) (no difference) psychotherapy or nefazodone Final n: Not stated of Psychotherapy (CBASP) drawing on p = 0.0003 (Rx3 vs. Rx1) (in favor of combined treatment) alone in reducing the HAM-D score techniques from behavioral, cognitive, and Men and women between the ages of 18 p = 0.02 (Rx3 vs. Rx2) (in favor of combined treatment) in patients with chronic Major interpersonal forms of psychotherapy and 75 (Mean of 43 ± 11) Depressive Disorder. SF-36 social functioning with HAM-D as covariate: Rx3: Combined nefazodone/CBASP 65% female, 91% white, p = 0.94 (Rx2 vs. Rx1) (no difference) Patients were not blind to 43% married/cohabiting p = 0.02 (Rx3 vs. Rx1) (in favor of combined treatment) treatment received p = 0.02 (Rx3 vs. Rx2) (in favor of combined treatment) Score of ≥ 20 on the 24-item Hamilton No placebo control group Rating Scale for Depression (HAM-D)

Table 4.11 Study, Treatment Groups Size & Total n Drug Study Population Results Comments

Fava, M. Rx1: High-dose fluoxetine Outpatients with Major Mean change in HAM-D-17 score (from visit 1-endpoint)for all patients For patients who fail to respond to a trial of a standard dose 2002 (RCT, (40 – 60 mg/day) Depressive Disorder (52 with partial response or nonresponse to fluoxetine of fluoxetine (20 mg/day), there are no significant double-blind) (n = 33) men and 49 women, 20 mg/day differences in efficacy among patients whose fluoxetine between 18 and 65 years Rx1: 5.1± 5.3 dose is raised to 40 to 60 mg/day, patients on fluoxetine Follow-up: 4 Rx2: fluoxetine (20 mg/day) old) who were either Rx2: 3.5 ± 5.6 plus low-dose desipramine weeks plus desipramine partial responders or Rx3: 3.6 ± 6.2 p = 0.4 (not significant) (25 – 50 mg/day), and patients on fluoxetine plus low-dose (25 – 50 mg/day) (n = 34) nonresponders to eight lithium (300 – 600 mg/day). Initial n: 101 weeks of treatment with Response rate % (at least 50% reduction in HAM-D score) Final n: 88 Rx3: fluoxetine (20 mg/day) fluoxetine 20 mg/day. Rx1: 50% Patients who partially respond to eight weeks of fluoxetine plus lithium Rx2: 33.3% 20 mg/day may respond more completely to higher doses (300 – 600 mg/day) (n = 34) Rx3: 33.3% p = 0.5 (not significant) of fluoxetine (with a response rate of 50%), although the Initial HAM-D-17 score of difference in response rates across the three treatment ≥ 16 Most common side effects: groups was not statistically significant. Rx1: gastrointestinal distress (54.5%), headache (42.4%), dizziness (30.3%), dry mouth (27.3%), sedation or fatigue (18.2%) No placebo control group – does not allow comparison with Rx2: dry mouth (55.9%), gastrointestinal distress (47.1%), dizziness continuing initial dose of antidepressant for a longer period (35.3%), insomnia (32.4%), agitation (29.4%), sedation or fatigue of time, and does not exclude placebo response to (26.5%) augmentation. Rx3: gastrointestinal distress (50.0%), dry mouth (38.2%), insomnia (35.3%), sedation or fatigue (32.4%), headache (26.5%) May have been underpowered.

There were no significant differences in dropout rates across the three groups.

Table 4.12 Study, Treatment Groups Size Study Population Results Comments Total n & Drug

Peet, M. Rx1: ethyl-eicosapentaenoate Patients of either sex, aged Change in HDRS (17-item Hamilton Depression Rating Scale) score for the Treatment with ethyl-eicosapentaenoate at a 2002 (RCT, 1 g/d plus three placebo 18 to 70 intent -to- treat (ITT) population dosage of 1 g/d, but not higher doses is effective double-blind) capsule (n = 17) (comparing active treatment with placebo) in treating depression in patients who remain HAM-D-17 score of 15 or Rx1: 9.9, p = 0.02 (statistically significant) depressed despite adequate standard therapy Follow-up: 12 Rx2: ethyl-eicosapentaenoate more despite ongoing Rx2: 5.8, p = 0.88 (no difference) (suggests a possible therapeutic window effect). weeks 2 g/d plus two placebo treatment with a standard Rx3: 5.4, p = 0.44 (no difference) capsules (n = 18) antidepressant at an adequate Rx4: 5.1 Small n Initial n: 70 dose Final n: 60 Rx3: ethyl-eicosapentaenoate Change in Montgomery-Asberg Depression Rating Scale (MADRS) score for 3 g/d plus one placebo ITT population (comparing active treatment with placebo) Intention-to treat capsule (n = 17) Rx1: 11.2, p = 0.006 (statistically significant) Rx2: 3.0, p = 0.41 (no difference) Rx4: Liquid paraffin placebo, Rx3: 8.5, p = 0.15 (no difference) four capsules Rx4: 5.4 (n = 18) Change in Beck Depression Inventory (BDI) score for the intention-to- treat (ITT) population (comparing active treatment with placebo)

Rx1: 12.5, p = 0.007 (statistically significant) Rx2: 5.7, p = 0.99 (no difference) Rx3: 9.3, p = 0.24 (no difference) Rx4: 5.5

Table 4.13 Study, Treatment Groups Size & Study Population Results Comments Total n Drug

Nemets, B. Rx1: Ethyl- eicosapentaenoate 17 women and 3 men Change in mean Hamilton Depression Rating Highly significant benefits of the addition of the 2001 (RCT, double-blind) (E-EPA), 2 g/day (18 – 75 years old) with a current Scale Score from baseline to week four omega-3 fatty acids compared with placebo were diagnosis of Major Depressive Disorder Rx1: 12.4 found by week 3 of treatment, Rx2: 1.6 Follow-up: 4 weeks Rx2: Placebo 24-item Hamilton Depression Rating Scale p = not stated Small n of 18 or higher Initial n = 20 No clinically relevant side effects were Final n = 19 Patients under standard antidepressant reported. treatment for at least three months except for one.

Table 4.14 Study, Treatment Groups Size & Study Population Results Comments Total n Drug

Perez, VS. Rx1: 5-HT reuptake inhibitors Adults 18 to 65 years Change in HAM-D score from day 0 to day 10 The study does not support the hypothesis that 1999 (RCT, double-blind) plus pindolol (2.5 mg tid) (n = 40) Existence of a Major Depressive Disorder, the addition of pindolol results in a rapid single or recurrent (DSM-IV) with a current Rx1: 2.2 ± 4.4 augmentation of the effects of SSRIs in depressed Follow-up: 10 days Rx2: 5-HT reuptake inhibitors episode resistant to pharmacological Rx2: 3.7 ± 5.9 patients resistant to initial treatment with plus placebo (tid) (n = 40) treatment Difference not significant, p value not given antidepressants. Initial n: 80 17-item Hamilton depression-rating scale Final n: 78 score of ≥ 16 All patients except 2 were outpatients.

5. Length of Treatment With Antidepressants In Patients With MDD

Problem Formulation 5

Clinical Question: How long should adults with MDD continue taking antidepressant medication?

Intended Use of To assist primary care physicians and other health care professionals the Guideline: in treating adults with Major Depression.

Population: All adult (age 19 and older) patients with Major Depression who receive treatment with antidepressant medication with:  One lifetime episode of MDD  Two or more episodes of MDD

Health Problem: MDD

Health Intervention: Continue antidepressant (SSRIs, TCAs, DAs, SNRIs, or NRIs) treatment for appropriate length of time Discontinue antidepressant treatment

Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators

Setting: Outpatient office visit, emergency department, urgent care clinics

Health Outcomes  Change in symptoms  Office/UCC/ER visits (associated with the  Quality of life  Hospitalizations intervention):  Missed school/work days  Mortality

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items 8/2005 0/129 Depressive Disorder"[All Fields] AND with to (“systematic"[All Fields] OR abstracts, 9/2007 “systematic review"[All Fields] OR Humans, “meta-analysis"[All Fields])) English, All Adult: 19+ years PubMed ("depression/drug therapy"[MeSH] OR Only items 8/2005 0/72 "depression/therapy"[MeSH] OR with to "depressive disorder/drug therapy"[MeSH] abstracts, 9/2007 OR "depressive disorder/prevention and Humans, control"[MeSH] OR "Antidepressive Randomized Agents/ administration and dosage"[MeSH] Controlled OR "depression recurrent"[All Fields] OR "depression chronic"[All Fields] OR "Major Trial, English, Depressive Disorder"[All Fields]) AND All Adult: ("drug administration schedule"[MeSH] OR 19+ years "Recurrence/prevention and control"[MeSH] OR "Treatment duration"[All Fields] OR "treatment discontinuation"[All Fields] OR "treatment continuation"[All Fields]) National Depression Systematic December N/A Institute Review, 6, 2004 for Meta- Clinical analyses and Excellence RCTs (NICE) Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Group Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("depression/drug therapy"[MeSH] OR Randomized, 01/01/03 3/81 "depression/therapy"[MeSH] OR controlled - "depressive disorder/drug therapy"[MeSH] trials 08/01/05 OR "depressive disorder/prevention and control"[MeSH] OR "Antidepressive Agents/administration and dosage"[MeSH] OR "depression recurrent"[All Fields] OR "depression chronic"[All Fields] OR "Major Depressive Disorder"[All Fields]) AND ("drug administration schedule"[MeSH] OR "Recurrence/prevention and control"[MeSH] OR "Treatment duration"[All Fields] OR "treatment discontinuation"[All Fields] OR "treatment continuation"[All Fields]) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "3000"[PDAT]) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT]) Systematic 03/05/03 0/295 Cochrane Depression reviews Systematic 09/22/03 1/86 Clinical Depression reviews & Evidence RCTs

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ((((("depression"[MeSH Terms] OR Randomized, 1980 0/344 depression[Text Word]) AND ("drug controlled - administration schedule"[MeSH Terms] OR trials , English, 9/2001 DRUG ADMINISTRATION Randomized SCHEDULE[Text Word])) 01/01/1980 5/308 Controlled ("depression/drug therapy"[MeSH] OR - Trial, All "depression/therapy"[MeSH] OR 04/01/2003 Adult: 19+ "depressive disorder/drug therapy"[MeSH] years, English, OR "depressive disorder/prevention and Human control"[MeSH] OR "Antidepressive Agents/administration and dosage"[MeSH] Meta-Analysis, 01/01/1980 0/4 OR "depression recurrent"[All Fields] OR All Adult: 19+ - "depression refractory"[All Fields] OR years, English, 04/01/2003 "depression chronic" [All Fields] OR Human "depression first episode"[All Fields] OR Review, All 01/01/1980 0/44 "Major Depressive Disorder"[All Fields]) Adult: 19+ - AND ("drug administration years, English, 04/01/2003 schedule"[MeSH] OR "treatment Human protocols"[MeSH] OR "Recurrence/prevention and control"[MeSH] OR "Treatment duration"[All Fields] OR "treatment discontinuation"[All Fields] OR "treatment continuation"[All Fields])

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. The Keller(135) study did not show up in our search results due to the way PubMed indexing is done. Other Information Sources:  Evidence report on the Treatment of Depression-Newer Pharmacotherapies. AHRQ(2)  The British Medical Journal(151)

Evidence Tables

Table 5.1

Inclusion & Exclusion Limitations / Intervention and dose Study Criteria Age Biases – N and Final N Duration Outcome Results NNT p value Keller, et al. Inclusion: 18-70 Limited external validity In acute phase, patients (N 44 weeks Primary outcome measure In continuation phase, there (2005) Relapse Adults with primary diagnosis of and generalizability due = 420) were given open- was number of patients was a statistically significant 8.5 prevention with recurrent Major Depression (per to exclusion of : label gepirone ER for 8 or with relapse, defined as lower percentage of overall gepirone ER in DSM-IV); screening and baseline 12 weeks, depending on HAM-D score 16+ at relapses in gepirone ER outpatients with HAM-D score 20+. a) patients with severe time to remission. endpoint (44 weeks). (23%) group than in placebo Major comorbidities (34.7%). (p=0.024). 0.024 Depression Exclusion: Patients who achieved HAM-D score that decreased by > b) patients with prior remission (N = 250) were Differences were statistically 20% between screening and treatment resistance or randomized into a double- significant from week 24 to baseline, history of treatment- who responded blind continuation phase: week 44. (p<0.05) < 0.05 refractory depression, pregnancy, insufficiently to substance abuse, pre-trial gepirone open label a) gepirone ER (N = 126) Gepirone well tolerated - treatment with MAO-I (within 3 treatment. b) placebo (N = 124) 3.2% in continuation phase weeks), fluoxetine (within 5 dropped out due to adverse weeks), other psychotropic agents events. (within 2 weeks).

