PROPOSAL FOR THE ADDITION OF A SQUARE BOX SYMBOL TO FLUOXETINE FOR THE TREATMENT OF DEPRESSIVE DISORDERS IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES WHO Collaborating Centre for Research & Training in Mental Health & Service Evaluation Verona, Italy

Persons to Contact:

Kavitha Kolappa, MD, MPH [email protected]

Corrado Barbui, MD [email protected]

Submitted for Review December 7, 2018 Submitted with Revisions 25 January, 2019

Contributors:

Kavitha Kolappa, MD, MPH Consultation/Liaison Psychiatrist, Massachusetts General Hospital Instructor in Psychiatry, part-time, Harvard Medical School Consultation/Liaison Psychiatrist, Boston Medical Center Boston, United States

Corrado Barbui, MD WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry Professor of Psychiatry, University of Verona Verona, Italy

Giovanni Ostuzzi, MD, PhD WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry Research Fellow in Psychiatry, University of Verona Verona, Italy

Kate Loveys, MS Department of Psychological Medicine PhD candidate, University of Auckland Auckland, New Zealand

None of the primary contributors have any conflicts of interest to declare.

Acknowledgments: We are grateful for the support, counsel, and technical input of the following individuals.

Dr. Nicola Magrini, WHO Department of Essential Medicines & Health Products Dr. Tarun Dua, WHO Department of Mental Health & Substance Abuse Ms. Bernadette Cappello, WHO Department of Essential Medicines & Health Products

CONTENTS GENERAL ITEMS 1. Summary statement of the proposal for addition of a square box symbol to fluoxetine for use in depressive disorders (as representative of the therapeutic class of SSRIs) 2. Name of WHO technical department and focal point supporting the application 3. Name of the organization(s) consulted and/or supporting the application 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine 5. Dose form(s) and strength(s) proposed for inclusion (for Adult Model List only) 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class

TREATMENT DETAILS, PUBLIC HEALTH RELEVANCE, EVIDENCE APPRAISAL AND SYNTHESIS 7. Treatment details (requirements for diagnosis, treatment and monitoring) 8. Information supporting the public health relevance 9. Review of benefits: summary of evidence of comparative effectiveness 10. Review of harms and toxicity: summary of evidence of safety 11. Summary of available data on comparative cost and cost-effectiveness of the medicine

REGULATORY INFORMATION 12. Summary of regulatory status and market availability of the medicine 13. Availability of pharmacopoeial standards

SUMMARY OF SSRIs CONSIDERED IN THIS APPLICATION

IMPLICATIONS FOR FUTURE WORK

REFERENCES

APPENDICES APPENDIX 1: mhGAP-IG, version 2.0 Depression Treatment APPENDIX 2: Excerpts from selected National Essential Medicines Lists APPENDIX 2: GRADE Tables 1-6

GENERAL ITEMS

1. Summary statement of the proposal for addition of a square box symbol (□) to fluoxetine

Section 24.2.1 (Medicines used in depressive disorders) of the 20th WHO Model List of Essential Medicines includes the following medications: amitriptyline and fluoxetine, a tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitor (SSRI), respectively. The listing for amitriptyline includes a square box symbol (□), indicating that there is similar clinical performance within the pharmacological class of TCAs. Fluoxetine, which was added to the Model List in 2007, is listed as an individual medicine and not as a representative of its class.

There have been no changes to this sub-section of the Model List since 2007. We would like to note that submissions have been made and rejected in the past for other SSRIs (paroxetine, 1998 & 2009; escitalopram, 2009; sertraline, 2009). Since that time, numerous studies and meta-analyses have emerged comparing the efficacy and acceptability of various antidepressants. In this application, we will consider best available evidence to date on efficacy and acceptability of both SSRIs and commonly used SNRIs (serotonin norepinephrine reuptake inhibitors) for moderate to severe depression. For the SSRIs in particular, we will discuss differential safety profiles and use in special populations. Additionally, we will consider availability, cost, and cost-effectiveness.

There are minimal clinically significant differences in efficacy amongst the SSRIs, though there are some differences in acceptability as well as safety profiles, especially in regards to special populations. Considering their comparable clinical efficacy and the growing availability of a number of generic formulations of SSRIs, we propose the addition of a square box symbol (□) to fluoxetine to the 21st WHO Model List of Essential Medicines. We recommend that the square box symbol (□) be restricted to the following SSRIs for which there is the strongest evidence for both efficacy and acceptability: citalopram, escitalopram, fluoxetine, and sertraline.

2. Name of WHO technical department and focal point supporting the application Dr. Tarun Dua, WHO Department of Mental Health & Substance Abuse

3. Name of the organization(s) consulted and/or supporting the application. WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine:

The INN for fluoxetine is 3883, and the ATC code for fluoxetine is N06AB03. For reference, the INN & ATC codes for the other SSRIs considered are summarized in the following table.

Table 1: INN & ATC codes for other commonly used SSRIs12:

Medication INN ATC Citalopram 4138 N06AB04 Escitalopram 7953 N06AB10 Fluoxetine 3883 N06AB03 Fluvoxamine 3879 N06AB08 Paroxetine 4327 N06AB05 Sertraline 5277 N06AB06

5. Dose form(s) and strength(s) proposed for inclusion (for Adult Model List only).

Fluoxetine: oral tablets containing 10 mg; oral capsules containing 10, 20, 40, and 60 mg

Fluoxetine gained US FDA-approval as a “new molecular entity” under the trade name Prozac produced by Eli Lilly on December 29, 1987 (NDA #018936)1. Fluoxetine went off-patent on August 3rd, 2001. Just prior to this, five companies had already gained FDA approval to produce generic fluoxetine (Barr Laboratories, Teva Pharmaceuticals, Geneva Pharmaceuticals, Pharmaceutical Resources, and Dr. Reddy’s Laboratories)2.

Thirty-one companies have obtained fifty-two separate FDA approvals for generic formulations of fluoxetine, thirty-three of which are still active3. In India alone, there are 102 “branded” generic versions of fluoxetine4. There are fifteen generic formulations by nine companies approved by the Medicines Control Council in South Africa. In addition, according to drugs.com, well over one hundred companies globally produce branded or unbranded generic versions of fluoxetine5.

For reference, see below Tables 2-4 with numbers of US FDA approvals of generic formulations of other SSRIs, as well as formulations in India and South Africa.

Table 2: US FDA Approvals for Generic SSRI formulations3

Medication # of US FDA approvals for generic formulation Citalopram 34 Escitalopram 29 Fluvoxamine 16 Paroxetine 21

1 International Nonproprietary Names (INN) obtained from MedNet (accessible online at https://mednet- communities.net/inn). 2 ATC codes obtained from WHO Collaborating Centre for Drug Statistics Methodology (accessible online at https://www.whocc.no/atc_ddd_index/). The ATC code for antidepressants is N06A and for SSRIs in particular is N06AB. Sertraline 29

Table 3: Generic Formulations of SSRIs in India4

Medication # of generic formulations in India Citalopram 70 Escitalopram 298 Fluvoxamine 42 Paroxetine 117 Sertraline 164

Table 4: Generic Formulations of SSRIs Approved by the MCC in South Africa6,3

Medication # of generic formulations in South Africa Citalopram 31 Escitalopram 0 Fluvoxamine 2 Paroxetine 13 Sertraline 21

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class

Fluoxetine has been on the WHO Model List since 2007. We are requesting the addition of a square box symbol (□) to fluoxetine to indicate that there are a number of agents with comparable efficacy, acceptability, and cost. We recommend the square box be restricted to the following SSRI medications: citalopram, escitalopram, fluoxetine, and sertraline. See Table 16 (Summary of SSRIs considered).

TREATMENT DETAILS, PUBLIC HEALTH RELEVANCE, EVIDENCE APPRAISAL AND SYNTHESIS

7. Treatment details

(a) Relevant International and National Guidelines:

WHO’s Department of Mental Health & Substance Abuse has developed evidence-based recommendations for the management of depression in non-specialized health settings. WHO compiled evidence profiles on psychopharmacological and psychological treatments for depression in 20127. Antidepressants including TCAs and SSRIs were found to be more effective for moderate to severe depression than for mild depression. When comparing TCAs and SSRIs, there were no significant differences in efficacy, however, there was an incremental benefit in

3 “Originator” products have been excluded. acceptability for SSRIs. Additionally, SSRIs were found to be more acceptable for elderly persons. Ultimately, the following recommendations were made.

Box 1: WHO Mental Health Gap Action Programme Evidence Resource Center (mhGAP ERC) Guidelines on Psychopharmacological Treatments of Depression

Antidepressants should not be considered for the initial treatment of adults with mild depressive episode. Strength of recommendation: STANDARD Tricyclic antidepressants (TCA) or fluoxetine should be considered in adults with moderate to severe depressive episode/disorder. Strength of recommendation: STANDARD If drug treatment is required in older people, tricyclic antidepressants (TCA) should be avoided if possible. Strength of recommendation: STANDARD If drug treatment is required in women with depressive episode who are planning a pregnancy or pregnant or breastfeeding, tricyclic antidepressants (TCA) or fluoxetine should be considered. Strength of recommendation: STANDARD

WHO’s Mental Health Gap Action Programme Intervention Guide (mhGAP-IG), version 2.0 (published in October 2016) provides treatment algorithms and dosing recommendations for medications to treat depression, including amitriptyline and fluoxetine8. See Appendix 1 for a quick reference guide to fluoxetine dosing from the mhGAP-IG, version 2.0.

The UK’s National Institute for Health and Care Excellence (NICE) published guidelines for the recognition and management of depression in 2013, as well as an accompanying interactive treatment algorithm9,10. NICE guidelines recommend SSRIs for the management of depression (though other medications including TCAs are discussed): “When an antidepressant is to be prescribed, it should normally be an SSRI in a generic form because SSRIs are equally effective as other antidepressants and have a favourable risk-benefit ratio.” Prescribers are also advised to consider the side effects of SSRIs, including increased risk of bleeding, drug-drug interactions (particularly with fluoxetine, fluvoxamine, and paroxetine), and discontinuation syndrome (most notably for paroxetine). If an antidepressant has been effective for a person and their depression has remitted, prescribers are asked to encourage the person to continue treatment for at least 6 more months, as this decreases the risk for relapse. Full text of these guidelines are available on the UK NICE website.

The American Psychiatric Association also published comprehensive Practice Guidelines for depression in 201011. The APA Guidelines discuss that there is comparable efficacy amongst different antidepressants, and as such the choice of antidepressants should be made with the consideration of numerous factors including safety and tolerability profiles, pharmacodynamics and pharmacokinetics, medication prices, as well as patient preferences (and history of previous medication trials). Further, the Guidelines discuss that “For most patients, a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion is optimal.” Full text of these guidelines are available on the APA website.

The Indian National Health Portal, established by the Ministry of Health and Family Welfare in India has a module on depression identification and management12. As for antidepressant use, the module discusses three classes of medications including SSRIs and atypical antidepressants, tricyclic antidepressants, and monoamine oxidase inhibitors, the first group of which are considered first-line agents. Full text of the NHP is also available online.

(b) Selected Sections of National Essential Medicines Lists:

See Appendix 2 for excerpts of National Essential Medicines Lists for India, Brazil, China, Ethiopia, Haiti, and Thailand, all of which were accessed online through the WHO repository of National Medicines Lists13. SSRIs are included in the Indian, Brazilian, Ethiopian and Thai lists, though the specific SSRIs included vary (fluoxetine and escitalopram for India, fluoxetine for Brazil, fluoxetine and sertraline for Ethiopia, fluoxetine and sertraline for Thailand).

(c) Requirements for Diagnosis, Treatment, and Monitoring:

Depressive disorders cover a range of syndromes categorized by severity of symptoms and duration of experience. A major depressive episode is generally thought of as the experience of feeling sad for most of the day most days for two weeks or more. Persons experiencing major depression may additionally suffer from poor sleep, appetite, or energy; diminished concentration or interest in activities they previously enjoyed; excessive feelings of guilt; psychomotor agitation or retardation; or thoughts of suicide or death. It is important to note here that experiences and expressions of depression may vary according to culture and context (as just one example, depression in some Asian cultures may be more likely to manifest with somatic symptoms, i.e. pain, dizziness, etc).14,15

For the purposes of this application to the WHO Model List and considering that the best evidence for the efficacy of antidepressant medication exists for moderate to severe depression (as opposed to mild depression or sub-threshold symptoms), we will limit our scope to major depressive disorder as defined by traditionally biomedical models of conceptualizing and diagnosing depression.

Here we will briefly introduce ICD-11 and DSM-5 categorization of depressive disorders. i. ICD-11 categorization of depressive disorders

The 11th version of WHO’s International Classification of Diseases (ICD-11) includes six categories of depressive disorders, with numerous sub-categories within these16. (See Box 2.) ICD-11 defines a single episode of depression as the following:

“Single episode depressive disorder is characterized by the presence or history of one depressive episode when there is no history of prior depressive episodes. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least two weeks accompanied by other symptoms such as difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue. There have never been any prior manic, hypomanic, or mixed episodes, which would indicate the presence of a bipolar disorder.”

Box 2: ICD-11 Categorization of Depressive Disorders

6A70 Single episode depressive disorder 6A70.1 Single episode depressive disorder, mild 6A70.2 Single episode depressive disorder, moderate, without psychotic symptoms 6A70.3 Single episode depressive disorder, severe, without psychotic symptoms 6A70.4 Single episode depressive disorder, severe, with psychotic symptoms 6A70.5 Single episode depressive disorder, unspecified severity 6A70.6 Single episode depressive disorder, currently in partial remission 6A70.7 Single episode depressive disorder, currently in full remission 6A70.Y Other specified single episode depressive disorder 6A70.Z Single episode depressive disorder, unspecified 6A71 Recurrent depressive disorder 6A71.0 Recurrent depressive disorder, current episode mild 6A71.1 Recurrent depressive disorder, current episode moderate, without psychotic symptoms 6A71.2 Recurrent depressive disorder, current episode moderate, with psychotic symptoms 6A71.3 Recurrent depressive disorder, current episode severe, without psychotic symptoms 6A71.4 Recurrent depressive disorder, current episode severe, with psychotic symptoms 6A71.5 Recurrent depressive disorder, current episode, unspecified severity 6A71.6 Recurrent depressive disorder, currently in partial remission 6A71.7 Recurrent depressive disorder, currently in full remission 6A71.Y Other specified recurrent depressive disorder 6A71.Y Recurrent depressive disorder, unspecified 6A72 Dysthymic disorder 6A73 Mixed depressive and anxiety disorder 6A7Y Other specified depressive disorders 6A7Z Depressive disorders, unspecified ii. DSM-5 categorization of depressive disorders

The 5th version of the Diagnostic and Statistical Manual of Mental Disorders includes eight categories of depressive disorders17. (See Box 3.)

Box 3: DSM-5 Categorization of Depressive Disorders

Disruptive Mood Dysregulation Disorder Major Depressive Disorder Persistent Depressive Disorder (Dysthymia) Premenstrual Dysphoric Disorder Substance/Medication-Induced Depressive Disorder Depressive Disorder Due to Another Medical Condition Other Specified Depressive Disorder Unspecified Depressive Disorder

Specifiers for the depressive disorders include the following: with anxious distress, severity (mild, moderate, moderate-severe, severe, severe with mixed features, severe with melancholic features, severe with atypical features, and severe with psychotic features), with mood congruent psychotic features, with mood-incongruent psychotic features, with catatonia, with peripartum onset, with seasonal pattern, remission status (in partial remission, in full remission), and current severity (mild, moderate, and severe). iii. Proposed therapeutic dosage regimen and duration of treatment

The below texts are excerpted from the WHO Model Formulary, last updated in 200818.

24.2.1 Medicines used in depressive disorders

Tricyclic and related antidepressants and selective serotonin reuptake inhibitors (SSRIs) are the most widely used drugs in the treatment of depressive disorders. The response to antidepressant therapy is usually delayed, with a lagperiod of up to 2 weeks and at least 6 weeks before maximum improvement occurs. It is important to use doses that are sufficiently high for effective treatment, but not so high as to cause toxic effects. Low doses should be used for initial treatment in the elderly. The use of more than one antidepressant at a time is not recommended since this does not enhance effectiveness and it may result in enhanced adverse effects or interactions.

Patients should be reviewed every 1–2 weeks at the start of treatment. Treatment should be continued for at least 4 weeks (6 weeks in the elderly) before considering a change to another antidepressant because of problems with suitability or efficacy. In the case of a partial response, treatment may be continued for a further 2 weeks (or possibly longer in elderly patients as they may take longer to respond). Remission usually occurs after 3–12 months. Treatment at full therapeutic dose should be continued for at least 6 months, but preferably up to 12 months after resolution of symptoms (about 12 months in the elderly). Treatment should not be withdrawn prematurely, otherwise symptoms are likely to recur. Patients with a history of recurrent depression should continue to receive maintenance treatment (for at least 5 years and possibly indefinitely). Lithium may be used as an alternative to anti-depressants for maintenance treatment (see section 24.2.2). The lithium dose should be reduced gradually over about 4 weeks, or even longer if withdrawal symptoms emerge (6 months in patients who have been on longterm maintenance treatment).

Tricyclic and related antidepressants can be divided into those with lesser sedative effect. Those with sedative properties include amitriptyline and those with less sedative effects include imipramine [not included on the 15th WHO Model List] . These drugs are most effective in the treatment of depression associated with psychomotor and physiological disturbances. Adverse effects include anticholinergic (more correctly, antimuscarinic) symptoms of dry mouth, blurred vision, constipation, and urinary retention. Arrhythmias and heart block can also occur. Minimal quantities of tricyclic antidepressants should be prescribed at any one time because their cardiovascular effects are dangerous in overdose. Amitriptyline in overdosage is associated with a high rate of fatality.

Fluoxetine is a SSRI which characteristically causes gastrointestinal disturbances, sleep disturbances, and hypersensitivity reactions including rash (may be a sign of an impending serious systemic reaction and discontinuation should be considered) but they are less sedating and have fewer anticholinergic (antimuscarinic) and cardiotoxic effects than tricyclic antidepressants. The SSRIs are less toxic in overdose than the older tricyclic compounds, but there is some concern that SSRIs may increase suicidal ideation, especially in children and adolescents.

Fluoxetine Capsule or tablet: 20 mg (present as hydrochloride). Uses: moderate to severe major depression. Contraindications: manic phase. Precautions: epilepsy; cardiac disease, bleeding disorders, diabetes mellitus; susceptibility to angle-closure glaucoma; history of mania (discontinue if patient entering manic phase); concurrent electroconvulsive therapy (prolonged seizures reported); pregnancy (Appendix 2) and breastfeeding (Appendix 3); hepatic impairment (Appendix 5); avoid abrupt withdrawal; children and adolescents (increased risk of suicide); interactions: Appendix 1.

SKILLED TASKS. May impair ability to perform skilled tasks, for example operating machinery or driving.

Dose: Depression, by mouth, ADULT, initially 20 mg once daily, increased as necessary after 3 weeks to a maximum of 80 mg daily (60 mg daily in the elderly); usual maintenance dose in the range, 20–60 mg once daily (20–40 mg once daily in the elderly). NOTE. Consider the long duration of action of fluoxetine when adjusting dosage.

Adverse effects: gastrointestinal disturbances, anorexia with weight loss, postural hypotension, pharyngitis, dyspnoea, headache, sleep disturbances, dizziness, ataxia, tremor, convulsions (consider discontinuation); altered blood glucose control in people with diabetes; taste disturbances, urinary retention and frequency, sexual dysfunction, galactorrhoea, arthralgia, myalgia, visual disturbances, photosensitivity, chills, increased sweating, dry mouth, alopecia, rash (may be sign of serious systemic reaction; consider discontinuation), urticaria, angioedema, vasculitis, anaphylaxis; yawning, idiosyncratic hepatitis, pulmonary fibrosis, restlessness, akathisia, hallucinations, manic reactions, confusion, agitation, anxiety, depersonalization, panic attacks, suicidal ideation, hyponatraemia, movement disorders and dyskinesias, bleeding disorders including ecchymosis; serotonin syndrome, and erythema multiforme (leading to Stevens-Johnson syndrome or toxic epidermal necrolysis) also reported; on withdrawal dizziness, nausea, anxiety, headaches, paraesthesia, sleep disturbances, fatigue, agitation, tremor, and sweating (particularly if withdrawn too abruptly).

Below text adapted from the WHO Model Formulary, Appendix 1 on Interactions:

In the following, the symbol * indicates a potentially hazardous interaction and the combined administration of the drugs involved should be avoided, or only taken with caution and appropriate monitoring. Interactions with no symbol do not usually have serious consequences.

Drug-drug interactions involving fluoxetine

* Acetylsalicylic acid: Increased risk of bleeding Alcohol: Possibly increased sedation * Artemether + lumefantrine: Manufacturer of artemether + lumefantrine advises avoid concomitant use * Carbamazepine: Plasma concentration of carbamazepine increased * Haloperidol: Plasma concentration of haloperidol increased * Ibuprofen: Increased risk of bleeding * Lithium: Increased risk of CNS effects (lithium toxicity reported) Phenobarbital: Antagonism of anticonvulsive effect (convulsive threshold lowered) * Phenytoin: Plasma concentration of phenytoin increased * Ritonavir: Plasma concentration of fluoxetine possibly increased * Warfarin: Anticoagulant effect possibly enhanced

Below text excerpted from the WHO Model Formulary, Appendix 2 on Pregnancy:

Fluoxetine: Manufacturer advises use only if potential benefit outweighs risk; risk of neonatal withdrawal

Below text excerpted from the WHO Model Formulary, Appendix 2 on Breastfeeding:

Fluoxetine: Present in milk; manufacturer advises avoid or use lowest effective dose

Below text excerpted from the WHO Model Formulary, Appendix 5 on Hepatic Impairment:

Fluoxetine: Reduce dose or administer on alternate days

iv. Need for special diagnostics, treatment, or monitoring facilities and skills

Depression may be diagnosed at the primary care level. No special monitoring is needed on a routine basis, however SSRIs in general can cause hyponatremia, which in certain patients may need to be monitored. Additionally, SSRIs including fluoxetine can cause prolonged QT, and if feasible, this may be monitored with ECG testing.

8. Information supporting the public health relevance

Depressive disorders are major drivers of the global burden of disease, as measured in prevalence, disability-adjusted life-years, and years lived with disability. Depressive disorders are estimated to affect over 260 million people, more than 160 million of whom have major depressive disorder; this translates to roughly 3.6% and 2.2% of the world’s population19. According to the 2017 Global Burden of Disease study, depressive disorders are responsible for over 43 million disability-adjusted life years (DALYs) annually, accounting for 1.7% of total estimated DALYs due to any disease. Depressive disorders are also responsible for over 43 million years lived with disability (YLD), accounting for 5.0% of the total YLD globally. The global burden of disease due to depression appears to be increasing over time. See Figure 1 for graphs showing the trend in DALYs and YLDs due to depression between 1990 & 2017.