Table 5.2 Intervention and dose p Study Inclusion & Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT value Montogomery, et Inclusion: 18+ Disproportionate Phase 1 Open label 12 months Primary outcome 22% cumulative probability of < 0.001 al. (2004), Adult outpatients with Major Depression contribution of number of treatment (N = 495): 100- was number of recurrence in venlafaxine- Venlafaxine (per DSM III-R criteria) who had a history participants (53 from 200mg/day venlafaxine for patients treated patients after 12 versus placebo in of recurrent Major Depression (≥1 Europe, remaining from 6 months experiencing months compared with 55% the preventive previous episode in the last 5 years with a USA). recurrence of Major for placebo group. treatment of symptom free period > 6 months between Phase 2 Maintenance (N Depression in the 12 < 0.001 recurrent Major episodes) and symptoms of depression for Some investigators might = 225): Those who months after a 21% venlafaxine-treated Depression > 1 month before study entry. have inadvertently been responded to treatment in successful Phase 2. patients discontinued delivering psychotherapy, Phase 1 were randomized treatment because of lack of Exclusion: in some way. into one of two groups - a) efficacy, compared with 48% Recent MI; history of drug or alcohol venlafaxine continuation placebo-treated patients. dependence, hepatic or renal disease, Short taper period for 100-200mg/day (N = 109) seizure disorder, psychotic disorder, those who switched to or b) placebo (N = 116) - bipolar disorder, hypersensitivity to placebo. for 12 months. venlafaxine; pregnancy; concomitant psychiatric disorders

Table 5.3

Inclusion & Exclusion Limitations / Intervention and dose Study Criteria Age Biases – N and Final N Duration Outcome Results NNT p value Rapaport, Bose Inclusion: 18-81 Two different phases, Phase 1 Open label 36 weeks The primary efficacy Time to relapse was 0.013 & Zheng (2004), Adults diagnosed with Major each with separate treatment (N = 502): 10-20 parameter was time to significantly longer and Escitalopram Depressive Disorder who had randomization. mg/day escitalopram, 20- relapse from the start of cumulative rate of relapse was continuation completed open label phase. 40mg/day citalopram, or the double-blind significantly lower in treatment Exclusion of patients placebo for 8 weeks. treatment. escitalopram group (26% prevents relapse Exclusion: with comorbid escitalopram vs. 40% of depressive Principal Axis I disorder (other than diagnoses (may not be Phase 2 Double-blind (N = placebo) through 36 weeks. episodes MDD), history of schizophrenia or representative of 274): Those who 8 any other psychotic disorder; patients in routine responded to treatment in Continuing treatment with suicidality, concomitant practice) Phase 1 were randomized escitalopram significantly psychotropic medication, into one of two groups - a) decreased percentage of pregnancy. Impact of lead-in escitalopram (N = 181) or b) patients meeting DSM-IV treatment on subject placebo (N = 93) for 36 criteria for Major Depressive outcomes. weeks. Disorder: Escitalopram 23% vs. Control 35%. Table 5.4 Study, Total n Treatment Groups Size & Drug Study Population Results Comments

Weihs, K.L. All patients were treated for an initial 8- Men and women of at least 18 Time to depression relapse (time from randomization to Treatment with bupropion 2002 (RCT, double-blind) weeks (acute phase), open- label phase in years old with moderate to intervention) SR for up to 44 weeks which they received bupropion SR (150 mg severe, recurrent Major decreases the risk of Follow-up: 44 weeks (11 months) to 300 mg/day). Patients who responded to Depression based on Rx1: 44 weeks depression relapse. the treatment and continued to meet the Diagnostic and Statistical Rx2: 24 weeks Initial N: 816 selection criteria, entered a 44-week Manual-IV (DSM-IV) criteria p = 0.003 (log-rank test) favoring continuation treatment Initial N (continuation phase) : 417 randomized, double-blind, placebo Minimum score of 18 on the 21- Final N: 103 controlled continuation phase. item Hamilton Depression Scale Survival estimates indicated 52% of placebo treated patients and (HAMD) 37% of bupropion patients would have become depressed by the Rx1: bupropion SR, 300 mg/day Patient’s current episode must end of the study (p = 0.004 favoring bupropion). (n = 207) have been preceded by at least one other episode within the last By the end of one year treatment, the odds of placebo-treated Rx2: Placebo (n = 210) 60 months. patients requiring treatment intervention for a relapse of depression were 1.83 times greater that those of bupropion SR- treated patients.

Table 5.5 Study, Total n Treatment Groups Size & Drug Study Population Results Comments Reimherr, F.W. Study phases: Male and female Relapse rate% (Kaplan-Meier estimates) The study shows significantly 1998 (RCT, double-blind) Baseline: outpatients 18 to 65 years lower relapse rates for A one week (5 to 9 day) medication-free baseline phase of age who met the DSM- After 12 weeks of continuation treatment: fluoxetine-treated patients Follow-up: 50 weeks III-R criteria for Major Rx1: 26.4% compared with placebo-treated after acute phase Open label acute phase: Depression with a Rx 4: 48.6% patients for at least 26 weeks 12 to 14 weeks of fluoxetine, duration of at least one p < 0.001 (favoring continuation treatment) after 12 weeks of successful Initial N: 839 20 mg/day month acute treatment (38 weeks of Initial N : (continuation All patients had a modified After 26 weeks of continuation treatment: treatment in total). phase) = 395 Continuation phase (Randomized double-blind allocation) 17-item Hamilton Rx2: 9.0% Rx1: 14 weeks of continuation therapy with fluoxetine followed by 38 weeks Depression Rating Scale Rx4: 23.2% There was no statistical Final N: Not given placebo(n = 97) score of at least 16. p < 0.001 (favoring continuation treatment) difference (p = 0.54) in the relapse rate Rx2: 38 weeks of continuation therapy with fluoxetine followed by 12 weeks After 50 weeks of continuation treatment: between the fluoxetine group placebo (n = 100) Rx3: 10.7% (10.7%) and placebo (16.2%) Rx4: 16.2% after 50 weeks of continuation RX3: 50 weeks of continuation therapy with fluoxetine (n = 102) p = 0.54 (no statistical difference) treatment (possibly due to lack of statistical power due to RX4: 50 weeks of placebo (no continuation phase) patient attrition, as only 53 (n = 96) patients were included in this analysis). Relapse rates were calculated during 12 week periods after each double-blind transfer from fluoxetine to placebo (weeks 12, 26, and 50).

Table 5.6 Study, Treatment Groups Total n Size & Drug Study Population Results Comments

Hochstrasser, B. Rx1 citalopram, Patients 18 to 65 years of age (in- Time from randomization to recurrence of a new depressive episode Time to recurrence was 2001 (RCT, double- blind) dose range 20 to 60 mg and out-patients) with recurrent (using Kaplan-Meier estimates) : longer in patients taking (n = 132) unipolar Major Depression (DSM- Time difference was significant, favoring citalopram group citalopram than in patients Follow-up: 48 to 77 weeks Rx2 placebo (n = 132) IV), a Montgomery – Asberg p < 0.0001 taking placebo (p < 0.001) Depression Rating Scale score of ≥ Initial N: 264 (maintenance phase) Patients were treated with 22 and two or more previous Rx1: 0.22 recurrences/person year at risk Final N: Not given citalopram (20 to 60 mg) depressive episodes, one within the Rx2: 0.76 recurrences/person year at risk for 6-9 weeks, acute past five years. phase (n = 427), if Intention-to-treat analysis responding, continued for Intent- to-treat population consisted 16 weeks (continuation of 29% males and 71% females phase) (n = 327) before randomized to double- blind maintenance treatment with citalopram or placebo for 48 to 77 weeks.

Table 5.7 Study, Treatment Groups Size Total n & Drug Study Population Results Comments

Gilaberte, I. All patients completed 32 Male and female outpatients, 18 to Recurrence Rate (%) Long-term maintenance treatment with 2001 (RCT, double-blind) weeks of open-label 65 years of age, who met DSM-III- fluoxetine appeared to be effective in the treatment phase consisting R criteria for unipolar Major Rx1: 20% prevention of recurrent depression. Follow-up: 48 weeks of maintenance of both an acute (8 weeks) Depression and had at least one Rx2: 40% treatment and a continuation period previous major depressive episode p = 0.010 Mean number of previous episodes for (6 months). in the last 5 years. fluoxetine group were 2.3 ± 1.2, and for Initial N: 253 Score of at least 18 on the 17-item Mean HAM-D-17 score at the end of maintenance phase: the placebo group 2.6 ± 1.5. Initial N (maintenance phase): 140 Maintenance phase Hamilton Rating Scale for Final N: 78 Rx1: fluoxetine, 20 mg/day depression (HAM-D-17) and at Rx1: 6.5 ± 8.6 (n = 70) least 4 on the Clinical Global Rx2: 9.9 ± 9.4 Rx2: placebo Impression (CGI) severity scale. p = 0.027 Intention-to-treat analysis (n = 70) The symptom-free period was significantly longer for patients treated with Fluoxetine versus placebo (295 days vs. 192 days; Kaplan-Meier estimates, log-rank test, p = 0.002)

Table 5.8 Study, Treatment Groups Size Total n & Drug Study Population Results Comments

Kocsis, J.H. All patients treated with Out patients who met DSM-III Only 41% of patients initially enrolled entered Long-term maintenance treatment with desipramine 1996 (RCT, double-blind) desipramine hydrochloride diagnostic criteria for “pure” maintenance phase treatment appeared to be effective in the prevention or during the acute phase (10 dysthymia (40%), chronic Major postponement of relapse of depression in patients Follow-up: 16 weeks for continuation weeks) and continuation Depression (10%) and dysthymia Relapse rates (%), maintenance phase who responded to desipramine during the acute phase phase (16 weeks), dose with current Major Depression Rx1: 15% (11% in abstract) and continuation phases. 24 months for maintenance phase range 50 to 325 mg/d). (50%) Rx2: 52% 88% white, 6% black, ARR = 37%, NNT = 3 Most placebo relapses occurred during the first 6 Initial N: 129 Maintenance phase 4% Hispanic, 4% Asians p = 0.01 favoring maintenance treatment months of maintenance therapy. Initial N (maintenance phase): 53 Rx1 desipramine (n = 28) Mean age 36 to 37, 51 to 64% (p listed as 0.004 in abstract) Final N: Not given in both cases Rx2 Tapered by 25% per female. 40% of patients studied did not have MDD, week in the first month to although results did not differ by subgroup. The Intention-to-treat analysis placebo (n = 25) three subtypes of chronic depression responded similarly to desipramine treatment in the acute, continuation, and maintenance phases.

Small sample size for maintenance phase

Table 5.9 Study, Treatment Groups Size Total n & Drug Study Population Results Comments

Keller, M.B. Patients completed 12 weeks Outpatients meeting a structured Rx2 n (%) Rx1 n (%) Log-Rank P Long-term maintenance treatment with sertraline 1998(RCT, double-blind) of treatment (acute phase) clinical interview diagnosis of Experienced 19 (23) 5 (6) 0.002 protects against recurrence or reemergence of and 4 months of continuation Chronic Major Depression (of at recurrence by strict protocol criteria depression and considerably extends the time in Follow-up: 76 weeks of phase treatment with least 2 years in duration) or remission for these high-risk patients. maintenance phase sertraline 50 to 200 mg/d Dysthymic Disorder with a Experienced 42 (50) 20 (26) 0.001 concurrent diagnosis of Major depression reemergence by Consensus assessment Initial N: 426 Maintenance phase Depression (double depression) Initial N (maintenance phase): Rx1 sertraline hydrochloride, based on DSM-III-R. Showed 50 (60) 26 (34) 0.001 161 daily dose of 50 to 200 mg Minimum baseline severity of 18 first symptoms of reemergence of depression by consensus Final N: 59 (n = 77) on the 24-item Hamilton assessment. Rx2 placebo Depression Scale (HAM-D) (n = 84) Strict protocol criteria: requiring 3 weeks of treatment and a confirmatory second evaluation one week later by an Intention-to-treat analysis independent senior investigator

6. Follow-Up For Patients In The Acute Phase (First Three Months) of Treatment For MDD

Problem Formulation 6

Clinical Question: What is the recommended follow-up for patients in the first three months of treatment for MDD? Intended Use of To assist primary care physicians and other health care professionals in the Guideline: treating adults with Major Depression. Population: All adult (age 19 and older) patients in acute phase treatment of Major Depression Health Problem: MDD Health Follow-up* in the first 12 weeks of treatment (“acute phase”) for Intervention: patients diagnosed with MDD:  Follow-up within four weeks and again at eight to twelve weeks  Three times in the first 12 weeks (HEDIS measure)  Other follow-up intervals  No follow-up Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics  Change in symptoms Health Outcomes  Office/UCC/ER visits  Quality of life (associated with  Hospitalizations  Missed school/work days the intervention):  Mortality  Adherence

* Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone calls/email between patient and a care manager.

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items 8/2005 0/129 Depressive Disorder"[All Fields] AND with abstracts, to (“systematic"[All Fields] OR Humans, 9/2007 “systematic review"[All Fields] OR English, All “meta-analysis"[All Fields])) Adult: 19+ years PubMed (((((((("depression/drug Only items 8/2005 0/87 effects"[MESH] OR "depression/drug with abstracts, to therapy"[MESH]) OR Humans, 9/2007 "depression/therapy"[MESH]) OR Randomized "depression"[All Fields] OR "Major Controlled Depressive Disorder"[All Fields]) Trial, English, AND ((("office visits"[MESH] OR All Adult: 19+ "office visits"[text word]) OR years "telephone"[text word]) OR "visits"[text word])) Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Cochrane Group Reviews Clinical Systematic January N/A Evidence, Chapter: Depressive Disorders Reviews and 2006 Issue 14 RCTs PubMed (((((((("depression/drug effects" Randomized, 01/01/03 1/20 [MESH] OR "depression/drug controlled - therapy"[MESH]) OR "depression/ trials 08/10/05 therapy"[MESH]) OR "depression" [All Fields] OR "Major Depressive Disorder"[All Fields]) AND ((("office visits"[MESH] OR "office visits"[text word]) OR "telephone"[text word]) OR "visits"[text word])) AND English[Lang]) AND "adult"[MeSH Terms]) AND "hominidae"[MeSH Terms])

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Systematic 03/05/03 0/295 Cochrane Depression reviews Systematic 03/05/03 0/80 Clinical Depression reviews and Evidence RCTs PubMed (((("depression"[MeSH Terms] OR All publication 1980 0/58 DEPRESSION[Text Word]) OR types, All - "depressive disorder"[MeSH Terms]) adults 19+ 04/25/2001 OR depressive disorder[Text Word]) years, English, AND ("office visits"[MeSH Terms] Human OR OFFICE VISIT[Text Word])) (((((((("depression/drug All publication 01/01/01 0/246 effects"[MESH] OR "depression/drug types, All - therapy"[MESH]) OR adults 19+ 04/01/03 "depression/therapy"[MESH]) OR years, English, "depression" [All Fields] OR"Major Human Depressive Disorder"[All Fields]) AND ((("office visits"[MESH] OR "office visits"[text word]) OR "telephone"[text word]) OR "visits"[text word]))

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed.