Figure 1: Global trend in DALYs and YLDs due to depression between 1990 & 20174

4 These graphs were created using the GBD Results Tool, which is accessible online at http://ghdx.healthdata.org/gbd-results-tool (accessed Dec 5, 2018).

Further, see Figures 2 and 3 for comparative tree maps of the global burden of major diseases according to DALYs and YLDs, respectively.

Figure 2: Tree Map of Global Causes of Disability-Adjusted Life Years5

5 Institute for Health Metrics and Evaluation (IHME). GBD Compare Data Visualization. Seattle, WA: IHME, University of Washington, 2018. Available from http://vizhub.healthdata.org/gbd-compare. (Accessed 12/5/18) Figure 3: Tree Map of Global Causes of Years Lived with Disability6

In addition to the large burden of disease caused by depression directly, there is a well-known relationship between depression and the stress-related non-communicable diseases including diabetes, heart disease, and cancers. Persons with depression have more than twice the risk of coronary artery disease as the general population, and persons with depression and unstable angina or heart attacks have higher mortality rates20–22. Epidemiologically, depression has long been understood to be a risk factor for chronic physical illnesses, and pathophysiological links between the brain and body are increasingly becoming better understood23. Depression has been linked with insulin resistance and coronary artery disease, as just two examples24,25.

6 Institute for Health Metrics and Evaluation (IHME). GBD Compare Data Visualization. Seattle, WA: IHME, University of Washington, 2018. Available from http://vizhub.healthdata.org/gbd-compare. (Accessed 12/5/18) Depression also incurs a major financial cost globally. The financial cost of depression in the US alone is estimated to be well over 200 billion USD annually26. WHO estimates that depression and anxiety together cost an estimated 1 trillion USD annually in workplace productivity alone27. Despite the enormous burden of disease caused by depression, access to treatment (both pharmacological and psychological) remains poor in many areas of the world. Access to affordable psychiatric medicines is variable, depending on the context. According to the 2017 Mental Health Atlas data, it is the case in 45% of countries in Africa that citizens have to pay for psychotropic medications out of pocket, as opposed to the Americas where citizens are either fully insured or reimbursed at least 20% of costs in 90% of countries28.

Providing access to medications is only one aspect of improving access to care, though a critically important one for persons with moderate to severe depression. Treating depression has been demonstrated to be greatly cost-effective, with an estimated four-fold return for every dollar invested in treatment29.

9. Review of benefits: summary of evidence of comparative effectiveness

In order to adequately assess the evidence of comparative effectiveness and acceptability, a systematic search was conducted by our team. Using the PICO strategy, we identified our target population, intervention, comparators, and outcomes as the following:

- Target population: adults with major depression or acute depressive episode. - Intervention of interest: anti-depressant medication (specifically SSRIs listed in Table 1 and the commonly used SNRIs duloxetine and venlafaxine). - Comparators: placebo and/or other anti-depressants. - Outcomes: efficacy, acceptability, and adverse events.

We conducted our search using the PubMed/National Center for Biotechnology Information (NCBI) database. Our search strategy included the following terms:

(depress*[Title/Abstract] AND SSRI[Title/Abstract]) OR (depress*[Title/Abstract] AND selective serotonin reuptake inhibitor[Title/Abstract]) OR (depress*[Title/Abstract] AND SNRI[Title/Abstract]) OR (depress*[Title/Abstract] AND serotonin norepinephrine reuptake inhibitor[Title/Abstract]) OR (depress*[Title/Abstract] AND antidepress*[Title/Abstract])

The search yielded 35,113 results and was subsequently filtered to: Systematic Reviews (Article types), Full text (Text availability), 5 years (Publication dates), and humans (Species). (See Figure 4.) The filtered results yielded 653 entries, which were saved in an MS Word document.

Figure 4: Systematic Literature Review

Of the papers of interest identified in our search, we have attempted to summarize the most relevant and up-to-date evidence on comparative effectiveness and acceptability. In Section 10, we also give attention to select adverse outcomes, side effects and special populations.

The most comprehensive meta-analysis to date of antidepressant efficacy and acceptability was published by Cipriani, Furukawa, and colleagues in February 201830. Cipriani and colleagues conducted a network meta-analysis reviewing data from 522 randomised controlled trials of 21 different antidepressants (TCAs, SSRIs, SNRIs, and atypical antidepressants) or placebo undertaken between 1979 and 2016. In total, these studies involved over 116,000 patients, with just over 87,000 receiving an antidepressant and over 29,000 receiving placebo. The vast majority (89%) of the studies focused on moderate to severe depression. Of the 522 studies, 304 were placebo-controlled. 194 studies were of head to head comparisons and involved over 34,000 patients. Geographically, nearly half (48%) of the studies were based in North America, approaching a third (27%) were based in Europe, 7% in Asia, and 11% involved more than one continent, with the remainder (7%) in other or unspecified regions.

For the purposes of this application, we will present analyses from this meta-analysis for all 6 of the 7 SSRIs studied, as well as the two most commonly used SNRIs (duloxetine and venlafaxine) for comparison. We will not discuss milnacipran, levomilnacipran, desvenlafaxine, or vilazodone, as there were no placebo-controlled trials analysed for the former and no head to head comparisons for the latter three. We will also not cover TCAs or atypical antidepressants (such as vortioxetine) in this application. Of note, vortioxetine shows promising data for efficacy and acceptability in the network meta-analysis; however, there is a lack of direct evidence for this by way of head to head studies and patient exposure to date has not been large. Further it is not an SSRI or SNRI, and as such we have not covered it in this application for comparison.

Cipriani et al concluded that all 21 antidepressants studied had greater impact (as measured by response) than placebo and these differences were statistically significant, which is noteworthy considering the long-standing controversy surrounding placebo effects in antidepressant trials31,32. See Table 5 below for comparisons in efficacy (assessed by response rate) and acceptability (assessed by dropouts due to any cause) between selected antidepressants and placebo. The greatest effect sizes were found for amitriptyline and mirtazapine (not covered in the table below); of the antidepressants we have considered, the greatest effect sizes were found for duloxetine and venlafaxine, followed by paroxetine. However, the wide overlap in confidence intervals would suggest there is minimal difference between at least the SSRIs. Regarding acceptability, only two of the antidepressants studied by the authors and only one antidepressant considered in this application (fluoxetine) had a statistically significant advantage over placebo.

Table 5: Efficacy & acceptability of selected antidepressants versus placebo30 Bolded ORs are statistically significant. For efficacy, ORs >1 favor the antidepressant. For acceptability, ORs <1 favor the antidepressant.

Antidepressant Efficacy compared to placebo Acceptability compared to placebo OR (95% CI) OR (95% CI) SSRIs Citalopram 1.52 (1.33 to 1.74) 0.94 (0.80 to 1.09) Escitalopram 1.68 (1.50 to 1.87) 0.90 (0.80 to 1.02) Fluoxetine 1.52 (1.40 to 1.66) 0.88 (0.80 to 0.96) Fluvoxamine 1.69 (1.41 to 2.02) 1.10 (0.91 to 1.33) Paroxetine 1.75 (1.61 to 1.90) 0.95 (0.87 to 1.03) Sertraline 1.67 (1.49 to 1.87) 0.96 (0.85 to 1.08) SNRIs Duloxetine 1.85 (1.66 to 2.07) 1.09 (0.96 to 1.23) Venlafaxine 1.78 (1.61 to 1.96) 1.04 (0.93 to 1.15)

Cipriani et al also considered head to head comparisons of 21 antidepressants using a network meta-analytic approach. See Table 6 below for a comparison between our antidepressants of interest, with reboxetine (a norepinephrine reuptake inhibitor) as a standard reference point. Most comparisons of efficacy (or impact) between selected SSRIs and SNRIs with reboxetine were not statistically significant. Only escitalopram and paroxetine were found to have greater impact than reboxetine. However, the wide overlap of confidence intervals would suggest minimal clinical difference amongst the SSRIs and SNRIs in the table below. With regards to acceptability, 5 of the 8 comparisons with reboxetine were statistically significant. All of the SSRIs except for fluvoxamine were found to have greater acceptability than reboxetine; of note, neither SNRI we considered had statistically significant differences from reboxetine with regards to acceptability. As is the case with efficacy, the wide overlap of confidence intervals would suggest minimal clinical difference amongst the SSRIs with respect to acceptability.

Table 6: Comparison of selected antidepressants with reboxetine Bolded ORs are statistically significant. For efficacy, ORs >1 favor the antidepressant besides reboxetine. For acceptability and dropouts due to adverse events, ORs <1 favor the antidepressant besides reboxetine.

Antidepressant Efficacy compared GRADE Acceptability GRADE to reboxetine confidence compared to confidence in OR (95% CI) in estimate reboxetine estimate OR (95% CI)

SSRIs Citalopram 1.27 (0.92 to 1.75) LOW 0.60 (0.41 to 0.87) LOW Escitalopram 1.60 (1.14 to 2.23) MODERATE 0.55 (0.37 to 0.81) MODERATE Fluoxetine 1.20 (0.88 to 1.62) LOW 0.63 (0.44 to 0.90) LOW Fluvoxamine 1.20 (0.83 to 1.71) LOW 0.77 (0.51 to 1.17) LOW Paroxetine 1.43 (1.05 to 1.94) LOW 0.66 (0.46 to 0.94) LOW Sertraline 1.34 (0.96 to 1.85) LOW 0.62 (0.43 to 0.92) LOW SNRIs Duloxetine 1.36 (0.95 to 1.95) LOW 0.86 (0.57 to 1.29) LOW Venlafaxine 1.42 (1.04 to 1.94) LOW 0.73 (0.50 to 1.06) LOW

For more information, see APPENDIX 3 for GRADE Tables 1 and 2 on Efficacy and Acceptability. Studies involved in these analyses have been graded for certainty of evidence.

Comments on GRADING of evidence:

Cipriani et al evaluated studies included in the head to head comparisons for degree of certainty using the GRADE (Grading of recommendations, assessment, development, and evaluation) approach. As this study is a network meta-analysis and the methodology for using the GRADE approach is still being developed and under discussion, we have adopted the author’s grading of the studies of interest, specifically for the comparisons with reboxetine, in our GRADE tables 1 - 3 (see Appendix 3). The certainty of data for most comparisons of interest were rated as low, with moderate certainty for comparisons involving escitalopram. Here we would like to highlight that the study’s authors have downgraded all studies for publication bias, and this is a decision we agree with.

Publication bias in the context of antidepressant medications (failure to publish unfavorable trials and analyzing published data in a favorable way) has been a major issue concerning antidepressant medications, including the SSRIs, SNRIs, and atypical antidepressants31–33. A meta-analytic comparison by Turner et al in 2008 of published trials versus reviews from trials of 12 antidepressants that were mandatorily reported to the FDA (involving over 12,000 patients) found that publication bias increased the apparent efficacy of antidepressant medicines on average by 32%, with a range of 11-69%31. This difference was due to unfavorable trials remaining unpublished and data for published trials being analyzed in such a way to appear more favorable (in comparison with FDA analyses of the same data). The greatest effect size differences between all data and published data were found for nefazodone (+69%), sertraline (+64%), mirtazapine (+61%), and bupropion (+55%). The lowest effect size differences were found for paroxetine CR (11%), fluoxetine (14%), and escitalopram (+16%).

See Table 7 below for efficacy and acceptability of comparing each of our antidepressants of interest with the other using head to head trials. With regards to efficacy or impact, few comparisons were statistically significant (roughly one-fifth, or 8 out of 36 comparisons). Escitalopram was found to have greater impact than citalopram, fluoxetine, fluvoxamine, and reboxetine. Paroxetine and venlafaxine were found to have greater impact than fluoxetine and reboxetine. With regards to acceptability, one-third of the comparisons were found to be statistically significant. Citalopram, escitalopram, fluoxetine, paroxetine, and sertraline were all found to have greater acceptability than duloxetine or reboxetine. Escitalopram was additionally found to have greater acceptability than fluvoxamine and venlafaxine. Of note, there were no statistically significant differences amongst other SSRI comparisons (apart from escitalopram and fluvoxamine mentioned above) with regards to acceptability.

Table 7: Efficacy and acceptability of selected antidepressants (head to head comparisons) Adapted from Figure 4 (Cipriani, et al 2008)30

Medications are listed in alphabetical order. Odds ratios listed are comparisons between medications in the defining column and row. For efficacy (impact/response rate), OR >1 favor the medication earlier in alphabetical order. For acceptability (drop-outs due to any cause), OR <1 favor the medication earlier in alphabetical order. Bolded ORs are statistically significant.

EFFICACY OF TREATMENT (IMPACT/RESPONSE RATE)

Citalopram 0.93 (0.71 0.79 (0.65 to 1.06 (0.87 1.06 (0.82 to 0.89 (0.72 1.27 (0.92 0.95 0.90 (0.72 to 1.22) 0.97) to 1.29) 1.39) to 1.09) to 1.75) (0.76 to to 1.10) 1.18) 0.70 (0.51 Duloxetine 0.85 (0.67 to 1.14 (0.91 1.14 (0.85 to 0.95 (0.76 1.36 (0.95 1.02 0.96 (0.77 to 0.95) 1.08) to 1.44) 1.54) to 1.19) to 1.95) (0.79 to to 1.21) 1.32) 1.09 (0.85 1.56 (1.19 Escitalopram 1.34 (1.11 1.34 (1.03 to 1.12 (0.93 1.60 (1.14 1.20 1.13 (0.93 to 1.42) to 2.01) to 1.61) 1.75) to 1.35) to 2.23) (0.97 to to 1.37) 1.48) 0.96 (0.76 1.37 (1.06 0.87 (0.70 to Fluoxetine 1.00 (0.80 to 0.84 (0.73 1.20 (0.88 0.89 0.84 (0.73 to 1.21) to 1.73) 1.09) 1.25) to 0.95) to 1.62) (0.76 to to 0.97) OUTS DUE TO ANY CAUSE) OUTS DUE TO ANY - 1.05) 0.78 (0.57 1.12 (0.80 0.71 (0.53 to 0.82 (0.64 Fluvoxamine 0.84 (0.67 1.20 (0.83 0.89 0.84 (0.66 to 1.06) to 1.53) 0.96) to 1.04) to 1.04) to 1.71) (0.70 to to 1.07) 1.13)

ENT (DROP ENT 0.91 (0.71 1.30 (1.02 0.83 (0.67 to 0.95 (0.83 1.16 (0.90 to Paroxetine 1.43 (1.05 1.07 1.01 (0.86 to 1.17) to 1.63 1.03) to 1.09) 1.49) to 1.94) (0.90 to to 1.17) 1.26) 0.60 (0.41 0.86 (0.57 0.55 (0.37 to 0.63 (0.44 0.77 (0.51 to 0.66 (0.46 Reboxetine 0.75 0.70 (0.51 to 0.87) to 1.29) 0.81) to 0.90) 1.17) to 0.94) (0.54 to to 0.97) 1.04) 0.97 (0.74 1.38 (1.04 0.88 (0.69 to 1.01 (0.84 1.23 (0.94 to 1.06 (0.88 1.61 (1.09 Sertraline 0.94 (0.78 to 1.25) to 1.80) 1.12) to 1.21) 1.63) to 1.28) to 2.34) to 1.13)

0.83 (0.64 1.18 (0.92 0.75 (0.60 to 0.87 (0.74 1.06 (0.80 to 0.91 (0.77 1.38 (0.94 0.86 Venlafaxine to 1.07) to 1.49) 0.94) to 1.01) 1.38) to 1.07) to 1.99) (0.70 to ACCEPTABILITY OF TREATM ACCEPTABILITY 1.05)

10. Review of harms and toxicity: summary of evidence of safety

Cipriani and colleagues also examined dropouts due to adverse events or side effects30. Four of the six SSRIs had lower risk of dropouts compared to reboxetine (citalopram, escitalopram, fluoxetine, and sertraline). There was no statistically significant difference in this regard between fluvoxamine, paroxetine, or the SNRIs when compared with reboxetine. See Table 8 below for summary of dropouts due to selected antidepressants compared with reboxetine.

Table 8: Dropouts due to adverse events for selected antidepressants with reboxetine Bolded ORs are statistically significant. ORs < 1 favor the antidepressant besides reboxetine.

Antidepressant Dropouts due to adverse GRADE confidence in events compared to estimate reboxetine OR (95% CI)

SSRIs Citalopram 0.41 (0.20 to 0.88) LOW Escitalopram 0.37 (0.19 to 0.77) MODERATE Fluoxetine 0.46 (0.25 to 0.85) LOW Fluvoxamine 0.58 (0.28 to 1.20) LOW Paroxetine 0.54 (0.30 to 1.02) LOW Sertraline 0.38 (0.20 to 0.76) LOW SNRIs Duloxetine 0.94 (0.45 to 1.99) LOW Venlafaxine 0.76 (0.41 to 1.44) LOW

For more information, see APPENDIX 3 for GRADE Table 3 on Dropouts due to adverse events. Studies involved in these analyses have been graded for certainty of evidence (details of which are discussed in the preceding section).

Consideration of SNRIs versus SSRIs:

In consideration of the data analyzed above, while duloxetine and venlafaxine have the highest efficacy compared to placebo of the drugs we considered, overall as a class the SNRIs appear to have lower acceptability than the SSRIs. There were no statistically significant differences on acceptability found between the two SNRIs considered and placebo, nor were there differences on acceptability with reboxetine. However, all of the SSRIs considered except for fluvoxamine were found to be more acceptable than reboxetine. Additionally, there were no statistically significant differences between the two SNRIs considered and reboxetine in terms of dropouts due to adverse events, whereas all of the SSRIs considered except fluvoxamine and paroxetine had fewer dropouts due to adverse events when compared with reboxetine. In terms of head to head comparisons, there were no differences between duloxetine and the SSRIs in efficacy, but it was found to be less acceptable than all of the SSRIs except for fluvoxamine. Venlafaxine was found to be more effective than fluoxetine and less acceptable than escitalopram, all other comparisons were statistically insignificant. Given the overall trend of lower acceptability of the SNRIs considered, we have chosen to focus our recommendations (and the rest of the application) on the SSRIs.

Additional Considerations: Safety/Tolerability Issues

Additionally, we would like to highlight three other outcomes of interest that were not necessarily covered in efficacy and acceptability meta-analyses: suicidality risk, QT- prolongation, and sexual side effects. The FDA issued a black-box warning on all SSRIs in 2004 due to increased suicidality risk in children and adolescents34. This warning was expanded to include young adults up until the age of 25 in 2006. Additionally, the FDA has issued black-box warnings related to QT-prolongation risk for citalopram35. The European Medicines Agency has also issued strong warnings related to QT-prolongation for both citalopram and escitalopram. Considering these warnings, we felt it necessary to explore differential risks posed by SSRIs with respect to suicidality and QT-prolongation. We will also examine differential risks for sexual side effects. Afterwards, we will discuss use in special populations and drug-drug interactions.

(a) Risk of suicidality

The US FDA undertook a large meta-analysis in 2006 using patient level data (from nearly 100,000 patients) from published and unpublished clinical trials based on mandatory reporting by pharmaceutical companies in order to assess the risk of suicidality (ideation or worse) amongst antidepressants36,37. Exactly half of the treatment indications were related to depression (45.6% for major depression and 4.6% for other depression), with the remaining 50% for other psychiatric or non-psychiatric indications. When analyzing data for adults with psychiatric diagnoses only, suicidality risk was found to be lowest for sertraline and fluoxetine (amongst the SSRIs). See GRADE Table 4 in Appendix 3 for more information.

(b) Risk of QT-prolongation

Many psychiatric medicines can cause delayed repolarization of cardiac myocytes, as reflected by a prolonged QT interval on electrocardiogram, which is worrisome as it can lead to life- threatening arrhythmias such as torsades de pointes. This is especially relevant for persons with a history of prolonged QT, other underlying cardiac disease, who have electrolyte abnormalities, or are on other commonly prescribed QT-prolonging medications (such as omeprazole, odansetron, or fluoroquinolone antibiotics).

A 2014 meta-analysis by Beach and colleagues examined the association between SSRI antidepressants and QTc (corrected QT)38. Results for fluoxetine and paroxetine were not statistically significant. Fluvoxamine was actually associated with shortened QTc, while sertraline was associated with the least amount of QTc prolongation. Citalopram and escitalopram were associated with the greatest amount of QTc prolongation. See Table 9 below for more information. Due to the heterogeneity of the study populations involved (healthy controls, persons with depression, persons with heart disease and depression), we were unable to GRADE the certainty of estimates in these studies.

Table 9: Differential effect of SSRIs on QTc compared to placebo (Bolded values are statistically significant)

Medication Number of studies Mean difference in p value included QTc (ms); 95% CI Citalopram 5 10.58 0.0018 (3.93 to 17.23) Escitalopram 3 7.27 <0.0001 (3.78 to 10.83) Fluoxetine 2 4.50 0.3176 (-4.32 to 13.32) Fluvoxamine 1 -5.00 <0.0001 (-6.05 to -3.95) Paroxetine 2 -1.04 0.6654 (-5.76 to 3.68) Sertraline 1 3.00 <0.0001 (2.95 to 3.05)

(c) Risk of sexual side effects

A known side effect of many antidepressants, especially the SSRIs, is sexual dysfunction. A network meta-analysis by Reichenpfader and colleagues in 2014 compared the risk of sexual side effects amongst 13 so-called second generation antidepressants including the six SSRIs we have examined in this application39. Sexual side effects can include difficulties with libido, arousal, ejaculation, and orgasm. Many comparisons did not demonstrate statistically significant differences. Bupropion (a norepinephrine-dopamine reuptake inhibitor) appeared to have lower risk of sexual dysfunction overall. Heterogeneity was noted in the studies analyzed, so strong conclusions comparing the SSRIs could not be made. Amongst the SSRIs, most comparisons did not demonstrate statistically significant results, with just two exceptions. Both escitalopram and paroxetine had statistically significantly higher risk of sexual dysfunction compared to fluoxetine. All other comparisons between SSRIs were not statistically significant.

Table 10: Pairwise Comparisons between selected SSRIs with respect to Sexual Dysfunction7 OR <1 favor the drug on the right-hand side; OR >1 favor the drug on the left-hand side. (Bolded ORs are statistically significant.)