Evidence Table

Table 6.1

Inclusion & Intervention and dose Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT p value

Swindle, et al. Inclusion: diagnosis of Mean CNS's often disagreed with the Control firm (N = 134): 12 months Primary outcomes No significant effects of the CNS (2003), Major Depression, age 56 PRIME-MD diagnosis and did Diagnosis of depression assessed at 3 and 12 intervention on overall depressive Integrating dysthymia or partially not believe treatment was documented in chart. months were symptoms at 3 months . 0.43 clinical nurse remitted Major appropriate or necessary for Intervention firm (N = 134): depressive symptoms specialists into Depression; ≥ 2 many of the subjects (affecting At initial visit, Clinical Nurse and patient satisfaction. No significant effects of the CNS the treatment of General Medicine the fidelity of the intervention). Specialist (CNS) would intervention on overall depressive primary care Clinics visits past one create an initial treatment symptoms at 12 months . 0.51 patients with year, telephone access, Subjects of study were veterans plan based on medical record depression. informed consent (96% men) with medically and responses to PRIME- Post hoc, within group analyses complex issues. MD. Components of the of BDI scores revealed that Exclusion: treatment plan could include intervention group patients with Incompetent for Unit of randomization was the medication, cognitive only Major Depression improved interview, nursing home firm and not the participant. behavioral therapy, and or significantly at 3 and 12 months. residence, active referral to Mental Health. suicidality, seen in No true control group (all Monitoring through telephone Differences between intervention VAMC (Veterans Affairs clinicians received educational and/or in person contacts and control groups in patient Medical Center) mental program). was to occur at two weeks, satisfaction were small and not health program, one month, and two months significant. substance abuse, Post hoc rather than a priori after initial visit. history of bipolar outcome assessment. disorder, terminal illness. Lacked power to detect differences between intervention and control for patients with Major Depressive Disorder.

Data on usual care patient follow-up not provided.

7. Follow-Up For Patients In The Continuation Phase (Months Four to 12) of Treatment For MDD

Problem Formulation 7

Clinical Question: What is the recommended follow-up for patients in remission during months four to 12 of treatment for MDD? Intended Use of To assist primary care physicians and other health care professionals in the Guideline: treating adults with Major Depression. Population: All adult (age 19 and older) patients in continuation phase treatment of Major Depression Health Problem: MDD Health Follow-up* for patients during months four to 12 of treatment Intervention: (“Continuation Phase”) for Major Depression:  Follow-up at five to six months  Additional follow-up visits  Other follow-up intervals  No follow-up Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics  Change in symptoms Health Outcomes  Office/UCC/ER visits  Quality of life (associated with  Hospitalizations  Missed school/work days the intervention):  Mortality  Adherence

* Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone calls/email between patient and a care manager.

Search Strategy No. Included Article Type and Search / Total Database: Search Terms: Other Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items with 8/2005 0/129 Depressive Disorder"[All Fields] abstracts, to AND (“systematic"[All Fields] OR Humans, English, 9/2007 “systematic review"[All Fields] OR All Adult: 19+ “meta-analysis"[All Fields])) years PubMed (((("depression/drug effects"[MESH] Only items with 8/2005 0/88 OR "depression/drug therapy" abstracts, to [MESH]) OR "depression/therapy" Humans, 10/2007 [MESH]) OR "depression"[All Randomized Fields] OR "Major Depressive Controlled Trial, Disorder"[All Fields]) AND English, All ((("office visits"[MESH] OR Adult: 19+ years "office visits"[text word]) OR "telephone"[text word]) OR "visits"[text word])) PubMed (((("depression"[MeSH Terms] OR Only items with 8/2005 0/31 DEPRESSION[Text Word]) OR abstracts, Humans, to "depressive disorder"[MeSH Terms]) Randomized 10/2007 OR depressive disorder[Text Word]) Controlled Trial, AND ("office visits"[MeSH Terms] English, All Adult: 19+ years OR OFFICE VISIT[Text Word])) PubMed "follow up" AND ("telephone" OR Only items with 8/2005 0/29 "office visit" or “remission”) AND abstracts, Humans, to ("depressive disorder" [MeSH Randomized 10/2007 Terms]) Controlled Trial, English, All Adult: 19+ years Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Group Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs

No. Included Article Type and Search / Total Database: Search Terms: Other Limits: Date Retrieved* PubMed (((((((("depression/drug effects"[MESH] Randomized, 01/01/03 0/20 OR "depression/drug therapy"[MESH]) controlled trials - OR "depression/ therapy"[MESH]) OR 08/10/05 "depression"[All Fields] OR "Major Depressive Disorder"[All Fields]) AND ((("office visits"[MESH] OR "office visits"[text word]) OR "telephone"[text word]) OR "visits"[text word])) AND English[Lang]) AND "adult"[MeSH Terms]) AND "hominidae"[MeSH Terms]) AND ("2001/01/01"[PDAT] : "2003/04/01"[PDAT])) AND "2003/07/23 13.27"[MHDA] : "2005/08/10 15.01"[MHDA] Systematic 03/05/03 0/295 Cochrane Depression reviews Systematic 03/05/03 1/80 Clinical Depression reviews and Evidence RCTs PubMed (((("depression"[MeSH Terms] OR All publication 1980 0/5 DEPRESSION[Text Word]) OR types, All adults - "depressive disorder"[MeSH Terms]) 19+ years, 04/25/01 OR depressive disorder[Text Word]) English, Human AND ("office visits"[MeSH Terms] OR OFFICE VISIT[Text Word])) (((((((("depression/drug All publication 01/01/01 0/246 effects"[MESH] OR types, All adults - "depression/drug therapy"[MESH]) 19+ years, 04/01/03 OR "depression/therapy" English, Human [MESH])OR "depression" [All Fields] OR "Major Depressive Disorder"[All Fields]) AND ((("office visits"[MESH] OR "office visits"[text word]) OR "telephone"[text word]) OR "visits"[text word]))

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed.

Evidence Table

Table 7.1

Inclusion & Intervention and dose Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT p value

Data on usual care patient follow-up not provided.

8. Follow-Up For Patients In Maintenance Phase (Beyond 12 Months) Treatment Of MDD

Problem Formulation 8

Clinical Question: What is the recommended follow-up for patients in remission who need ongoing treatment for MDD beyond 12 months? Intended Use of To assist primary care physicians and other health care professionals in the Guideline: treating adults with Major Depression. Population: All adult (age 19 and older) patients in maintenance phase treatment of Major Depression Health Problem: MDD * Health Frequency of follow-up for patients with MDD who need ongoing Intervention: treatment beyond 12 months (“maintenance phase”):  Annual follow-up  Other follow-up intervals  No follow-up Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics  Change in symptoms Health Outcomes  Office/UCC/ER visits  Quality of life (associated with  Hospitalizations  Missed school/work days the intervention):  Mortality  Adherence

Search Strategy No. Included Article Type and Search / Total Database: Search Terms: Other Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items with 8/2005 0/129 Depressive Disorder"[All Fields] abstracts, to AND (“systematic"[All Fields] OR Humans, English, 9/2007 “systematic review"[All Fields] OR All Adult: 19+ “meta-analysis"[All Fields])) years PubMed (((("depression/drug effects" Only items with 8/2005 0/88 [MESH] OR "depression/drug abstracts, to therapy"[MESH]) OR "depression/ Humans, 10/2007 therapy"[MESH]) OR "depression" Randomized [All Fields] OR "Major Depressive Controlled Trial, Disorder"[All Fields]) AND ((("office English, All visits"[MESH] OR "office visits"[text word]) OR "telephone"[text word]) OR Adult: 19+ years "visits"[text word])) PubMed (((("depression"[MeSH Terms] OR Only items with 8/2005 0/31 DEPRESSION[Text Word]) OR abstracts, Humans, to "depressive disorder"[MeSH Terms]) Randomized 10/2007 OR depressive disorder[Text Word]) Controlled Trial, AND ("office visits"[MeSH Terms] OR English, All Adult: OFFICE VISIT[Text Word])) 19+ years PubMed "follow up" AND ("telephone" OR Only items with 8/2005 0/29 "office visit" or “remission”) AND abstracts, Humans, to ("depressive disorder" [MeSH Randomized 10/2007 Terms]) Controlled Trial, English, All Adult: 19+ years Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Group Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs

Evidence Table

Table 8.1

Inclusion & Intervention and dose Study Exclusion Criteria Age Limitations / Biases N and Final N Duration Outcome Results NNT p value

Data on usual care patient follow-up not provided.

9. Discontinuation of Antidepressants In Patients With MDD

Problem Formulation 9

Clinical Question: How should antidepressants be discontinued in patients with MDD? Intended Use of To assist primary care physicians and other health care professionals the Guideline: in treating adults with Major Depression. Population: All adult (age 19 and older) patients with Major Depression Health Problem: MDD Health  Gradual tapering of antidepressants Intervention:  Stopping antidepressants without tapering Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics Health Outcomes  Change in symptoms  Office/UCC/ER visits (associated with the  Quality of life  Hospitalizations intervention):  Missed school/work days  Mortality Side Effects Associated With  Medication withdrawal symptoms the Intervention

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items with 8/2005 0/129 Depressive Disorder"[All Fields] AND abstracts, to (“systematic"[All Fields] OR “systematic Humans, English, 9/2007 review"[All Fields] OR “meta-analysis"[All All Adult: 19+ Fields])) years PubMed (("depression/drug effects"[MeSH] OR Randomized 01/2005 0/37 "depression/drug therapy"[MeSH]) OR Controlled Trial, to "depressive disorder/drug therapy"[MeSH]) All Adult: 19+ 10/2007 OR "Major Depressive Disorder"[All years, English, Fields] AND ("discontinuation" OR Human "withdrawal" OR "tapering") PubMed ("antidepressive agents"[MeSH]) AND Randomized, 01/2005 0/40 ("discontinuation" OR "withdrawal" OR controlled trial, to "tapering") All Adult: 19+ 10/2007 years English, Human Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Group Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs PubMed (("depression/drug effects"[MeSH] OR Randomized, 01/01/03 1/77 "depression/drug therapy"[MeSH]) OR controlled trials - "depressive disorder/ drug therapy"[MeSH]) OR "Major Depressive Disorder"[All Fields] AND 08/01/05 (("antidepressive agents/adverse effects"[MeSH] OR "serotonin uptake inhibitors/adverse effects"[MeSH]) OR "substance withdrawal syndrome"[MeSH]) AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "3000"[PDAT]) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT])

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Systematic 03/05/03 0/295 Cochrane Depression reviews Systematic 09/22/03 0/86 Clinical Depression reviews and Evidence RCTs PubMed ((((((("depression"[MeSH Terms] OR Clinical trials, 1980 2/347 depression[Text Word]) OR "depressive All adults 19+ - disorder"[MeSH Terms]) OR depressive years, English 04/01/01 disorder[Text Word]) AND ("drug administration schedule"[MeSH Terms] OR DRUG ADMINISTRATION SCHEDULE [Text Word])) AND Randomized Controlled Trial[ptyp]) AND English[Lang]) AND ("1980"[PDat] : "3000"[PDat])) (("depression/drug effects"[MeSH] OR All publication 01/01/01 1/286 "depression/drug therapy" types, All - [MeSH]) OR "depressive disorder/ adults 19+ 04/01/03 drug therapy"[MeSH]) OR "Major years, English, Depressive Disorder"[All Fields]) AND Human (("antidepressive agents/adverse effects"[MeSH] OR "serotonin uptake inhibitors/adverse effects"[MeSH]) OR "substance withdrawal syndrome"[MeSH]))

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed.

Evidence Tables

Table 9.1

Inclusion & Limitations / Intervention and dose – p Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT value

Sunder, et al. Twenty two pregnant Mean Postpartum women Sertraline (N = 14) or placebo (N = 8) 20 weeks Depression symptoms No significant difference 0.96 (2004), women (mean age 32) age 32 only. administered for 17 weeks post birth: assessed every two months between sertraline and Postpartum who had recovered 25mg/day for first four days, in follow-up phase. placebo treated groups on Depression from at least one prior Only 11 out of 22 50mg/day through first four weeks, sum of ASE-derived Recurrence episode of Postpartum patients initially treated 75mg/day through week 17. symptoms in taper phase. Versus Major Depressive for postpartum MDD Intervention tapered weeks 18-20: Discontinuation Disorder (PMDD) entered the tapering 50 mg/day in week 18, 25 mg/day Syndrome: phase: week 19, 25 mg/day week 20. Observations Discontinued after week 20. One from a year follow-up phase began after Randomized RCT; assessments for depression Controlled Trial every two months.