SSRI comparison Odds ratio of Sexual Dysfunction (95% Confidence Interval) Citalopram vs escitalopram 1.31 (0.41 to 3.15) Citalopram vs fluoxetine 0.46 (0.11 to 1.30) Citalopram vs fluvoxamine 0.59 (0.08 to 2.16) Citalopram vs paroxetine 1.57 (0.41 to 4.13) Citalopram vs sertraline 0.96 (0.30 to 2.32) Escitalopram vs fluoxetine 0.37 (0.13 to 0.85) à favors fluoxetine Escitalopram vs fluvoxamine 0.48 (0.08 to 1.58) Escitalopram vs paroxetine 1.26 (0.50 to 2.58)

7 Adapted from Table 1 in Reichenpfader, et al (2014). Escitalopram vs sertraline 0.79 (0.39 to 1.54) Fluoxetine vs fluvoxamine 1.49 (0.24 to 5.07) Fluoxetine vs paroxetine 3.86 (1.44 to 8.40) à favors fluoxetine Fluoxetine vs sertraline 2.44 (0.94 to 5.26) Fluvoxamine vs paroxetine 4.08 (0.81 to 12.73) Fluvoxamine vs sertraline 2.59 (0.53 to 7.98) Paroxetine vs sertraline 0.68 (0.30 to 1.35)

(d) Use in special populations: ischemic heart disease

We considered persons with ischemic heart disease and depression as a special population of interest, considering the high co-morbidity of these illnesses. A forthcoming meta-analysis by Ostuzzi et al on antidepressant use in depression and ischemic heart disease gives us insight into efficacy and acceptability of SSRIs in this population40. Sertraline had greater efficacy (impact) in this population as assessed by SMD (mean change scores for depression scales) than other antidepressants, though SMDs for only sertraline and citalopram were statistically significant. GRADE confidence in these estimates ranged from very low to moderate. With regards to acceptability (as assessed by dropouts), only the relative risk of dropouts with citalopram was statistically significant, and it was found to have greater acceptability than placebo. GRADE confidence in these estimates ranged from low to moderate. See GRADE Tables 5 and 6 in Appendix 3 for more information. As for association with cardiovascular events, the subgroup analyses for single drugs did not find significant differences between any antidepressants and placebo. The overall risk difference was 0 (95% CI from -0.1 to 0.1).

Figure 5: CVD events associated with SSRIs40,8

(e) Use in special populations: elderly

SSRIs carry risks when used in the elderly owing to increased risk of hyponatremia, risk of QT- prolongation, risk of bleeding due to antiplatelet effects, and drug-drug interactions; the safety profiles of the various SSRIs differ across these parameters. Accordingly, the risk that SSRIs pose for elderly persons depends on the person’s specific medical history and current condition. The

8 Figure 5 above was created by Giovanni Ostuzzi, using data from a forthcoming paper on antidepressant use in depression and ischemic heart disease. US FDA recommends a reduction in the maximum dose of Celexa from 40 mg per day to 20 mg per day for persons over the age of 60 due to the risk of QT-prolongation. All SSRIs carry a risk of hyponatremia, and caution is advised for patients who have metabolic disarray at baseline and/or may be on diuretic medication. Additionally, all SSRIs also carry a risk of serotonin syndrome (a life-threatening condition characterized by confusion, neuromuscular excitability, and dysautonomia) when used with other serotonergic agents. See below for more information regarding drug-drug interactions.

A systematic review and meta-analysis by Tham and colleagues in 2016 compared the efficacy and tolerability of antidepressants for people over the age of 65 with major depression41. Citalopram, escitalopram, and fluoxetine were SSRIs included in these studies. Interestingly, SSRIs were not found to be more effective than placebo in causing remission of major depression; however, SSRIs were more effective than placebo in preventing relapse of major depression after remission. In terms of adverse events, escitalopram and fluoxetine were found to have higher rates of nausea, weight loss, and decreased libido than placebo during treatment of an acute episode of MDD, while there were no differences between citalopram and placebo. However, the authors used the GRADE approach and noted the certainty of evidence regarding adverse events was very low. Duloxetine was also studied and found to be more effective than placebo in causing remission. However, duloxetine was associated with more adverse events (including dizziness, dry mouth, diarrhea, and constipation), and the quality of this evidence was rated from low to moderate.

(f) Use in special populations: pregnancy

We have not exhaustively reviewed the literature for the use of SSRIs during pregnancy and breastfeeding in this application. All SSRIs carry some risk during the perinatal and post-partum period. The US FDA has labeled all of the SSRIs we discuss in this application as pregnancy risk category C, except for paroxetine, which is labeled category D42. According to the US FDA, pregnancy risk category C means the following: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Pregnancy risk category D means the following: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. All SSRIs carry the risk of complications after birth potentially including persistent pulmonary hypertension of the newborn (PPHN). Paroxetine additionally carries an extra risk of congenital malformations and fluoxetine carries an extra risk of cardiovascular malformations. Fluvoxamine also carries the risk of fetal eye abnormalities, decreased fetal weight, and increased embryofetal death42.

According to Stahl’s Prescriber’s Guide, 6th edition, and as above, all SSRIs carry risk during pregnancy43. Risks to the mother include the risk of gestational hypertension and preeclampsia, as well as increased risk of bleeding after birth. Risks to the fetus/baby include septal heart defects (when exposed in beginning of pregnancy), pulmonary hypertension (when exposed after 20 weeks of pregnancy), as well as other complications at birth (if exposed late in pregnancy, specifically late in the third trimester) necessitating respiratory support, tube feeding, and prolonged hospitalization. Symptoms reported in FDA-approved labeling of SSRIs include the following symptoms, “respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying44.” These symptoms may be attributable to either SSRI toxicity, withdrawal, or serotonin syndrome. Paroxetine additionally carries the risk of cardiovascular malformations43. See Summary section below for FDA-approved labeling on paroxetine and risk in pregnancy.

The risks of using SSRIs need to be weighed against the risks of untreated depression in pregnancy.

(g) Drug-drug interactions

In order to assess drug-drug interactions associated with the SSRIs and SNRIs of interest, we ran drug interaction searches using the Lexicomp Drug Interaction database (accessed via UptoDate.com)45. Fluoxetine was found to have the most drug-drug interactions (164), followed by fluvoxamine (157). Of note, many drug-drug interactions that have been identified are theoretical and not necessarily clinically relevant. For reference, see Table 11 below with numbers of drug-drug interactions per medication.

Table 11: Number of Drug-drug Interactions for selected antidepressants

Medication Number of Drug-Drug interactions SSRIs Citalopram 121 Escitalopram 118 Fluoxetine 164 Fluvoxamine 157 Paroxetine 144 Sertraline 93 SNRIs Duloxetine 97 Venlafaxine 121

For detailed discussion, we will focus on SSRIs alone. Here, we are citing information from UptoDate.com, Lexi-Interact, and Stahl’s Prescriber’s Guide. SSRIs have numerous effects on and are affected by cytochrome p450 enzymes. According to UptoDate, amongst the SSRIs, citalopram, escitalopram, and sertraline are considered to be less problematic than fluoxetine, fluvoxamine, and paroxetine in terms of drug-drug interactions46. Fluoxetine, fluvoxamine, and paroxetine inhibit cytochrome p450 enzymes, which can affect the metabolism of other medications in the body. Fluoxetine and paroxetine are potent CYP2D6 inhibitors. Fluvoxamine is a potent CYP1A2 inhibitor. Fluoxetine and fluvoxamine are also moderate 2C19 inhibitors. One example of a CYP2D6 metabolite is tamoxifen, a breast cancer medication. Tamoxifen is a breast cancer medication and requires CYP2D6 to be converted to its active form. While in theory fluoxetine and paroxetine can affect this process, the clinical significance of this interaction is debated46.

Most of the SSRIs confer some risk for QT-prolongation, and it is well known that combining medications with QT-prolonging effects can potentiate each other. According to Lexi-interact, fluoxetine and sertraline carry indeterminate risk of QT-prolongation. Citalopram and escitalopram confer moderate risk. Fluvoxamine or paroxetine are not listed as conferring any risk, specifically in the context of drug-drug interactions.

Half-lives of the SSRIs vary, which can affect their interactions with other medications as well as risk for withdrawal symptoms on discontinuation43. SSRI discontinuation symptoms can include a constellation of neurological, cognitive, emotional, sexual, and gastrointestinal symptoms, and can be very distressing for people47. Fluoxetine has the longest half-life, with the half-life of its active metabolite being two weeks. Fluoxetine’s long half-life translates into a longer washout period, which confers higher risk for serotonin syndrome if used too close temporally to other serotonergic medications. Paroxetine has the shortest half-life (one day), which is thought to cause higher risk of a withdrawal syndrome upon discontinuation. SSRI withdrawal symptoms can be very distressing for people. Half-lives of the citalopram, escitalopram, fluvoxamine, and sertraline are 23-45 hours, 27-32 hours, 9-28 hours, and 22-36 hours (with 62- 104 hours for sertraline’s metabolite), respectively. A systematic review by Fava et al in 2015 found that all SSRIs have been associated with withdrawal symptoms upon discontinuation, however these phenomena have been most often reported with paroxetine47. Per UptoDate, paroxetine confers the greatest risk of discontinuation symptoms, fluoxetine confers the least risk, while citalopram, escitalopram, and sertraline confer intermediate risk48.

Significant drug-drug interactions reported in Stahl’s for the SSRIs are summarized as follows:

Summary of significant drug-drug interactions for SSRIs

Adapted from Stahl’s Prescriber’s Guide, 6th Edition43

For all SSRIs, there is a risk of serotonin syndrome if combined with serotonergic agents, including MAOIs. SSRIs are associated with an increased risk of bleeding and this may be worsened by blood thinning medication. Non-steroidal anti-inflammatory medications may make SSRIs less efficacious. There is an increased risk of seizures if combined with tramadol. Additionally, SSRIs may cause problems when combined with triptans including weakness, lack of coordination, and hyper-reflexia.

Citalopram may increase levels of TCAs and may displace warfarin (or other highly protein- bound medications). Cimetidine inhibits CYP2C19 and this may increase citalopram levels as the latter is a CYP2C19 substrate; this may increase the risk of QT-prolongation. Additionally, citalopram is a weak CYP2D6 inhibitor and as such may increase levels of thioridazine and some beta-blockers.

Escitalopram: No additional interactions other than those listed above for all SSRIs.

Fluoxetine may increase levels of TCAs and may displace warfarin (or other highly protein- bound medications). There are numerous theoretical risks owing to fluoxetine’s CYP3A4 and CYP2D6 inhibition. As a CYP3A4 inhibitor, fluoxetine may increase levels of some statins, some benzodiazepines, buspirone, and pimozide. As a CYP2D6 inhibitor, fluoxetine may increase levels of trazodone, thioridazine, and some beta-blockers.

Fluvoxamine may increase levels of TCAs and may displace warfarin (or other highly protein- bound medications). There are numerous theoretical risks owing to fluvoxamine’s CYP 3A4, 2C9/2C19, and 1A2 inhibition. As a CYP3A4 inhibitor, fluvoxamine may increase levels of some statins, some benzodiazepines, carbamazepine, and pimozide. As a CYP1A2 inhibitor, fluvoxamine may increase levels of clozapine and theophylline. Fluvoxamine used in combination with theophylline or caffeine may cause seizures. Smoking may reduce levels of fluvoxamine.

Paroxetine may increase levels of TCAs and may displace warfarin (or other highly protein- bound medications). There are some theoretical risks owing to paroxetine’s CYP2D6 inhibitor, including that paroxetine may increase levels of thioridazine and some beta-blockers. Elevates levels of pimozide. Paroxetine may also increase levels of theophylline. Paroxetine has anticholinergic effects and may enhance this effect of other medications.

Sertraline may increase levels of TCAs and may displace warfarin (or other highly protein-bound medications). There are numerous theoretical risks owing to sertraline’s CYP3A4 and CYP2D6 inhibition. As a CYP3A4 inhibitor, sertraline may increase levels of some statins, some benzodizapines, buspirone, and pimozide. As a CYP2D6 inhibitor, sertraline may increase the levels of thioridazine and some beta blockers.

11. Summary of available data on comparative cost and cost-effectiveness of the medicine

(a) Comparative cost data amongst SSRIs

The availability and affordability of SSRIs varies widely across countries and according to sector (public versus private), as well as supplier (originator versus generic) prices. Fluoxetine remains the most widely available and cheapest SSRI.

SSRIs are routinely available in different countries at a range of prices, depending on the sector (public versus private). The International Medical Products Price Guide has published buyer prices for the following antidepressants in 2015: amitriptyline, fluoxetine, sertraline, and venlafaxine49. We have compiled supplier and buyer prices for each SSRI for the latest year available. The MSH Pricing Guide did not contain data for citalopram, escitalopram, or fluvoxamine (years searched 2000-2015). See below table for most recently available lowest, median, and highest supplier and buyer prices in USD.

Table 12: Supplier and buyer prices for SSRIs (most recent year available) Source: MSH International Medical Products Price Guide

Medication Year Lowest Price (USD) Highest Price (USD) Median Price (USD) Fluoxetine 2015 N/A N/A Only price 20 mg tab/cap available: 0.0431 (supplier) per tab/cap Fluoxetine 2015 0.0083 per tab/cap 0.0309 per tab/cap 0.0103 per tab/cap 20 mg tab/cap (buyer) Paroxetine 2013 N/A N/A N/A 20 mg tab/cap (supplier) Paroxetine 2013 0.0750 per tab/cap 0.1386 per tab/cap 0.1068 per tab/cab 20 mg tab/cap (buyer) Sertraline 2015 N/A N/A N/A 50 mg tab/cap (supplier) Sertraline 2015 0.0185 per tab/cap 0.0377 per tab/cap 0.0234 per tab/cap 50 mg tab/cap (buyer)

For trends in supplier and buyer median prices for fluoxetine, sertraline, and paroxetine over the years, see below graphs, generated by MSH.

Figure 6: Trends in Supplier and Buyer Prices for Fluoxetine (2000 – 2015) Source: MSH International Medical Products Price Guide

Figure 7: Trends in Buyer Prices for Paroxetine (2003-2013) Source: MSH International Medical Products Price Guide

Figure 8: Trends in Buyer Prices for Sertraline (2011 – 2015) Source: MSH International Medical Products Price Guide

Health Action International has also compiled global pricing information for medicines according to WHO/HAI survey methodology50. Currently, pricing information for six antidepressants is available through the HAI data set (amitriptyline, citalopram, fluoxetine, mirtazapine, paroxetine, and sertraline). There is no data available for escitalopram or fluvoxamine. We have compiled global pricing information using HAI survey data for citalopram below. We have not covered fluoxetine, paroxetine, or sertraline here, as we have utilized MSH data for these medications above, however numerous country surveys are available through the HAI database for each of these medicines.

Table 13: Pricing and Availability of Citalopram in the Public and Private Sector Source: HAI Price and Availability Database (Prices are listed in USD per unit/tablet)

Country Public Sector Public Sector Private Sector Procurement Price Patient Price, Patient Price, Mean Availability Mean Availability Saudi Arabia Originator brand: Free Lowest price generic: (May 2015) 0.66 USD 0.805 USD

Lowest price generic: Availability: 25.7% Availability: 53.3% 0.029 USD Ukraine Price N/A Price N/A Price N/A (2007) Availability: 16.7% Availability: 22.2-33.3%

(b) Comparative cost-effectiveness data

In 2015 Khoo and colleagues conducted a network meta-analysis of randomised controlled trials involving ten antidepressant medications and estimated cost-effectiveness using simulated cost, incremental cost, and effectiveness for quality-adjusted life years (QALYs) gained51. Treatment effects were estimated using pairwise and network meta-analyses, and cost-effectiveness was then estimated using a decision-tree of simulated costs for depression treatment over 6 months. Treatment in Singapore was used as a model. Costs in Singapore dollars were compared with incremental costs and effectiveness per QALY gained. In this study, agomelatine was estimated to be most cost-effective, followed by venlafaxine and mirtazapine. Estimated costs for 6 months, incremental costs, and effectiveness per QALY gained for SSRIs only is included in Table 14 below. Citalopram was not included in this analysis. According to this analysis, escitalopram is most cost-effective amongst the SSRIs, with fluvoxamine following. Of note, there are multiple limitations to this study’s model including the fact that the effectiveness is based on efficacy (rather than recorded costs); further the projected/estimated costs of each drug over 6 months of treatment are specific to Singapore’s health system, which may not be generalizable.

Table 14: Estimated costs, incremental costs, and effectiveness per QALY gained for SSRIs Costs are included in SGD (Singapore dollars). Incremental costs are costs compared to mirtazapine (6542 SGD) as a reference point.

SSRI medication Cost Incremental cost Effectiveness per QALY gained Escitalopram 7054 512 0.2641 Fluoxetine 6669 127 0.2601 Fluvoxamine 6682 140 0.2629 Paroxetine 6699 157 0.2608 Sertraline 6769 227 0.2602

A 2012 study of cost-effectiveness of SSRIs in the United States used pharmacy and medical claims data for a random sample of people with depression who were also Medicare recipients52. SSRIs compared included escitalopram, citalopram, and sertraline, with the percentages of usage being 34%, 35%, and 31%, respectively. Study authors found that escitalopram usage was associated with higher drug costs than citalopram or sertraline. After instrumental variable adjustment, both escitalopram and sertraline were found to have decreased non-drug costs compared with citalopram usage. Ultimately, there was no statistically significant difference in costs between escitalopram and sertraline.

REGULATORY INFORMATION

12. Summary of regulatory status and market availability of the medicine

As described in section 5, fluoxetine gained US FDA-approval as a “new molecular entity” under the trade name Prozac produced by Eli Lilly on December 29, 1987 (NDA #018936)1. Fluoxetine went off-patent in on August 3rd, 2001. Just prior to this, five companies had already gained FDA approval to produce generic fluoxetine (Barr Laboratories, Teva Pharmaceuticals, Geneva Pharmaceuticals, Pharmaceutical Resources, and Dr. Reddy’s Laboratories)2.

Thirty-one companies have obtained fifty-two separate FDA approvals for generic formulations of fluoxetine, thirty-three of which are still active3. In India alone, there are 102 “branded” generic versions of fluoxetine4. There are fifteen generic formulations by nine companies approved by the Medicines Control Council in South Africa. In addition, according to drugs.com, well over one hundred companies globally produce branded or unbranded generic versions of fluoxetine5.

All other SSRIs we have considered in this application (citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline) are also off-patent and generic formulations are available globally.

13. Availability of pharmacopoeial standards

Results for fluoxetine (a) United States Pharmacopoeia: (Yes. Source: United States Pharmacopoeia9) (b) British Pharmacopoeia: (Yes. Source: British Pharmacopeia10) (c) European Pharmacopoeia: (Yes. Source: European Pharmacopeia Online 9.711) (d) Japanese Pharmacopoeia: (Unavailable. Source: Japanese Pharmacopeia 17th Edition12)

9 United States Pharmacopoeia http://www.usp.org/ 10 British Pharmacopoeia https://www.pharmacopoeia.com/ 11 European Pharmacopoeia Online 9.7. http://online6.edqm.eu/ep907/ 12 Japanese Pharmacopoeia, 17th Edition https://www.pmda.go.jp/english/rs-sb-std/standards- development/jp/0020.html (e) International Pharmacopoeia: (Unavailable. Source: WHO Pharmacopeia Library13)

For reference, results for other SSRIs:

Table 15: Availability of reference standards per commonly used pharmacopoeias

Availability in commonly used pharmacopoeias Medication United British European Japan International States Citalopram Yes Yes Yes No No Escitalopram Yes No Yes No No Fluvoxamine Yes Yes Yes No No Paroxetine Yes Yes Yes No No Sertraline Yes Yes Yes No No

SUMMARY OF SSRIs CONSIDERED IN THIS APPLICATION

See Table 16 for a summary and comparison of the SSRIs considered in this application. We have considered all SSRIs that are listed in both the WHO Collaborating Centre for Drug Statistics Methodology53 and are also FDA-approved54. Medications that were not part of both lists have been excluded, as we do not have adequate data at this time and we imagine patient exposure to date to be insufficient. Alaproclate, etoperidone, zimeldine, and vilazodone were excluded on this basis. Alaproclate, Etoperidone, and Zimeldine have not been FDA-approved, and these medicines were not covered in the Cipriani et al (2018) review. Vilazodone has been FDA-approved, but is not on the WHO listing. Further, although vilazodone is covered in the Cipriani et al (2018) review, we do not have sufficient head to head comparison information.

Of the remaining SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, and paroxetine), summaries are provided below on efficacy, acceptability, safety profiles, drug interactions, special populations, and FDA-indications. FDA-indications should be up-to-date as of 201743. Of note, fluvoxamine is FDA-approved for anxiety disorders, but not depression.

With regards to efficacy, all six of the SSRIs considered below are more effective than placebo. Only escitalopram and paroxetine are more effective than reboxetine. Most head to head comparisons on efficacy amongst the SSRIs considered were not statistically significant, with a few exceptions: escitalopram is more effective than citalopram, fluoxetine, and fluvoxamine; and paroxetine is more effective than fluoxetine. With regards to acceptability, only fluoxetine is more acceptable than placebo. All SSRIs considered below are more acceptable than reboxetine EXCEPT fluvoxamine. Most head to head comparisons on acceptability amongst the SSRIs considered were not statistically significant, with one

13 WHO Pharmacopoeia Library http://apps.who.int/phint/en/p/docf/ exception: escitalopram is more acceptable than fluvoxamine. When considering dropouts due to adverse events only (i.e. not all-cause dropouts), all of the SSRIs considered are better than reboxetine EXCEPT fluvoxamine and paroxetine. Overall, there seems to be lower acceptability of fluvoxamine, though we recognize the limitations of the data available and lack of statistical significance of many comparisons involved.

Additionally, we have summarized safety profiles, drug interactions, special populations, and FDA indications. Citalopram and escitalopram have the highest risk of QT-prolongation amongst the SSRIs, while it appears sertraline and fluvoxamine carry the lowest risk. Fluoxetine and sertraline appear to carry the lowest risk of suicide amongst the SSRIs. Fluoxetine also appears to have a lower risk of sexual side effects in head to head comparisons, whereas escitalopram and paroxetine have higher risk of this (specifically when compared with fluoxetine).

As for drug-drug interactions and pharmacokinetics, citalopram, escitalopram, and sertraline are thought to have fewer drug-drug interactions, while fluoxetine, fluvoxamine, and paroxetine are thought to have more. Fluoxetine’s active metabolite has the longest half-life, which confers elevated risk of serotonin syndrome when used in close temporality with other serotonergic medications. Paroxetine has a very short half-life, which confers elevated risk of withdrawal symptoms upon discontinuation.

With regards to special populations, the FDA recommends lower maximum dosing for citalopram in the elderly, owing to risk of QT-prolongation. Lastly, all of the SSRIs carry risk with pregnancy and in the perinatal period, with paroxetine known to confer additional risks. Special caution should be advised when SSRIs are used in women of child-bearing age and who may become pregnant, especially paroxetine. FDA-approved labeling of paroxetine (trade name: Paxil) states the following, “If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harms to the fetus. Unless the benefits of paroxetine to the mother justify continued treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant. For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options”55.

Considering all of the above information, we would recommend that the following SSRIs be added to the WHO Model List: citalopram, escitalopram, fluoxetine, and sertraline. While we have concerns about the acceptability of paroxetine and the additional risk it confers in pregnancy and withdrawal symptoms upon discontinuation, we also recognize that its efficacy profile may make it an appropriate choice for certain patients.

Table 16: SUMMARY OF SSRIs CONSIDERED IN THIS APPLICATION

Abbreviations: +SS = statistically significant; No SS = No statistically significant (difference); wcw = when compared with; rebox = reboxetine; AE = adverse events NB: Reboxetine below is used as a standard reference point by Cipriani et al (2018)’s meta-analysis30.