Table 9.2 Study, Total n Treatment Groups Size & Drug Study Population Results Comments Judge, R. At visit one all patients received blinded Male or female outpatient aged ≥ 18 Mean change following treatment Comparison between treatment groups following 2002 (RCT, double-blind) drug equivalent to their current daily Diagnosis of unipolar depressive interruption: treatment interruption indicates paroxetine-treated maintenance dose (fluoxetine 20-60 mg disorders for which the current effective patients had significantly greater increases in Follow-up: Not given or paroxetine 20-50 mg) maintenance therapy with fluoxetine or Mean change ± SD for Discontinuation MADRS and CGI- severity than did fluoxetine- paroxetine was prescribed Emergent Signs and Symptoms (DESS), treated patients. The deterioration from baseline Initial N: 150 Rx1: fluoxetine (n = 75) within the paroxetine treatment group was also Rx2: paroxetine (n = 75) Montgomery-Asberg Depression Rating Rx1: -0.2 ± 2.5 significant for both MADRS (p = 0.010) and CGI- Final N: 141 Scale (MADRS) score of 12 or less Rx2: 2.2 ± 5.5 Severity scores (p = 0.001). These patients were then randomized to: p = 0.001 active therapy at visit 2, Current continuous maintenance Eighteen interruption-emergent symptoms were placebo at visit 3, treatment for depression (fluoxetine 20 Mean change ± SD for reported by significantly more paroxetine-treated original active therapy at visit 4 to 60 mg/day or paroxetine 20 to Montgomery-Asberg Depression Rating patients than fluoxetine-treated patients placebo at visit 2, 50mg/day) lasting more than 4 months Scale (MADRS) active therapy at visit 3 and the rest of and less than 24 months Did not examine for treatment withdrawal side the study Rx1: 0.2 ± 2.9 effects beyond 5 days of discontinuation, when side All white, 77% female Rx2: 1.8 ± 5.0 effects of the longer half life medication fluoxetine Periods of treatment interruption lasted p = 0.021 might be expected to emerge. between 3-5 days. Mean change ± SD for No evaluation of side effects between low and Clinical Global Impressions-Severity higher doses of fluoxetine. (CGI-severity scores) Industry funded (Eli Lilly, maker of fluoxetine). Rx1: 0.0 ± 0.5 Rx2: 0.3 ± 0.8 p = 0.034

10. Treatment Preferences For MDD In Different Ethnic Groups

Problem Formulation 10

Clinical Question: Do adult patients from different ethnic groups have a preference among treatment options for MDD? Intended Use of To assist primary care physicians and other health care professionals in the Guideline: treating adults with Major Depression. Population: Adults (age 19 and older) patients from diverse ethnic backgrounds who have Major Depression Health Problem: MDD Health  Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs) Intervention:  Psychotherapy (Interpersonal Therapy, Cognitive Behavioral Therapy, Problem-Solving Therapy)  Combination of antidepressants & psychotherapy  Cultural healers  Traditional/herbal remedies  Clergy  No treatment Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, and health educators Setting: Outpatient office visit, emergency department, urgent care clinics  Office/UCC/ER visits Health Outcomes  Change in symptoms  Hospitalizations (associated with the  Quality of life  Mortality intervention):  Missed school/work days  Patient satisfaction  Patient dissatisfaction Side Effects  Sexual problems  Elevated blood Associated With  Drowsiness pressure the Intervention:  Headache  Constipation  Nausea  Diarrhea  Insomnia  Abdominal pain  Agitation/  Dizziness nervousness  Blurred vision  Dry mouth  Weight gain  Seizures  GI bleeding  Noncompliance  Falls

Search Strategy Article No. Type and Included Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items 8/2005 0/129 Depressive Disorder"[All Fields] AND with to (“systematic"[All Fields] OR “systematic abstracts, 9/2007 review"[All Fields] OR “meta-analysis"[All Humans, Fields])) English, All Adult: 19+ years PubMed ((("depression/drug therapy"[Mesh Terms] OR Only items 8/2005 0/129 "depressive disorder/ drug therapy"[Mesh Terms])OR with to "Major Depressive Disorder"[All Fields]) AND abstracts, ((((((("cultural diversity"[MeSH Terms] OR "cultural Randomized 9/2007 diversity"[Text Word]) OR "culture"[MeSH Terms] Controlled OR "ethnic groups"[MeSH Terms]) OR "ethnic Trials, groups"[Text Word]) OR "Asians"[text word]) OR Humans, "Blacks"[Text Word]) OR "Hispanics"[Text word]) English, All OR "social class"[MeSH Terms] OR "health Adult: 19+ knowledge, attitudes, practice"[MeSH Terms])) years Cochrane Depression, Anxiety and Neurosis Group Systematic Q4, 2005 0/131 Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs PubMed ((("depression/drug therapy"[Mesh Terms] OR All 01/01/03 1/74 "depressive disorder/ drug therapy"[Mesh Terms])OR - "Major Depressive Disorder"[All Fields]) AND ((((((("cultural diversity"[MeSH Terms] OR "cultural 08/01/05 diversity"[Text Word]) OR "culture"[MeSH Terms] OR "ethnic groups"[MeSH Terms]) OR "ethnic groups"[Text Word]) OR "Asians"[text word]) OR "Blacks"[Text Word]) OR "Hispanics"[Text word]) OR "social class"[MeSH Terms] OR "health knowledge, attitudes, practice"[MeSH Terms])) AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "3000"[PDAT]) AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT])

Article No. Type and Included Other Search / Total Database: Search Terms: Limits: Date Retrieved* Systematic 03/05/03 0/295 Cochrane Depression reviews Systematic 03/05/03 0/80 Clinical Depression reviews Evidence and RCTs PubMed (("depression"[MeSH Terms] OR Clinical 1998 2/170 DEPRESSION[Text Word]) AND trials, All - ((("therapy"[Subheading]OR"therapeutics" adults 19+ 3/2001 [MeSH Terms]) OR TREATMENT[Text years, Word]) AND PREFERENCE[All Fields])) English, Human PsychInfo Major Systematic 1985 0/43 Depression/Preferences/Blacks/Asians/Hisp reviews - anics/American Indians and RCTs 04/1/03 PubMed [All Fields]) AND ((((((("cultural diversity" All Adult: 01/01/01 0/9 [MeSH Terms] OR "cultural diversity"[Text 19+ years - Word]) OR "culture" [MeSH Terms]OR English, 04/01/03 "ethnic groups"[MeSH Terms]) OR "ethnic Human groups"[Text Word]) OR "Asians"[text word]) OR "Blacks"[Text Word]) OR "Hispanics"[Text word])OR "social class" [MeSH Terms] OR "knowledge, attitudes, practice"[MeSH Terms]))

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed. The Cooper(168) study did not show up in our search results due to the way PubMed indexing is done. Other Information Source:  Evidence report on the Treatment of Depression-Newer Pharmacotherapies. AHRQ.(2)

Evidence Table

Table 10.1 Intervention and Inclusion & Exclusion Limitations / dose Study Criteria Age Biases N and Final N Duration Outcome Results NNT p value

Dwight-Johnson, et al. Inclusion: 18+ Small sample. N/A N/A Conjoint analysis survey Study patients expressed: (2004), Using conjoint English and Spanish administered to 42 analysis to assess speaking patients with Low response rate. participants to assess: Preference for individual over depression treatment depression or dysthymia group treatment. (p<0.001) < 0.001 preferences among low- age 18 and older seen as Most participants were 1) Treatment choice income Latinos outpatients in general women (95%), and (counseling, Preference for combination medicine and women's most were Latino from antidepressants, or therapy over counseling clinics Mexico and El Salvador combination) (p=0.009) 0.009 (93%). Exclusion: 2) Treatment format Preference for combination Suicidality, history of bipolar Most completed the (individual or group) therapy over medication < 0.0010 or psychotic disorder, survey in Spanish alone. evidence of gross cognitive (86%) 3) Treatment location impairment. (primary care or mental No comparison for preference No comparison group. health clinic) of psychotherapy alone vs. medication alone. 4) Barrier reduction strategies including system No significant preference for navigation (help making treatment setting (p=0.833) 0.833 appointments vs. no help), reducing transportation Helpful barrier reduction barriers (bus pass, strategies included: telephone appointments, or no assistance); and written educational < 0.001 educational interventions information (individual education telephone appointment = 0.001 session, group education session, pamphlets, or bus pass < 0.001 videos) help making appointments < 0.001

11. Patient Self-Management Strategies For Improving Symptoms of MDD

Problem Formulation 11 Clinical What patient self-management strategies are effective in improving the Question: symptoms of MDD? Population: All adult (age 19 and over) patients in maintenance phase treatment of Major Depression Health  Exercise/physical activity  Bibliotherapy Intervention:  Community resources  Music therapy  Internet resources  Computer- or internet-based  Support groups/befriending self-study materials  Light therapy  No patient self-directed  Life review therapy intervention Most  Change in symptoms  Office/UCC/ER visits Important  Quality of life  Hospitalizations Health  Missed school/work days  Mortality Outcomes:  Adherence to treatment plan

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Cochrane Depression N/A 2005 0/134 Systematic to Reviews 2007 9/2007 0/70 to 9/14/2009 Clinical Depression Systematic 1/2006 - 0/2 Evidence Reviews and 9/2009 RCTs; Adults PubMed ("Depression"[MeSH] OR "Major Only items with 8/2005 0/129 Depressive Disorder"[All Fields] abstracts, to AND (“systematic"[All Fields] OR Humans, 9/2007 “systematic review"[All Fields] OR English, All 9/2007 2/135 “meta-analysis"[All Fields])) Adult: 19+ years to 9/14/2009 PubMed ("depression" [MeSH] OR Only items with 8/2005 1/75 "depressive disorder" [MeSH] OR abstracts, to "Major Depressive Disorder" [all Humans, 9/2007 fields]) AND ("self care" [MeSH] OR Randomized "self efficacy" [MeSH] OR "patient Controlled Trial, participation" [MeSH] OR "choice English, All 9/2007 to 1/84 behavior" [MeSH] OR Adult: 19+ years 9/2009 "bibliotherapy" [MeSH] OR "befriending" [all fields] OR "behavioral activation" [all fields] OR "exercise" [Mesh] OR "community resources" [all fields] OR "self-help groups" [MeSH] OR "Internet"[MeSH]) Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Group Reviews

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Clinical Chapter: Depressive Disorders Systematic January N/A Evidence Reviews and 2006 RCTs PubMed ("depression"[MeSH] OR "depressive All Adult: 19+ 01/01/03 4/62 disorder"[MeSH] OR "Major years, English, - Depressive Disorder"[all fields]) Randomized 08/01/05 AND ("self care"[MeSH] OR "self Controlled Trial, efficacy"[MeSH] OR "patient Humans participation"[MeSH] OR "choice behavior"[MeSH] OR "bibliotherapy"[MeSH] OR "befriending"[all fields] OR "exercise"[Mesh] OR "community resources"[all fields] OR "self-help groups"[MeSH] OR "Internet"[MeSH]) AND Randomized Controlled Trial[ptyp] AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT]) Systematic Cochrane Depression 03/05/03 0/295 reviews Systematic Clinical Depression reviews and 03/05/03 1/80 Evidence RCTs PubMed ("depression" [MeSH] OR All publication 01/01/1965 9/655 "depressive disorder" [MeSH] OR types, All adults - "Major Depressive Disorder" [all 19+ years, 04/01/2003 fields]) AND ("self care" [MeSH] OR English, Human "self efficacy" [MeSH] OR "patient participation" [MeSH] OR "choice behavior" [MeSH] OR "bibliotherapy" [MeSH] OR "befriending" [all fields] OR "behavioral activation" [all fields] OR "exercise" [Mesh] OR "community resources" [all fields] OR "self-help groups" [MeSH] OR "Internet"[MeSH])

Evidence Tables

Table 11.1: Included Studies of Patient-Self-Management Strategies for Improving Depression Symptoms Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value SELF-HELP MATERIALS Salkovskis et al Inclusion: depressive Mean Small sample size Self-help materials 26 weeks Beck Compliance: 76% NA (2006) disorder; recently age: 40.2 (SH, N = 50) Depression Follow-up rate: 85% prescribed ±11.9 Majority were women Inventory (BDI) A randomized antidepressant 39.2±13.3 Treatment as usual score Baseline values: controlled trial of the medication; aged 17– Possible selection bias (TAU, N = 46) SH: 27.1±10.5 use of self-help 70 years. % TAU: 27.5±9.8 materials in addition Exclusion: difficulty Female: to standard general reading English; 83.0% for Follow-up values: practice treatment severe (life- self-help SH: 14.3±12.5 of depression threatening) medical vs. 78.3% TAU: 12.6±9.6 compared to illness, history of for standard treatment psychosis or bipolar treatment Absolute effect: alone. disorder, current as usual 1.7 P >0.5 alcohol or substance dependency, and taking antidepressants for > 4 weeks. EXERCISE Craft et al (2007) 32 low-income, Mean No control group Participants stratified 3 months Outcome 46.9% of all participants NA minority women age: 40.4 by current depression measures were experienced a > 50% Intervention study of volunteers from + 10.6 Short duration and treatment (no txt, changes in reduction in depressive exercise for Boston’s center for Female: follow-up medication, therapy, BDI-II (Beck symptoms. depressive Excellence in Women’s 100% medication and Depression symptoms in Health. Race: Small sample size therapy) and Inventory), Overall effect size for women. 68.8% randomized into one of BMI, % fat, and exercise on depressive Inclusion: English black, Low power two groups: cardiovascular symptoms were large in speaking; aged 18.7% fitness. both groups between pre- N initial: 32 between 18-55; DSM- white, and No blinding Clinic-based exercise and post-intervention (d= - N Final: not IV criteria for MDD, 12.5% (N = 16): provided 0.97 vs. -1.3 for home- reported dysthymia, or Latino. Some women were also feedback and and clinic-based, depressive disorder not under other treatment information on respectively). otherwise specified as for depression. exercise; 4-week clinic- diagnosed and scoring based training for 2 At 3-months follow-up, NS >9 on BDI-II; sedentary Possible selection bias. times/wk + once/wk at there were no significant

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value lifestyle; and average home; followed by 8- difference between the or below average Low generalizability. wks transitioned to two groups on BDI-II fitness level by home-based phase. depression score, self- exercise testing. reported physical activity, Home-based exercise BMI, % body fat, and Exclusion: CHD; (N = 16): feedback and cardiovascular fitness. <0.05 diabetes; mental health info on exercise and diagnosis; and one instructional At 3-months, clinic-based contraindication to session. group walked further each exercise. day than home-based according to pedometer readings.