SSRI Efficacy Acceptability Safety Profile Drug interactions/ Special FDA-approved Recommend Pharmacokinetics Populations psychiatric for Model indications List? Alaproclate N/A N/A N/A N/A N/A Not FDA-approved

Citalopram PLACEBO: PLACEBO: US FDA black-box Half-life: 23-45 FDA Depression YES More effective than No SS difference wcw warning and EMA hours recommends placebo (+SS). placebo. warning re: risk of lower maximum QT-prolongation. Fewer drug-drug dosing for REBOXETINE: REBOXETINE: interactions. elderly due to No SS difference wcw More acceptable than Highest risk of QT QT-prolongation rebox. rebox (+SS). Lower prolongation risk. dropouts due to AE amongst SSRIs HEAD TO HEAD: wcw rebox (+SS). (+SS). Pregnancy Less effective than category C* escitalopram (+SS). HEAD TO HEAD: No SS difference wcw other SSRIs.

Escitalopram PLACEBO: PLACEBO: EMA warning re: Half-life: 27-32 Pregnancy Major depressive YES More effective than No SS difference wcw risk of QT- hours category C* disorder, placebo (+SS). placebo. prolongation. generalized anxiety Fewer drug-drug disorder REBOXETINE: REBOXETINE: Second highest interactions More effective than More acceptable than risk of QT- rebox (+SS). rebox (+SS). Lower prolongation

HEAD TO HEAD: dropouts due to AE amongst SSRIs More effective than wcw rebox (+SS). (+SS). citalopram, fluoxetine, and HEAD TO HEAD: Higher risk of fluvoxamine (+SS). More acceptable than sexual side No SS difference wcw fluvoxamine (+SS). No effects than sertraline or SS difference wcw fluoxetine (+SS). paroxetine. other SSRIs.

Etoperidone N/A N/A N/A N/A N/A Not FDA-approved

Fluoxetine PLACEBO: PLACEBO: Per FDA review, More drug-drug Pregnancy Major depressive YES More effective than More acceptable than lower risk of interactions category C* disorder, panic placebo (+SS). placebo (+SS). suicide amongst disorder, SSRIs (+SS). Longest half-life, obsessive- REBOXETINE: REBOXETINE: lower risk of compulsive No SS difference wcw More acceptable than Indeterminate withdrawal disorder, bulimia rebox. rebox (+SS). Lower risk of QT symptoms nervosa, dropouts due to AE prolongation per premenstrual HEAD TO HEAD: Less wcw rebox (+SS). Lexi-interact. dysphoric disorder effective than Insignificant escitalopram and HEAD TO HEAD: results per Beach paroxetine (+SS). No SS difference wcw et al review. other SSRIs. Lower risk of sexual side effects than escitalopram or paroxetine (+SS). Fluvoxamine PLACEBO: PLACEBO: Associated with Half-life: 9-28 Pregnancy Not FDA-approved NO More effective than No SS difference wcw QT decrease hours category C* for depression. placebo (+SS). placebo. (+SS). More drug-drug FDA-approved for REBOXETINE: REBOXETINE: interactions obsessive- No SS difference wcw No SS difference wcw compulsive rebox. rebox in acceptability disorder, social or dropouts due to AE. anxiety disorder.

HEAD TO HEAD: Less HEAD TO HEAD: Less effective than acceptable than escitalopram (+SS). escitalopram (+SS). No No SS difference wcw SS difference wcw other SSRIs. other SSRIs. Sertraline PLACEBO: PLACEBO: Per FDA review, Half-life: 22-36 Greater efficacy Major depressive YES More effective than No SS difference wcw lower risk of hours in patients with disorder, panic placebo (+SS). placebo. suicide amongst ischemic heart disorder, obsessive SSRIs (+SS). Fewer drug-drug disease. compulsive REBOXETINE: REBOXETINE: interactions disorder, social No SS difference wcw More acceptable than Indeterminate Pregnancy anxiety disorder, rebox. rebox (+SS). Lower risk of QT category C* post-traumatic dropouts due to AE prolongation per stress disorder, HEAD TO HEAD: wcw rebox (+SS). Lexi-interact. and premenstrual No SS difference wcw Lowest risk of QT- dysphoric disorder. other SSRIs. HEAD TO HEAD: No SS prolongation difference wcw other amongst SSRIs SSRIs. besides fluvoxamine per Beach et al review (+SS). Paroxetine PLACEBO: PLACEBO: Insignificant More drug-drug Pregnancy FDA-approved for NO More effective than No SS difference wcw results re: QT interactions category D**; major depressive placebo (+SS), placebo. prolongation per carries extra risk disorder, highest efficacy Beach et al Shortest half-life of congenital generalized anxiety when compared to REBOXETINE: review. (one day), higher malformations disorder, panic placebo of the SSRIs. More acceptable than risk of withdrawal disorder, obsessive rebox (+SS). No SS Higher risk of symptoms compulsive REBOXETINE: difference in dropouts sexual side disorder, social More effective than due to AE wcw rebox. effects than anxiety disorder, rebox (+SS). fluoxetine (+SS) post-traumatic HEAD TO HEAD: No SS stress disorder, HEAD TO HEAD: difference wcw other and premenstrual More effective than SSRIs. dysphoric disorder. fluoxetine (+SS). No SS difference wcw other SSRIs.

Vilazodone N/A N/A N/A N/A N/A FDA-approved, not part of WHO listing Zimeldine N/A N/A N/A N/A N/A Not FDA-approved

*US FDA Pregnancy risk category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

**US FDA Pregnancy risk category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. IMPLICATIONS FOR FUTURE WORK:

In this application, we have considered best available evidence to date on efficacy and acceptability of SSRIs and commonly used SNRIs for moderate to severe depression. While SNRIs (duloxetine and venlafaxine) were considered in this application, we have focused our recommendations on SSRIs given overall trends of better acceptability with the latter group. Amongst the SSRIs, we have considered differential acceptability, safety profiles, and use in special populations. Additionally, we have discussed availability, cost, and cost-effectiveness.

Considering the comparable clinical efficacy and the growing availability of a number of generic formulations of SSRIs, we propose the addition of a square box symbol (□) to fluoxetine to the 21st WHO Model List of Essential Medicines. We recommend that the square box symbol (□) be restricted to the following SSRIs for which there is the strongest evidence as to efficacy and safety: citalopram, escitalopram, fluoxetine, and sertraline. Fluvoxamine and paroxetine were excluded due to concerns for acceptability. See Table 16 on the preceding pages for a summary comparison of the SSRIs considered in this application.

To date, there is not compelling, clinically significant data to choose another SSRI, SNRI, or atypical antidepressant over fluoxetine on the basis of efficacy and acceptability combined; however, this may change as newer medicines continue to be studied and with larger trials. Vortioxetine for example is a promising atypical antidepressant that may prove to be more effective in the coming years. As of now, there are few head to head comparisons and the available data is not robust.

Future work on the mental & behavioural disorders section of the WHO Model List includes bringing each sub-category in line with ICD-11 diagnostic classifications. For example, the sub- section on medicines for anxiety disorders (24.3) could be expanded. The ICD-11 sub-category of anxiety and fear-related disorders includes 9 sub-categories. It may be useful to separate generalized anxiety disorder and panic disorder within the WHO EML. Currently the subsection on medicines used for anxiety disorders includes diazepam only; SSRIs can also be used for anxiety disorders and may be considered. Lastly, it may be worthwhile to add post-traumatic stress disorder as its own sub-category under a new category of stress-related disorders, as pharmacological recommendations may be sufficiently different than the other disorders covered. Comprehensive and systematic evidence reviews for each of these disease categories would be useful in future application cycles.

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APPENDIX 1: mhGAP-IG, 2.0, Depression Chapter, Pharmacological Interventions

APPENDIX 2: EXCERPTS FROM SELECTED NATIONAL ESSENTIAL MEDICINES LISTS Source: WHO repository of National Medicines Lists13

Excerpt: Indian National List of Essential Medicines (NLEM) 201556

Section 27.2.1 Medicines used in depressive disorders Medicine Level of Healthcare Amitriptyline Primary, secondary, tertiary Escitalopram Secondary, tertiary Fluoxetine Primary, secondary, tertiary

Excerpt: Relação Nacional de Medicamentos Essenciais 2010 (Brazil)57

Excerpt: National Essential Medicine List for Primary Healthcare Facilities 2009 (China)58

Excerpt: National Essential Medicine List 5th edition, Ethiopia (2015)59

Excerpt: Liste Nationale Des Médicaments Essentiels 2012 (Haiti)60

Excerpt: National List of Essential Medicines (Thailand)61

APPENDIX 3: GRADE TABLE 1: IMPACT (EFFICACY) OF SELECTED ANTIDEPRESSANTS

Author(s): KK, CB, GO Date: 11/29/18 Question: Response of selected antidepressants compared to reboxetine for depression Setting: Any Bibliography: Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder : a systematic review and network meta-analysis. Lancet 2018; 391: 1357– 66. Certainty assessment

№ of Study Risk of Other Impact Certainty Importance Inconsistency Indirectness Imprecision studies* design bias considerations

ESCITALOPRAM

42 randomised not not serious not serious not serious publication OR 1.60 (95% CI 1.14 to 2.23) ⨁⨁⨁◯ CRITICAL trials serious bias strongly MODERATE suspected a

PAROXETINE

114 randomised serious not serious not serious not serious publication OR 1.43 (95% CI 1.05 to 1.94) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

VENLAFAXINE

68 randomised serious not serious not serious not serious publication OR 1.42 (95% CI 1.04 to 1.94) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

DULOXETINE

30 randomised serious not serious not serious not serious publication OR 1.36 (95% CI 0.95 to 1.95) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

SERTRALINE Certainty assessment

№ of Study Risk of Other Impact Certainty Importance Inconsistency Indirectness Imprecision studies* design bias considerations

54 randomised serious not serious not serious not serious publication OR 1.34 (95% CI 0.96 to 1.85) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

CITALOPRAM

38 randomised serious not serious not serious not serious publication OR 1.27 (95% CI 0.92 to 1.75) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

FLUOXETINE

117 randomised serious not serious not serious not serious publication OR 1.20 (95% CI 0.88 to 1.62) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

FLUVOXAMINE

32 randomised serious not serious not serious not serious publication OR 1.20 (95% CI 0.83 to 1.71) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

CI: Confidence interval

Explanations *Number of studies included in the network meta-analysis. a. Per Cipriani et al 2018: "Considering that the field of antidepressant trials in the past has been prone to publication bias, the review team decided by default to downgrade all the included studies for potential publication bias by one level." b. Per Cipriani et al 2018, more than 70% contribution came from moderate risk of bias comparisons.

APPENDIX 3: GRADE TABLE 2: ACCEPTABILITY (DROP-OUTS DUE TO ANY REASON) OF SELECTED ANTIDEPRESSANTS

Author(s): KK, CB, GO Date: 11/30/18 Question: Acceptability (drop-outs due to any reason) of selected antidepressants compared to reboxetine for depression Setting: Any Bibliography: Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder : a systematic review and network meta-analysis. Lancet 2018; 391: 1357– 66. Certainty assessment

№ of Study Risk of Other Impact Certainty Importance Inconsistency Indirectness Imprecision studies* design bias considerations

ESCITALOPRAM

42 randomised not not serious not serious not serious publication OR 0.55 (95% CI 0.37 to 0.81) ⨁⨁⨁◯ CRITICAL trials serious bias strongly MODERATE suspected a

CITALOPRAM

38 randomised serious not serious not serious not serious publication OR 0.60 (95% CI 0.41 to 0.87) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

SERTRALINE

54 randomised serious not serious not serious not serious publication OR 0.62 (95% CI 0.43 to 0.92) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

FLUOXETINE

117 randomised serious not serious not serious not serious publication OR 0.63 (95% CI 0.44 to 0.90) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

PAROXETINE Certainty assessment

№ of Study Risk of Other Impact Certainty Importance Inconsistency Indirectness Imprecision studies* design bias considerations

114 randomised serious not serious not serious not serious publication OR 0.66 (95% CI 0.46 to 0.94) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

VENLAFAXINE

68 randomised serious not serious not serious not serious publication OR 0.73 (95% CI 0.50 to 1.06) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

FLUVOXAMINE

32 randomised serious not serious not serious not serious publication OR 0.77 (95% CI 0.51 to 1.17) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

DULOXETINE

30 randomised serious not serious not serious not serious publication OR 0.86 (95% CI 0.57 to 1.29) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

CI: Confidence interval

Explanations *Number of studies included in the network meta-analysis. a. Per Cipriani et al 2018: "Considering that the field of antidepressant trials in the past has been prone to publication bias, the review team decided by default to downgrade all the included studies for potential publication bias by one level." b. Per Cipriani et al 2018, more than 70% contribution came from moderate risk of bias comparisons.