A home-based program can increased physical activity and reduce depressive symptoms similar to clinic-based program. Dunn (2005), Inclusion: Mean Participants not blinded Participants 12 weeks HAM-D score Adjusted mean HAM-D NNT* for reduction of Exercise treatment Sedentary men and age: to treatment randomized into one of after 12 weeks. scores at 12 weeks were HAM-D at 12 wks for depression: women with mild 35.9 + 6.4 assignment. five groups: reduced 47% from compared to efficacy and dose (HAM-D 12-16) to baseline for PHD, a participant’s baseline: response moderate (HAM-D 17- Participants required to LD/3: Low dose significant difference 25) MDD. (75% exercise under exercise compared with PHD vs. LD: 0.006 women, 75% white); supervision; might have (7 kcal/kg/week) three 30% for LD 5.9 0.02 aged 20-45 compromised external times per week. 29% for control validity. (N = 16) PHD vs. Cntrl: The LD condition was not 5.6 Exclusion: Sample size small LD/5: Low dose significantly different from 0.38 Not receiving any other compared with exercise the control condition. LD vs. Cntrl: treatment for pharmacologic (7 kcal/kg/week) five 100 depression; ≥160% treatment studies. times per week. The 3 day/week condition over ideal weight, ≥21 (N = 18) was not significantly 0.58 drinks per week, different from the 5 suicidal risk, suicide PHD/3: Public health day/week condition. attempt last two years, dose hospitalization or (17 kcal/kg/week) three psychiatric disorder times per week. (N = last five years, 17) substance abuse,

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value inability to exercise, PHD/5: Public health planned or current dose pregnancy. (17 kcal/kg/week) five times per week. (N = 16)

Placebo control: 3 days/week of stretching flexibility exercise for 15-20 minutes per session. (N = 13) Mather, A.S. Out-patients 53 years and older Preponderance of Rx1: Exercise group (n Follow-up: Change in 17- Change in 17-item NNT* for >30% 2002 (RCT) with a diagnosis of depression women in the exercise = 43) 10 weeks item Hamilton Hamilton Rating Scale for reduction in HRSD Score of at least 10 on the Geriatric group Rating Scale Depression (HRSD) from score from baseline: Effects of exercise Depression Scale (GDS) Rx2: Nonexercise for Depression baseline at 10 weeks (%) on depressive Actual HRSD pre and social control (health (HRSD) from Rx1 vs. Rx2: p = 0.05 symptoms in older Have been taking a therapeutic post scores were not education talks) (n = baseline at 10 Rx1: 55% 4.5 (favoring adults with poorly dose of antidepressant therapy for given 43) weeks (%) Rx2: 33% exercise group) responsive at least 6 weeks depressive disorder: No ongoing structured Short term All exercise session randomized psychotherapy lasted for 45 minutes Response was defined as controlled trial. No regular exercise more than Definition of threshold and comprised a ≥ 30% reduction in twice weekly for response (30% predominantly weight- HRSD score from Initial N: 86 16% male, 84% female reduction) is lower than bearing exercise; 2 baseline Final N: 86 usual 50% seen in most sessions per week studies This RCT found that 10 Intention-to-treat All patients continued weeks of twice-weekly analysis to take antidepressant exercise was associated therapy throughout the with a modest reduction in trial depression symptoms in a group of older people with depression. Singh, N.A. Age 60 and older with a BDI score Small sample size Phase I (weeks 1-10) Follow-up: BDI score BDI score at 20 weeks NNT* for participants 2001 (RCT) of >12 Rx1: Supervised 20 weeks , Rx1: Decreased from classified as non- p= 0.036 Diagnosis of either unipolar major Population elderly exercise in laboratory with follow- 21± 2.0 to 9.2 ± 2.8 depressed (BDI<9) at (favoring The efficacy of or minor depression or dysthymia Rx2: Control group up at 26 Rx2 : Decreased from 20 wks: exercise) exercise as a long- according to DSM-IV diagnostic Final difference between (health education months 18.28 ± 1.8 to 11.0 ± 2.36 term antidepressant criteria BDI scores between lectures) in elderly subjects: a Excluded if suicidal, currently groups may not be BDI score after 26 months Exercise vs. Control: randomized, seeing a psychiatrist or had been clinically significant. Phase II (weeks 11-20) Rx1: Decreased from 2.7 p= 0.036 © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 264 National Adult Depression Clincial Practice Guideline

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value controlled trial. on antidepressant drugs within the Rx1: Unsupervised 21± 2.0 to 13 ± 2.2 (favoring last three months No long-term difference exercise at home, Rx2: Decreased from exercise group) Initial N: 32 Subjects participating in aerobic between groups if laboratory or health 18.4 ± 1.7 to 14.4 ± 2.2 Final N: 29 exercise more than twice a week in exercise not continued club setting (N = 15) , the month prior to enrollment were 18±2 weight lifting The relative improvements also excluded Response occurred over exercise sessions in depression scores in time even in control Rx2: Control group (N the exercisers were 1.5 to 37% male, 63% female group = 14) 2.5 times greater than Mean age: 71 + 2 those in the controls at the Phase III (Months 6-26) end of Phase II. Rx1: No study requirements The exercise group Rx2: No study showed significantly requirements reduced depression compared with control group at both 20 weeks and 26-month follow-up. McNeil, J.K. Elderly outpatients with a mean age Elderly patients Rx1: Exercise, walking Follow-up: Total and BDI score (total) NA 1991 (RCT) of 72.5 years between 20- 40 6 weeks psychosocial Rx1: decreased from 16.6 p < 0.05 BDI score of 12-24 Short-term results minutes, three times a subscale of the to 11.1 (favoring The effect of week Beck Rx2: decreased from 16.0 exercise or exercise on Small n Rx2: Social Contact , Depression to 11.8 social contact) depressive two home visits (20 - Inventory. Rx3 : decreased from 15.2 symptoms in the 40 minutes) each week to 14.7 moderately by an undergraduate p < 0.5 (favoring depressed elderly. psychology student BDI score (somatic exercise) Rx3: Wait-list (control symptoms) Initial N: 30 group) Rx1: decreased from 7.7 Final N: 30 to 5.3 Rx2: decreased from 6.9 to 6.0 Rx3 : decreased from 6.8 to 6.4

Exercise and social contact both resulted in significant reductions in both total and the psychosocial subscale of the Beck Depression Inventory. The exercise

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value condition, however, resulted in decreased somatic symptoms of the BDI. North, T.C. Depressed patients 11 to 55 years There are a lot of Rx1: exercise (aerobic Follow-up: Exercise The overall Effect Size of NA p < 0.001 1990 (Meta- with a mean of 31.8 ±12.4 differences in the study endurance and Varied from scores the studies included was – analysis) designs of the studies muscular strength) 4 weeks to 0.53 ± 0.85. That 20 studies were all males, used in this meta- varying in number of 24 weeks indicates that patients in Effect of exercise on analysis. That includes sessions with exercise groups (Rx1) depression. 16 studies were all females. differences in the mode majorities of decreased their scores an of exercise, length of the Rx2: comparison studies average of 0.53 of a # studies included in effect of exercise programs and groups (control, leisure being standard deviation unit exercise on depressioN = 80 types of control groups). activity, and between 5 - more than subjects in # studies included in effect of age = psychotherapy) 12 weeks comparison groups (Rx2). 63 Meta-analysis excludes (p < 0.05) # of studies included for the effect older patients A significant, negative of gender = 36 correlational relationship was found between mean age and ES. The negative relationship suggests that the older the subjects, the greater the decrease in depression with exercise. (p > 0.05) The ESs for males and females were not significantly different, suggesting that exercise had an equally beneficial effect in improving symptoms of depression in both genders.

The overall results indicated that exercise has a beneficial effect on improving symptoms of depression.

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value COMPUTER / INTERNET Meyer et al. (2009) Participants were Mean No placebo-control Internet program as Duration: Outcome Change in depression NNT* clinical significant recruited via internet age: group add-on to usual care (N 6 months measures were scale: improvement/recovered Follow-up: 6 months depression forum in 34.76 + = 320): Consisted of 10 changes in the  Using last-observation- (change of at least 8.46 Germany. 11.6 Short duration and content modules adapted carried forward ITT points on BDI, with N initial: 396 follow-up representing different German BDI analysis, those in the posttest score of N at 9 weeks: 216 Inclusion/ exclusion: psychotherapeutic (Beck internet program <14.29): N at 18 weeks: 146 provided consent, Participants were not approaches. Depression demonstrated a , p<0.001 N at 6 months: 99 above 18 years, and clinically diagnosed with Inventory), and reduction of 3.11 BDI Internet vs. wait-list completed at least half MDD Wait-list control plus work and social points (d=0.29) vs. no controls: of baseline depression usual care (N = 76): adjustment change observed in 4.3 questionnaire. High attrition rate (at No internet access until scale (WSA). participants assigned to least 55% at 9 weeks) 9 weeks after the wait-list controls (BDI NS (0.96) Female: 76% treatment group has change: -0.04). Race: Not reported Some participants were completed.  between-groups effect also under other size at 9 weeks, using Many of the treatment for this ITT sample, was participants were depression. Cohen’s d = .30. incapacitated in terms  In completers, effect of symptom severity Possible selection bias size was reported at and social dysfunction. – participants were more Cohen’s d = .64 (CI Over half of the sample experienced/comfortabl 95% = 0.33 - 0.94). was currently e with Change in work and unemployed, more internet/computer; social scale: p<0.001 than half reported heterogeneous sample  Similarly, ITT analysis currently being in of users. found small decrease in treatment (medication internet group (d=0.17), and/or psychotherapy), Low generalizability. versus no significant and 85% stated they change. had been feeling  Between-group effect depressed for several size at T1 was Cohen’s months (29%) or even d = .36. several years (56%).  Follow-up:  Improvements in depression symptoms were maintained at 6- months follow-up for completers (d=0.74).

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value the wait-list control reached the criteria of clinical significant improvement/recovered (change of at least 8.46 points on BDI, with posttest score of <14.29).

Users who engaged more often and intensively with the program were more likely to complete the follow-up assessment and to benefit from the program. Clarke, et al. (2005) Inclusion: 18+ Subjects lost to follow- Rx1 Treatment as 16 weeks Primary Control and intervention NNT* for patients who Overcoming Kaiser Permanente implied, up were older, more usual without access to outcome groups had statistically moved over time from Depression on the Northwest HMO adults not stated depressed, and less the internet site.(N = measure was equivalent baseline the “disordered” to the Internet (ODIN) (2): with either 1) likely to be in the control 100) score on depression (CES-D) and “non disordered” CES- A Randomized depression – received group. Center for SF-12 scores. D ranges: Trial of a Self-Help depression medication Rx2 Access to Epidemiological Depression Skills or psychotherapy, and Low enrollment (255 depression internet site Studies (CES- In the intention-to-treat Rx3 vs. Rx1 = 5 0.03 Program With had a chart diagnosis, patients out of over (www.believebetter.org D) self-report analysis, intervention Reminders or 2) no previous 12,000 initially eligible) ) with postcard questionnaire participants (Rx2 and depression diagnosis, and completion (57% in reminders (N = 75) at 5, 10, and 16 Rx3) reported greater but age and gender intervention group vs. weeks after reductions in CES-D matched to the first 80% in usual care) Rx3 Access to enrollment depression scores group rates. depression internet site compared with the control with brief telephone group (Rx1) Exclusion: Only one self-reported reminders delivered by None stated. measure of depression. nonclinician study staff Baseline 16 weeks (N = 80) Rx1 28.0 22.3 Brief follow-up period – Rx2 31.3 18.2 16 weeks. All participants were Rx3 30.3 19.0 permitted to obtain any physical or mental Intervention had a greater 0.02 health services during effect on those who were the study. more severely depressed at baseline.

Baseline 16 weeks

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value Rx1 35.4 26.7 Rx2 35.2 19.7 Rx3 36.2 20.1

No significant difference between treatment groups with regard to outcome measures. Christensen, Men and women from 18-52 Short follow-up time (six 525 participants were 6 weeks Primary In Intent to treat analysis, NA Griffiths, & Jorm the community of weeks) does not offer randomized into one of outcome was CES score improvement (2004) Delivering Canberra, Australia. information about the three groups: score on (in points) was: interventions for Participants had sustainability of internet Center for Blue Pages 3.9 depression by using scored 22 or higher on interventions. Internet "Blue Pages" Epidemiological MoodGYM 4.2 the internet: a the Kessler scale and (N = 165): provided Studies (CES) Control 1.0 randomized were not being High drop-out rate for depression literacy, scale. controlled trial clinically treated by a MoodGYM. offering evidence- In Completer analysis, psychologist or based information on CES score improvement psychiatrist. No information on depression and its (in points) was: whether or not patients treatment. Blue Pages 4.9 were concurrently taking Mood Gym 5.8 antidepressants. Internet "Mood GYM" Control 1.2 (N = 182): offered cognitive behavioral Therefore, in both therapy for the analyses: prevention of MoodGYM was < 0.05 depression. significantly more effective than control. (p<0.05) < 0.05 Control "Attention Blue Pages was placebo" (N = 178): significantly more effective > 0.05 weekly contact with a than control. (p<0.05) lay interviewer to MoodGYM was slightly discuss lifestyle factors (but not significantly) more such as exercise, effective than Blue Pages. education, and health habits.

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value Clarke, G. Combination of depressed and High attrition rate (41%) Rx1: Access to Follow-up: Change in Change in CES-D score NA 2002 (RCT) nondepressed cases Depression Internet 32 weeks CES-D score (baseline to week 32 Heterogeneous sample. site (n = 144), Depressed cases only: Overcoming Rx1: Mean age of 43.3, with an SD depression cases mean(SD) depression on the of 12.2, 73.6% females Over three-quarter of (n = 107) Rx1: 30.7(12.9) to p = 0.12 Internet (ODIN): a sample was female. Rx2: Usual Care only 22.2(12.8) randomized Rx2: Mean age of 44.4 with an SD (n = 155), depression Rx2: 31.3(11.5) to controlled trial of an of 12.4, 77.4% females cases (n = 116) 25.2(14.2) Internet depression skills intervention Much of the internet Stratified analyses by high program. site content was vs. low baseline CES-D Initial N: 299 adapted from group scores, gender, and age Final N: 177 CBT psychotherapy greater or less than 45 all manuals showed no statistically Intention-to treat significant between group analysis differences.

The study found no differences between the control and experimental conditions on self-reported depression (CES-D) over the study period, indicating a lack of treatment effect. LIGHT THERAPY Martiny, et al. Inclusion: 18+ No follow-up to All patients received a 5 weeks Primary Rx2 showed a significantly NNT* for response < 0.01 (2005) Adjunctive Adults, 18 and older, determine lasting fixed dose of 50mg outcome greater decrease in HAM- (50% or greater bright light in fulfilling diagnostic effects. sertraline daily. measure was D scores at five weeks. reduction of nonseasonal Major criteria for Major Increments or dose change in Baseline 5 weeks baseline scores on the Depression: results Depression according Unequal duration of reductions, oxazepam, HAMD-17 Rx1 22.1 11.6 HAM-D6) at 5 wks: from clinician-rated to the DSM-IV; HAMD treatments (30 vs. 60 and mianserin were score from Rx2 22.4 9.0 depression scales score ≥13. minutes). allowed as necessary. baseline to endpoint. Response rates at 5 Bright vs. Dim light: Exclusion: Percentage of patients Patients were weeks: 3.1 0.006 Seasonal Depression in ongoing treatment randomized into one of Rx1: 38.9% (SAD); fulfillment of with antidepressants at two groups: Rx2: 70.8% seasonal pattern inclusion or who had specifier; psychotic stopped treatment within Rx1: Red dim light (50 Remission rates at 5 disorder; organic brain the last month before lux, 30 minutes daily), weeks: 0.015

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value disorder; mental inclusion was noticeably N = 54 Rx1: 18.5% retardation, alcohol or higher in bright light Rx2: 41.7% drug abuse; group (46% vs. 30%). Rx2: Bright white light pregnancy; history of This difference was (10,000 lux, 60 minutes light-induced migraine determined not to be daily), N = 48 or epilepsy; retinal statistically significant, blindness or severe but no analysis of cataract; glaucoma; difference (p value) retinal diseases; reported. ongoing treatment with antipsychotics; suicidal ideation; severe agitation; score of <13 on HAMD. LIFE REVIEW THERAPY Serrano & Latorre Volunteer clients (men 65-93 No placebo control Participants were 8 weeks Primary Significant Time x Group NNT* for improvement < 0.0001 (2004), Life review and women of Social where participants randomized into two outcome effect indicated in CES-D to below therapy using Services in Almansa, received same amount groups: measures were experimental group major depression autobiographical Spain. All participants of attention, but without scores on CES- improvements in CES-D, among those with CES- retrieval practice for receiving one hour of intervention. Experimental Group (N D, LSIA, and LSIA, and BHS. D diagnosed older adults with social services per day, = 20): given life review BHS. depression: depressive five days per week. Prompting questions therapy while Secondary Mean CES-D change symptomatology Participants had to during intervention continuing with social outcome was 10.25 for treatment group Experimental vs. have clinically targeted primarily services. Life review change in vs. 0 for control group. control: significant symptoms of positive memories. therapy consisted of specificity of NNT = 5 < 0.001 depression (CED-D autobiographical memories from Experimental group >16), no evidence of No follow-up to indicate retrieval practice pretest to showed significant dementia, and could maintenance of focusing on a particular posttest. increase in recall of not be receiving changes. period (childhood, specific memories. 0.01 pharmacological adolescence, treatment for Small sample size. adulthood, summary) This was found to be a depression. Patients each week for four significant predictor of 0.03 were 70% women. Not all participants had consecutive weeks. posttest hopelessness MDD (although many had significant Control group (N = 23): This was also found to be depressive symptoms). social services as a significant predictor of 0.06 usual. posttest life satisfaction. Limited to older population receiving There was a trend in the social services, in Spain. same direction for posttest

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value CES-D. BIBLIOTHERAPY Smith, N.M. Mean age Small sample size Observational study of Follow-up: HRSD and BDI Follow-up analysis NA p <0.05 each 1997(Observational) of 41.6 bibliotherapy only; no 3-year scores revealed a significant ±10.0 No control group comparative group. decrease in HRSD and BDI scores from Initial N: 50 Sensitivity analysis not pretreatment to follow-up p>0.05 each Final N: Not given included to account for patients who completed No changes from post the initial study but did treatment to follow-up not participate in the follow-up (some of Treatment gains were whom may have maintained over the 3- relapsed) year follow-up period and participants were less depressed than when they began the program.

Study suggests that there maybe long-range benefits to participants in structured, minimal- contact bibliotherapy programs for depression. Jamison, C. Mean age of 40 years Participants and Treatment phase (4 Follow-up: HRSD and BDI Treatment phase NNT* of clinical 1995 (RCT) Score of 10 or greater on the researchers not-blinded. weeks) 4 weeks of scores HRSD score improvement at 3- Hamilton Rating Scale for Rx1: Cognitive treatment Rx1: decreased from 20.2 months follow-up (BDI p < 0.05; The outcome of Depression 21-item version (HRSD) bibliotherapy (n = 33) and 3 to 9.9 cutoff < 11; HRSD favoring cognitive Score of 10 or greater on the 21- Wait-list control showed months of Rx2: decreased from 19.6 cutoff < 12): bibliotherapy bibliotherapy with item Beck Depression Inventory marked symptom Rx2: Waiting list follow-up to 19.0 depressed adults. (BDI) improvement in f/u (control group) BDI: p < 0.05; Met the DSM-III-R criteria for a mild phase (n = 39) BDI score 2.17 favoring Initial N: 80 or moderate Major Depression Rx1: decreased from 21.9 bibliotherapy Final N: 65 Rx1: 30% females, 10% males Follow-up phase (3 to 9.2 HRSD: Rx2: 37% females, 3% males months) Rx2: decreased from 20.9 1.7 Rx1: Cognitive to 19.5 p < 0.05 bibliotherapy (n = 31) (favoring Follow-up phase treatment) when Rx2: Waiting list HRSD score starting from (control group) Rx1: decreased from 10.0 baseline

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value (n = 34) to 9.2 Rx2: decreased from 18.7 p < 0.05 to 10.0 (favoring treatment) when BDI score starting from Rx1: decreased from 9.6 baseline. to 7.7 Rx2: decreased from 18.9 to 11.1

Study suggests that cognitive bibliotherapy for depression is an effective treatment for depression. Scogin, F. 60 years and older, mean of 67.2 No male participants Rx1: Behavioral and Follow-up: HRSD scores HRSD score change from NA 1990 cognitive bibliotherapy 2-year post -treatment to 2-year Two-year follow-up Mean age: 67.2 + 6.9 years No control group (n = 22) follow-up of bibliotherapy for those who had read (n depression in older Race: 3 Black, 27 White Small sample size = 16) Rx1: 8.1 to 7.4, no p < 1.00 adults. significant effect for time Gender: 30 female, 0 male Sensitivity analysis not those who had not (n = Initial N: 30 included to account for 14) Structured bibliotherapy’s Final N: Not given patients who completed effect for mild to the initial study but did moderate depression in not participate in the older adults is maintained follow-up (some of 2 years after treatment whom may have relapsed) Unknown how often participants referred to materials over time Scogin, F. 60 years and older Only included older Rx1: Behavioral Follow-up: HRSD Score HRSD Score changes NNT* for clinical (Rx2 vs. Rx3) p 1989 (RCT, double- adults bibliotherapy (n = 23), Initial study changes from time 1 to 2 to 3 improvement from < 0.05, favoring blind) Score of 10 or higher on the reading a copy of 4 weeks of bibliotherapy (scores cognitive Comparative Hamilton Rating Scale for Predominantly female Control Your treatment Rx1: 17.8 to 9.7 to 9.1 outside range of bibliotherapy efficacy of cognitive Depression (HRSD) Depression and a 6- Rx2: 16.3 to 7.5 to 8.9 dysfunctional and behavioral Small sample size (Lewinsohn, et al. month Rx3: 16.4 to 15.9 to 7.2 population): bibliotherapy for Score of 8 or higher on the Mental 1986) book follow-up mildly and Status Questionnaire Short follow-up No significant differences 2.13 moderately Rx2: Cognitive between Rx1 and Rx2. depressed older Not being on psychotropic bibliotherapy (n = 22), adults. medication or, if so, then stabilized reading a copy of Treatment gains were © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 273 National Adult Depression Clincial Practice Guideline

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value on the medication Believing Good (Burns, maintained 6 months after Initial N: 67 1980) book treatment for Rx1 and Final N: 44 Not being in psychotherapy Rx2. There was no Rx3 : Delayed control group for follow-up Scogin, 1990 (RCT, 57 females and 10 males treatment (control after the delayed double-blind) group) (n = 22) treatment group received treatment. The Rx1 and Rx2 were assessed at: This study supports the Pre-treatment =Time 1 efficacy of self-paced Immediately following bibliotherapy for mild to treatment = Time 2 moderate depression in 6-month follow-up = older adults. Time 3

The Rx3 participants were assessed at time 1 and at 1 month following time 2, at which point their own treatment began, and a third time immediately following treatment. MUSIC THERAPY Hanser, S.B Older adults (61 to 86 years old) Small sample size Rx1: Home based Follow-up: Change in Change in Geriatric Depression NA 1994 (RCT) 77% female music therapy 8 weeks Geriatric Scale sore (pretest to posttest) Diagnosis of major or minor Predominantly female (n = 10) Depression Effects of a music depressive disorder, based on a Scale sore Rx1: 17.30 to 7.70 p < 0.05 therapy strategy on structured interview using the Relative short follow-up Rx2: Self-administered Rx2: 17.60 to 12.30 (favoring the two depressed older Schedule of Affective Disorders and music therapy (n = 10) Rx3: 15.30 to 16.20 music therapy adults. Schizophrenia groups) Rx3: Wail-list control Follow-up results at nine Initial N: 30 group (n = 10) months revealed no significant Final N: 28 differences on the GDS score from post test results in all three groups.

This study supports the use of music therapy strategies with older adults experiencing symptoms of depression. © 2012 Kaiser Permanente Medical Care Program For use within Kaiser Permanente only. 02/12 274 National Adult Depression Clincial Practice Guideline

Intervention and Inclusion & Limitations / dose Study Exclusion Criteria Age Biases N and Final N Duration Outcome Results NNT P/ 2 value EXERCISE & LIGHT THERAPY Leppamaki, et al. 120 Volunteers from 26-63 Participants were not a Participants were 8 weeks Primary Based on HDRS, 42 The NNT for light was 2= 0.02 (2004), Drop-out Occupational Health random sample of the randomized into one of outcome responders (50% 3.8. and mood Centers: men and population. three groups: measures were improvement); 83% of improvement: a women free from prior changes in these responders received randomized mental disorders and Participants did not Aerobics training in HDRS, ATYP, light therapy, which was controlled trial with with HAM-D ≥ 8. have a clinical diagnosis bright light (N = 40) and SIGH- significant. light exposure and of Major Depression; SAD-SR physical exercise. they had varying Aerobics in normal Based on ATYP, 51 degrees of depressive lighting of gym (N = 38) responders; 73% of these symptoms. responders received light Relaxation and therapy. Unclear on how many stretching in bright light 2= 0.02 participants may have (N = 42) Based on SIGH-SAD-SR, had Seasonal Affective 45 responders; 82% of Disorder. these responders received light therapy, which was No placebo control significant group.

No information on whether patients were using other treatments. INTERNET AND TELEPHONE Patten, S.B. Volunteers were Mean age Included predominantly Rx1: Active group, Follow-up: Changes in % of patients exceeding NNT* for reduction in 2003 (RCT) screened for diagnosis 45.2 ± older women. using web and 3 months depression Center for Epidemiological CES-D score of >15: NS (p not of current Major 11.9 telephone-based rating scale Studies Depression rating stated) Prevention of Depression by using Possible selection bias program (n = 420) (CES-D) scale (CES-D) score of Rx1 vs. Rx2: depressive the Composite – participants may be Rx2: Control group (n = more than 15 111 symptoms through International more comfortable with 366) Rx1: 37.4% (baseline the use of distance Diagnostic Interview the internet. 35.7%) technologies. (95% CIDI) and eligible The preventive Rx2: 34.1% (baseline participants were intervention was an 33.3%) Initial N: 786 assigned to treatment interactive computer Difference statistically not Final N: 764 or control groups. No program accessible significant. other information were through the Web or by provided. interactive voice telephone. The study did not find any Gender: 90.1% female, significant differences and 9.9% male between the groups.

12. Behavioral Health Education Classes For Adults With MDD (Cognitive Behavioral Skills or Problem-Solving Classes)

Problem Formulation 12

Clinical Question: Are behavioral health education classes (cognitive behavioral skills or problem-solving classes) effective in improving the symptoms of MDD? If so, are they recommended for adults with MDD?

Intended Use of To assist primary care physicians and other health care professionals the Guideline: in treating adults with Major Depression. Population: All adult (age 19 and over) patients with Major Depression Health Problem: MDD Health Multi-Session behavioral health education classes: Intervention:  Cognitive behavioral skills for managing depression  Problem-solving  No behavioral health education classes Practitioners: KP primary care physicians, physician assistants, nurse practitioners, pharmacists, health educators, and social workers Setting: Outpatient office visit, emergency department, urgent care clinics, health education, social work  Office/UCC/ER visits Health Outcomes  Change in symptoms  Hospitalizations (associated with the  Quality of life  Mortality intervention):  Missed school/work days  Relapse prevention  Adherence to treatment plan  Patient satisfaction

Note: Behavioral Health Education Classes (BHE) differ in content, structure, and scheduling from protocolized psychotherapy delivered to patients with specifically defined diagnoses in a specialty behavioral health setting. BHE delivers a specific educational curriculum (as opposed to a structured, tailored psychotherapeutic intervention) focusing on coping and self-care skills, targets patients with mild to moderate depressive symptoms (including patients without Major Depression), and excludes patients with more severe Major Depression.

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* PubMed ("Depression"[MeSH] OR "Major Only items with 8/2005 0/129 Depressive Disorder"[All Fields] AND abstracts, to (“systematic"[All Fields] OR “systematic Humans, English, 9/2007 review"[All Fields] OR “meta- All Adult: 19+ analysis"[All Fields])) years Pubmed ("depression"[MeSH] OR "depressive Only items with 8/2005 0/0 disorder"[MeSH] OR "Depressive abstracts, to disorder/therapy"[MeSH] OR "Major Humans, 9/2007 Depressive Disorder"[all fields]) AND Randomized ("health education"[MeSH] OR "patient Controlled education"[MeSH] OR "behavior Trial, English, therapy/methods"[MeSH] OR "patient All Adult: 19+ satisfaction"[MeSH] OR years "cognition"[MeSH] AND "psychoeducation"[all fields] OR "behavioral classes"[all fields]) Cochrane Depression, Anxiety and Neurosis Systematic Q4, 2005 0/131 Group Reviews Clinical Chapter: Depressive Disorders Systematic January N/A Evidence, Reviews and 2006 Issue 14 RCTs PubMed ("depression"[MeSH] OR "depressive All publication 01/01/03 0/4 disorder"[MeSH] OR "Depressive types, All - disorder/therapy"[MeSH] OR "Major adults 19+ 08/01/05 Depressive Disorder"[all fields]) AND years, English, ("health education"[MeSH] OR "patient Human education"[MeSH] OR "behavior therapy/methods"[MeSH] OR "patient satisfaction"[MeSH] OR "cognition"[MeSH] AND "psychoeducation"[all fields] OR "behavioral classes"[all fields]) AND English[Lang] AND "adult"[MeSH Terms] AND "humans"[MeSH Terms] AND ("2003/01/01"[PDAT] : "2005/08/01"[PDAT])

No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Systematic 03/05/03 0/295 Cochrane Depression reviews Clinical Systematic 03/05/03 0/80 Depression reviews and Evidence RCTs PubMed ("depression" [MeSH] OR "depressive All publication 01/01/1965 2/704 disorder" [MeSH] OR "Depressive types, All - disorder/therapy" [MeSH] OR "Major adults 19+ 04/01/2003 Depressive Disorder" [all fields]) AND years, English, ("health education" [MeSH] OR "patient Human education" [MeSH] OR "behavior therapy/methods" [MeSH] OR "patient satisfaction" [MeSH] OR "cognition" [MeSH], "psychoeducation" [all fields] OR "psychosocial classes" [all fields] OR "behavioral classes" [all fields])

Some studies found and used in this guideline did not appear in PubMed search results due to the way studies are indexed in PubMed.

Evidence Tables

Table 12.1 Study, Total n Treatment Groups Size & Drug Study Population Results Comments Brown, R.A. Rx1: Class (n = 25) Adults 16-65 years old Participants in the three treatment groups Proportions of individuals receiving concurrent 1984 (RCT) 70% female improved more during the 8-week period treatment for depression in each group not Rx2: Individual tutoring (n = 13) All met Research Diagnostic Criteria than did the wait-list control group, p<0.05 specified Follow-up: One and 6 months (RDC) for a current episode of unipolar Rx3: Phone contact (N = 14) depression There were no statistically significant Difference in response between those receiving Initial N: 63 Mean Beck Depression Inventory (BDI) differences among the three treatment concurrent treatment and those not receiving Final N: Not Stated Rx4: Wait-list control (N = 11) score of 22.2 (consistent with mild to groups, when compared at 8weeks other treatment for depression not specified moderate Major Depression) (treatment duration) and one and 6 months (4.6% drop-out rate) “Coping with Depression” course format Unclear if patients with severe Major follow-up sessions 34 of 122 individuals chose not to participate in was standardized across the three Depression or chronic Major the study, differences between enrolled and not treatment conditions. It included a text, Depression excluded. Among the participants in the three enrolled group not specified Control Your Depression from which Patients with concurrent substance treatment groups, only 25% still met the reading assignments were made. abuse excluded. criteria for depression at the 6-month Course consisted of 12 sessions over an follow-up session 8 week period plus a visit or phone contact (Rx3 group) at one and 6 month Those with residual depression tended to post treatment have depression onset at an earlier age than those who responded Patients receiving concurrent treatment for depression were included From an economic point of view, the class condition was by far the most cost effective

Table 12.2 Study, Treatment Groups Size Total n & Drug Study Population Results Comments Dowrick, C. Rx1: Six individual sessions of Adults ages 18 to 65 Mean difference in Beck Depression Inventory (BDI) score Study concludes both Problem-Solving 2000 (RCT) Problem-Solving treatment Rx1 at 6 months =-2.63 (-4.95 to –0.32), p=0.026 (significant) treatment and the course on prevention delivered in a setting Diagnosis of depressive disorder At 12 months =-1.00 (-3.31 to 1.31), p=0.398 (not significant) of depression reduces the severity and Follow-up: 6 and 12 months convenient for the patient (71%) according to DSM-IV, duration of depressive disorders and (usually the patient’s home) by dysthymia (16%) , adjustment Rx2 at 6 months = –1.50 (-4.16 to 1.17), p=0.272 (not significant) improves subjective mental and social Initial N: 452 behavioral health, allied disorder (4%) or other depressive At 12 months = 1.11 (-1.30 to 3.52), p=0.901 (not significant) functioning. Final N: 212 health, or nursing personnel disorders (9%) (N = 128) There were significant improvements in SF36 scores (mental role, social Intention-to-treat-analysis Suicidal patients and patients function, and mental health) at 6 months for patients in the depression Mixed population (patients with different Rx2: Eight group sessions (2.5 with concurrent substance abuse prevention course (p=0.042, 0.048, and 0.028 respectively), when types of depression, not all Major hours each) of a course on excluded. compared with baseline scores Depressive Disorder) with the results prevention of depression not stratified by condition (n = 108) Unclear if patients with severe There were significant improvements in SF36 scores (mental role, social Major Depression who were not function, and mental health) at 6 months for patients in the Problem-Solving Rx3: Control group (n = 189) suicidal were excluded or therapy group compared with controls at 6 months (p=0.030, 0.012, and The number of different individuals included. 0.005 respectively). delivering the Problem-Solving therapy was not specified, the problem-solving There was no significant differences in SF36 scores at 12 months therapy protocol was not specified, and the inter-provider variability of At 6 months there was a 17% difference in numbers of depressed patients adherence to the therapy protocol was between participants assigned to Problem-Solving and controls (NNT = 6). not analyzed. Therefore, this may not At 12 months there was no difference between Rx1 and Rx3 be directly comparable to the Problem- Solving therapy delivered by trained At six months there was a 14% difference in numbers of depressed patients mental health personnel in traditional between participants assigned to prevention of depression and controls behavioral health settings. (NNT = 7). At 12 months there was no difference between Rx2 and Rx3.

Unweighted (complete case analysis) odds ratio for RX1 at 6 months : 0.51 (0.27 to 0.97) RX1 at 12 months : 0.92 (0.48 to 1.77)

Rx2 at 6 months : 0.50 (0.21 to 1.15) Rx2 at 12 months: 1.02 (0.46 to 2.23)

More patients completed Problem-Solving therapy ((63%) than the course (44%) p = 0.006.

Table 12.3 Study, Total n Treatment Groups Size & Drug Study Population Results Comments Brown, R.A. Rx1: Class (n = 25) Adults 16-65 years old Participants in the three treatment groups Proportions of individuals receiving concurrent 1984 (RCT) 70% female improved more during the 8-week period treatment for depression in each group not Rx2: Individual tutoring (n = 13) All met Research Diagnostic Criteria than did the wait-list control group, p<0.05 specified Follow-up: One and 6 months (RDC) for a current episode of unipolar Rx3: Phone contact (N = 14) depression There were no statistically significant Difference in response between those receiving Initial N: 63 Mean Beck Depression Inventory (BDI) differences among the three treatment concurrent treatment and those not receiving Final N: Not Stated Rx4: Wait-list control (N = 11) score of 22.2 (consistent with mild to groups, when compared at 8weeks other treatment for depression not specified moderate Major Depression) (treatment duration) and one and 6 months (4.6% drop-out rate) “Coping with Depression” course format Unclear if patients with severe Major follow-up sessions 34 of 122 individuals chose not to participate in was standardized across the three Depression or chronic Major the study, differences between enrolled and not treatment conditions. It included a text, Depression excluded. Among the participants in the three enrolled group not specified Control Your Depression from which Patients with concurrent substance treatment groups, only 25% still met the reading assignments were made. abuse excluded. criteria for depression at the 6-month Course consisted of 12 sessions over an follow-up session 8 week period plus a visit or phone contact (Rx3 group) at one and 6 month Those with residual depression tended to post treatment have depression onset at an earlier age than those who responded Patients receiving concurrent treatment for depression were included From an economic point of view, the class condition was by far the most cost effective

Table 12.4 Study, Treatment Groups Size Total n & Drug Study Population Results Comments Dowrick, C. Rx1: Six individual sessions of Adults ages 18 to 65 Mean difference in Beck Depression Inventory (BDI) score Study concludes both Problem-Solving 2000 (RCT) Problem-Solving treatment Rx1 at 6 months =-2.63 (-4.95 to –0.32), p=0.026 (significant) treatment and the course on prevention delivered in a setting Diagnosis of depressive disorder At 12 months =-1.00 (-3.31 to 1.31), p=0.398 (not significant) of depression reduces the severity and Follow-up: 6 and 12 months convenient for the patient (71%) according to DSM-IV, duration of depressive disorders and (usually the patient’s home) by dysthymia (16%) , adjustment Rx2 at 6 months = –1.50 (-4.16 to 1.17), p=0.272 (not significant) improves subjective mental and social Initial N: 452 behavioral health, allied disorder (4%) or other depressive At 12 months = 1.11 (-1.30 to 3.52), p=0.901 (not significant) functioning. Final N: 212 health, or nursing personnel disorders (9%) (N = 128) There were significant improvements in SF36 scores (mental role, social Intention-to-treat-analysis Suicidal patients and patients function, and mental health) at 6 months for patients in the depression Mixed population (patients with different Rx2: Eight group sessions (2.5 with concurrent substance abuse prevention course (p=0.042, 0.048, and 0.028 respectively), when types of depression, not all Major hours each) of a course on excluded. compared with baseline scores Depressive Disorder) with the results prevention of depression not stratified by condition (n = 108) Unclear if patients with severe There were significant improvements in SF36 scores (mental role, social Major Depression who were not function, and mental health) at 6 months for patients in the Problem-Solving Rx3: Control group (n = 189) suicidal were excluded or therapy group compared with controls at 6 months (p=0.030, 0.012, and The number of different individuals included. 0.005 respectively). delivering the Problem-Solving therapy was not specified, the problem-solving There was no significant differences in SF36 scores at 12 months therapy protocol was not specified, and the inter-provider variability of At 6 months there was a 17% difference in numbers of depressed patients adherence to the therapy protocol was between participants assigned to Problem-Solving and controls (NNT = 6). not analyzed. Therefore, this may not At 12 months there was no difference between Rx1 and Rx3 be directly comparable to the Problem- Solving therapy delivered by trained At six months there was a 14% difference in numbers of depressed patients mental health personnel in traditional between participants assigned to prevention of depression and controls behavioral health settings. (NNT = 7). At 12 months there was no difference between Rx2 and Rx3.

Unweighted (complete case analysis) odds ratio for RX1 at 6 months : 0.51 (0.27 to 0.97) RX1 at 12 months : 0.92 (0.48 to 1.77)

Rx2 at 6 months : 0.50 (0.21 to 1.15) Rx2 at 12 months: 1.02 (0.46 to 2.23)

More patients completed Problem-Solving therapy ((63%) than the course (44%) p = 0.006.

13. Antidepressants To Avoid During Pregnancy or Breastfeeding

Problem Formulation 13 Clinical Question(s) Which antidepressants should be avoided in women who are pregnant or breastfeeding? Population Patients diagnosed with MDD who may be pregnant or breastfeeding Health Intervention(s)  Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs)  No treatment Most Important Health  Hospitalizations Outcomes  Mortality  Spontaneous abortion  Congenital malformations  Perinatal complications (mother and child)  Long-term behavioral sequelae

Search Strategy No. Article Type Included and Other Search / Total Database: Search Terms: Limits: Date Retrieved* Cochrane Depression N/A 2005 0/134 Systematic to Reviews 9/2007 9/2007 0/58 to 10/01/2009 PubMed ("Depression"[MeSH] OR "Major Only items with 8/2005 0/129 Depressive Disorder"[All Fields] AND abstracts, to (“systematic"[All Fields] OR “systematic Humans, 9/2007 review"[All Fields] OR “meta- English, All 9/2007 5/137 analysis"[All Fields])) Adult: 19+ years to 10/01/2009 PubMed "depression"[MeSH Terms] OR Only items with 1966 8/262 DEPRESSION[Text Word]) OR "depressive abstracts, - disorder"[MeSH Terms]) OR depressive Humans, 9/2007 disorder[Text Word]) OR "Antidepressive English, All Agents"[Mesh] AND “neonate” OR “neonatal” Adult: 19+ years OR “pregnancy” OR “lactation” OR “breastfeeding” (((("depression"[MeSH Terms] OR Only items with 9/2007 5/483 DEPRESSION[Text Word]) OR "depressive abstracts, to disorder"[MeSH Terms]) OR depressive Humans, 10/01/2009 disorder[Text Word]) OR "Antidepressive English, All Agents"[Mesh]) AND ((((((“neonate” OR Adult: 19+ years “neonatal”) OR “pregnancy”) OR “lactation”) OR “breastfeeding”) OR "prenatal") OR "antenatal") Hand search NA 9/2007 1 to 10/01/2009

Evidence Tables

Table 13.1: Meta-Analyses of Antidepressants in Pregnancy Studies Study Population Total N Groups Size & Drug Results Comments Hemels MEH 2005 Observational cohort studies including pregnant Rate of spontaneous abortion in Nonsignificant differences Authors’ conclusions: (meta-analysis) women on antidepressant therapy women exposed to all seen among drug classes. Maternal exposure to antidepressants is associated 1 study of trazodone or nefazodone antidepressants was 12.4%, with an increased risk of spontaneous abortion. # studies found: 156 1 study of venflaxine compared with 8.7% in women not # studies included: 6 1 study of sertraline/paroxetine/fluvoxamine exposed to antidepressants (RR = Biases, etc. 2 studies of fluoxetine 1.45) Time of exposure to antidepressants varied, studies Total N = 3567 1 study of TCA may represent overlapping populations, no verification made of spontaneous abortion versus elective Heterogeneity: overall heterogeneity termination of pregnancy. was nonsignificant (used fixed-effects model?) Lattimore KA 2005 Prospective cohort studies of second and third Outcome NNT OR (95% CI) p Authors’ conclusions: (meta-analysis) trimester exposure to SSRIs. Prematurity 29 1.85 (0.79, 0.1295 SSRI exposure appears to increase the incidence of Low birth wt 31 4.29 0.0481 prematurity, low birth weight, special-care nursery # studies found: 194 1 study of paroxetine only SNU/NICU 7 3.64 (1.01, 0.0192 admissions, and the diagnosis of poor neonatal # studies included: 9 2 studies of fluoxetine only Poor adaptation 9 13.08) 0.0694 adaptation. 3.30 (1.45, Total N = 326 7.54) Biases, etc. 4.08 (1.20, Some studies included smokers and women using Heterogeneity: a nonlinear mixed 19.93) other psychotropic medications. effect model was used in statistical analysis due to the absence of homogeneity Moses-Kolko EL 2005 Cohort studies of patients who had been exposed Outcome OR (95% CI) Authors’ conclusions: There is an increased risk of (meta-analysis) to SSRIs in the final trimester of pregnancy that Neonatal behavioral syndrome 3.0 (2.0-4.4) neonatal behavior syndrome and other CNS included assessment of neonatal outcomes SNU/NICU 2.6 (1.4-4.7) symptoms following gestational exposure to SSRIs. # studies found: not reported compared with control groups who had early or Respiratory difficulty 2.3 (1.6-3.2) # studies included: 9 no exposure Seizure 4.1 (1.5-11.0) Biases, etc. No information regarding heterogeneity of data, Total N = 1,111 1 study of paroxetine only 3 studies of fluoxetine only What model used for MA?

Table 13.2: Cohort and Case-Control Studies of Antidepressants in Pregnancy Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* Pedersen et Not reported. Exposure: Fair 3,4 al (2009) Information from all SSRI (Fluoxetine, live-born children in Citalopram, Cohort study Denmark between Paroxetine, 1/11966 – Sertraline) during 12/31/2005. 1st trimester of pregnancy

Outcomes: Birth defects including major and minor malformations, septal heart defects, non- cardiac malformations

Sub-analyses included women with one or more redemptions for antidepressants: 3010 women redeemed one or more SSRI, 265 for tricyclic antidepressants, and 150 for venlafaxine."

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* Andrade et al Females >15 years Exposure: 2 1104 3 1104 RR = for antidepressants used: 0.06 – 5.82 Poor 3,4 (2009) who were admitted Antidepressants 0.67 between 1996 – used (SSRIs, Case-control 2000 for delivery. tricylics, RR = for SSRIs: study miscellaneous) 0.79 0.07 – 6.89 Exposure and during 3rd nonexposure trimester. women were matched by age, Outcomes: health plan, year of Infant persistent admission. pulmonary hypertension (PPHN). Wichman et al Women presented Exposure: Poor 3,4 (2009) at Mayo Clinic from SSRI use 1993 – July 15, (fluoxetine, Retrospective 2005.. paroxetine, cohort study sertraline, citalopram, escitalopram, venlafaxine) during pregnancy.

Outcomes: Congenital heart disease (CHD) and PPHN.

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* Toh et al Women who gave Exposure: Poor-Fair 3,4 (2009) birth to SSRI use during nonmalformed an pregnancy Case-control non-hypertensive study babies and who participated in the Outcomes: Slone Gestational Epidemiology hypertension and Center Birth preeclampsia Defects Study from 1998 – 2007

Jordan et al Pregnant women Exposure: 13 46 10 59 RR = NA NA Poor 3,4 (2008) with psychiatric SSRI use during 1.67** illness in prenatal pregnancy Retrospective clinic from Sept cohort study 2005 - Aug 2006. Outcome: Neonatal Women not treated behavioral with SSRI syndrome (NBS) considered controls – irritability, jitteriness, hypo- or hypertonia, hyperreflexia, oxygen requirement, apnea, flaring, grunting, retractions, vomiting, poor

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* feeding or hypoglycemia. Ramos et al Pregnant women Exposure: Fair 4 (2008) aged 15 – 45 in Antidepressants Quebec; have at (SSRIs, - Case-control least 1 diagnosis of citalopram, study psychiatric disorder fluoxetine, before pregnancy. fluvoxamine, paroxetine and sertraline; tricyclic – amitriptyline, clomipramine, deipramine, doxepin, imipramine, nortriptyline, trimipramine; and new antidepressants – bupropion, mirtazapine, moclobemide, nefazodone, trazodone, venlafaxine) during 1st trimester of pregnancy.

Outcome: Major congenital malformation.

Diav-Citrin et Pregnant women Exposure: Table 2. Pregnancy outcomes. Poor 2,3,4 al (2008) who contacted the Paroxetine or Israeli, Italy and fluoxetine or non- Prospective Germany teratogenic cohort study Teratology exposure (e.g., Information Service antibiotics, oral (TIS). contraceptives,

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* etc.).

Outcome: Major congenital abnormalities (i.e. structural abnormalities with medical, surgical or cosmetic consequences; VSD, neurodevelopmen tal or functional problems)

Table 3. Logistic regression analysis for miscarriage rate and cardiovascular anomalies.

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* Salkeld et al Women aged 16 – Exposure: Poor 2,3,4 (2008) 46 years in Ontario Antidepressant who received (SSRIs – Nested case- government-funded fluoxetine, control study drug coverage 2 fluvoxamine, years prior to sertraline, delivery. paroxetine, and citalopram; and Cases were non-SSRIs – matched with cyclic controls in ratio antidepressants, 1:10 bupropion and venlafaxine) use in 3rd trimester.

Outcomes: Postpartum hemorrhage

Kallen and Swedish women in Exposure: Poor – Fair 3,4 Olausson Register who gave SSRI during (2008) birth between 1997 pregnancy. – 2005 to infants Prospective diagnosed with Outcome: cohort study PPHN. PPHN

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* Oberlander et Records of live Exposure: Fair 3 al (2008) births between 1st trimester SSRI 4/1/97 – 3/31/2002 (Citalopram, Retrospective in British Colombia Fluoxetine, cohort study from women Fluvoxamine, diagnosed with Paroxetine, depression. Data Sertraline, And derived from Venlafaxine) hospital, pharmacy and/or and physician benzodiazepines billing registries. (BZ). Poly drug exposure was defined as SSRI and BZ were dispensed for same day during 1st trimester.

Outcome: Major congenital anomalies and subset of cardiovascular defect (VSD and ASD).

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases*

Maschi et al Women who called Exposure: 14 200 50 1200 OR = 1.73* NS Poor - Fair 3 (2008) the Drug and Antidepressants, Health Information including Case-control Center in Milan, paroxetine (most took used drug), antidepressants fluoxetine, during pregnancy amitriptyline, and and delivered benzodiazepine. infants between 1995-2003. Outcome: poor neonatal Cases were adaptation – matched for respiratory maternal age and distress, gravidity to 6 hypoglycemia, randomly selected jitteriness, controls lethargy, hypotonia, weak/absent cry, feeding difficulties, convulsions and hyperbilirubinaemi a

Exposure/ EXPOSED NONEXPOSED Name Sample Outcome of p- Study design characteristics interest Cases N Cases N OR/ RR 95% CI value Quality† Biases* Chambers CD Study groups were Exposure: 14 377 6 836 6.1 2.2-16.8 0.001 N/A N/A 2006 age-matched SSRI (which Case control SSRIs used in study studies?) during 2nd and 3rd trimester

Outcome: Pulmonary Hypertension

† Based on KP system for grading the strength of a body of evidence (refer to Appendix A). * Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization) ** Calculated based on provided data.

Table 13.3: Meta-Analyses of Antidepressants in Lactation Studies Study Population Total N Groups Size & Drug Results Comments Rubin ET 2004 All studies of breast milk or breastfeeding and Average breast fed infant exposure levels were Authors’ conclusions: (meta-analysis) CNS-acting drugs less than 10% of the therapeutic dose of CNS-acting drugs used by breast-feeding mothers do not antidepressant medications per kilogram of body pose any risk to the infant # studies found: 345 The infant exposure level (%) was defined as weight. # studies included: 123, 17 studies of follows: [Drug concentration in milk (mg/mL)] x Biases, etc. antidepressants [Daily milk intake (mL/kg/d)] x 100 / Maternal Most studies evaluated were case reports dose (mg/kg/d). Total N = 642 in antidepressant studies Weissman AM 2004 All studies of antidepressant levels in nursing Levels of most medications found in breast milk Authors’ conclusions: (pooled analysis) mother-infant pairs were extremely generally less than 10% of the Breastfeeding infants exposed to nortriptyline, paroxetine or average maternal level sertraline unlikely to develop detectable or elevated plasma # studies found: 67 drug levels, while those exposed to fluoxetine appear to be # studies included: 57 Fluoxetine levels exceeded 10% of maternal at higher risk, especially following prenatal exposure. levels in 22% (N = 8) of infants studied. Citalopram was also noted to produce elevated plasma Total N = 337 mothers, 237 infants drug levels in some infants. Citalopram levels exceeded 10% of maternal levels in 17% (N = 2) of infants studied. Biases, etc. Most studies evaluated were case reports. Most studies did not include all the parameters studied. Maternal weight, timing of maternal dosing, and use of other medications was not recorded. Small n for fluoxetine and citalopram fetal drug level evaluation.

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