APPENDIX 3: GRADE TABLE 3: DROP-OUTS DUE TO ADVERSE EVENTS OF SELECTED ANTIDEPRESSANTS

Author(s): KK, CB, GO Date: 12/1/18 Question: Dropouts due to adverse events of selected antidepressants compared to reboxetine for depression Setting: Any Bibliography: Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder : a systematic review and network meta-analysis. Lancet 2018; 391: 1357– 66. Certainty assessment

№ of Study Risk of Other Impact Certainty Importance Inconsistency Indirectness Imprecision studies* design bias considerations

ESCITALOPRAM

42 randomised not not serious not serious not serious publication OR 0.37 (95% CI 0.19 to 0.77) ⨁⨁⨁◯ CRITICAL trials serious bias strongly MODERATE suspected a

SERTRALINE

54 randomised serious not serious not serious not serious publication OR 0.38 (95% CI 0.20 to 0.76) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

CITALOPRAM

38 randomised serious not serious not serious not serious publication OR 0.41 (95% CI 0.20 to 0.88) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

FLUOXETINE

117 randomised serious not serious not serious not serious publication OR 0.46 (95% CI 0.25 to 0.85) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

PAROXETINE Certainty assessment

№ of Study Risk of Other Impact Certainty Importance Inconsistency Indirectness Imprecision studies* design bias considerations

114 randomised serious not serious not serious not serious publication OR 0.54 (95% CI 0.30 to 1.02) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

FLUVOXAMINE

32 randomised serious not serious not serious not serious publication OR 0.58 (95% CI 0.28 to 1.20) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

VENLAFAXINE

68 randomised serious not serious not serious not serious publication OR 0.76 (95% CI 0.41 to 1.44) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

DULOXETINE

30 randomised serious not serious not serious not serious publication OR 0.94 (95% CI 0.45 to 1.99) ⨁⨁◯◯ CRITICAL trials b bias strongly LOW suspected a

CI: Confidence interval

Explanations *Number of studies included in the network meta-analysis. a. Per Cipriani et al 2018: "Considering that the field of antidepressant trials in the past has been prone to publication bias, the review team decided by default to downgrade all the included studies for potential publication bias by one level." b. Per Cipriani et al 2018, more than 70% contribution came from moderate risk of bias comparisons

APPENDIX 3: GRADE TABLE 4: SUIIDALITY RISK ASSOCIATED WITH SELECTED ANTIDEPRESSANTS

Author(s): GO, KK, CB Date: 11/30/18 Question: Suicidality (ideation or worse) associated with selected antidepressants Setting: Any Bibliography: Stone M, Laughren T, Jones LM, et al. Risk of suicidality in clinical trials of antidepressants in adults : analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339. DOI:10.1136/bmj.b2880.

Certainty assessment № of patients Effect

Other Relative Import- № of Study Risk of Im- Anti- Absolute Certainty Inconsistency Indirectness consider- placebo (95% ance studies design bias precision depress. (95% CI) ations CI)

SERTRALINE (Stone et al., 2009) (assessed with: number of events - ideation or worse)

60 Random- serious not serious serious b not none 18/6363 28/5081 OR 0.51 3 fewer ⨁⨁◯◯ CRITICAL ised trials a serious (0.3%) (0.6%) (0.29 to per LOW 0.91) 1,000 (from 0 fewer to 4 fewer)

CITALOPRAM (Stone et al., 2009) (assessed with: number of events - ideation or worse)

9 Random- serious not serious serious b serious c none 24/2661 7/1371 OR 2.11 6 more ⨁◯◯ CRITICAL a ised trials (0.9%) (0.5%) (0.90 to per ◯ 4.94) 1,000 VERY (from 1 LOW fewer to 20 more)

ESCITALOPRAM (Stone et al., 2009) (assessed with: number of events - ideation or worse) Certainty assessment № of patients Effect

Other Relative Import- № of Study Risk of Im- Anti- Absolute Certainty Inconsistency Indirectness consider- placebo (95% ance studies design bias precision depress. (95% CI) ations CI)

15 Randomis- serious not serious serious b serious c none 10/3130 5/2604 OR 2.44 3 more ⨁◯◯ CRITICAL ed trials a (0.3%) (0.2%) (0.90 to per ◯ 6.63) 1,000 VERY (from 0 LOW fewer to 11 more)

FLUVOXAMINE (Stone et al., 2009) (assessed with: number of events - ideation or worse)

26 Randomis- serious not serious serious b serious c none 22/2187 13/1828 OR 1.25 2 more ⨁◯◯ CRITICAL a ed trials (1.0%) (0.7%) (0.66 to per ◯ 2.39) 1,000 VERY (from 2 LOW fewer to 10 more)

FLUOXETINE (Stone et al., 2009) (assessed with: number of events - ideation or worse)

62 Randomis- serious not serious serious b,d not none 81/7180 67/4814 OR 0.71 4 fewer ⨁⨁◯◯ CRITICAL ed trials a serious (1.1%) (1.4%) (0.52 to per LOW 0.99) 1,000 (from 0 fewer to 7 fewer)

PAROXETINE (Stone et al., 2009) (assessed with: number of events - ideation or worse)

52 Randomis- serious not serious serious b,e serious c none 50/9919 29/6972 OR 0.93 0 fewer ⨁◯◯ CRITICAL a ed trials (0.5%) (0.4%) (0.62 to per ◯ 1.42) 1,000 VERY (from 2 LOW fewer to 2 more) Certainty assessment № of patients Effect

Other Relative Import- № of Study Risk of Im- Anti- Absolute Certainty Inconsistency Indirectness consider- placebo (95% ance studies design bias precision depress. (95% CI) ations CI)

DULOXETINE (Stone et al., 2009) (assessed with: number of events - ideation or worse)

35 Randomis- serious not serious serious b,f serious c none 25/2327 18/1460 OR 0.88 1 fewer ⨁◯◯ CRITICAL a ed trials (1.1%) (1.2%) (0.47 to per ◯ 1.63) 1,000 VERY (from 6 LOW fewer to 8 more)

VENLAFAXINE (Stone et al., 2009) (assessed with: number of events - ideation or worse)

39 Randomis- serious not serious serious b serious c none 29/5593 30/3904 OR 0.71 2 fewer ⨁◯◯ CRITICAL ed trials a (0.5%) (0.8%) (0.44 to per ◯ 1.16) 1,000 VERY (from 1 LOW more to 4 fewer)

CI: Confidence interval; OR: Odds ratio

Explanations a. No risk of bias assessment was performed, and data on dropouts are not reported. b. This meta-analysis includes participants with many possible psychiatric indications, not only major depressive disorder. c. The 95% CI crosses both no difference (1), an appreciable benefit for the antidepressant (reduced risk ratio of 25% or more), and/or appreciable harm for the antidepressant (increased risk ratio of 25% or more). d. Another meta-analysis (Beasley et al., 2007) pooling RCTs on patients with major depressive disorder only provided similar results (RR 0.53; 95% CI 0.30 to 0.93). In this review, however, only studies sponsored by the Eli Lilly and Company were included, while no searches for independent or other sponsored trials were performed. e. Another meta-analysis (Carpenter et al., 2011) pooling RCTs on patients with major depressive disorder only provided similar results (OR 1.3; 95% CI 0.7 to 2.8). In this review, however, only studies sponsored by the Eli Lilly were included, while no searches for independent or other sponsored trials were performed. f. Another meta-analysis (Acharya et al., 2006) pooling RCTs on patients with major depressive disorder only provided similar results (RR 1.12; 95% CI 0.62 to 2.01). In this review, however, only studies sponsored by the Eli Lilly and Company and by Shionogi Company, Ltd were included, while no searches for independent or other sponsored trials were performed.

APPENDIX 3: GRADE TABLE 5: IMPACT (EFFICACY) OF SSRIs FOR PEOPLE WITH ISCHEMIC HEART DISEASE

Author(s): GO, KK, CB Date: 12/4/18 Question: SSRI antidepressants compared to placebo for depression in people with ischemic heart disease Setting: Any Bibliography: Ostuzzi G, Turrini G, Gastaldon C, Papola D, Rayner L, Caruso R, Grassi L, Hotopf M, Barbui C. “Efficacy and acceptability of antidepressants in people with ischemic heart disease: systematic review and meta-analysis.” International Clinical Psychopharmacology. [In Press]. Certainty assessment № of patients Effect

Other Relative № of Study Risk of Im- Anti- Placebo Absolute Certainty Importance Inconsistency Indirectness consider- (95% studies design bias precision depressants (EFFICACY) (95% CI) ations CI)

ESCITALOPRAM - EFFICACY (assessed with: mean change score at validated rating scales for depression)

3 randomised serious serious b not serious serious c none 354 351 - SMD ⨁◯◯◯ IMPORTANT trials a 0.58 SD VERY LOW lower (1.25 lower to 0.1 higher)

CITALOPRAM - EFFICACY (assessed with: mean change score at validated rating scales for depression)

2 randomised not not serious very serious not none 142 142 - SMD ⨁⨁◯◯ IMPORTANT trials serious d serious 0.33 SD LOW lower (0.57 lower to 0.1 lower)

SERTRALINE - EFFICACY (assessed with: mean change score at validated rating scales for depression) Certainty assessment № of patients Effect

Other Relative № of Study Risk of Im- Anti- Placebo Absolute Certainty Importance Inconsistency Indirectness consider- (95% studies design bias precision depressants (EFFICACY) (95% CI) ations CI)

4 randomised serious not serious not serious not none 282 269 - SMD ⨁⨁⨁◯ IMPORTANT trials a serious 1.19 SD MODERATE lower (2 lower to 0.39 lower)

FLUOXETINE - EFFICACY (assessed with: mean change score at validated rating scales for depression)

1 randomised serious not serious not serious very none 27 27 - SMD ⨁◯◯◯ IMPORTANT trials a serious 0.38 SD VERY LOW c,e lower (0.92 lower to 0.16 higher)

CI: Confidence interval; SMD: Standardised mean difference

Explanations a. Serious risk of attrition bias b. I-squared = 94% c. The 95% CI crosses both no difference (zero) and appreciable benefit in favor of the antidepressant. d. The two comparisons included in the analysis are from the same study where citalopram and psychological interventions are administered together; therefore we cannot rule out the effect of citalopram only (downgraded of -2). e. Only 54 patients were included.

APPENDIX 3: GRADE TABLE 6: ACCEPTABILITY (DROP-OUTS) OF SSRIs FOR PEOPLE WITH ISCHEMIC HEART DISEASE

Author(s): GO, KK, CB Date: 12/4/18 Question: SSRI antidepressants compared to placebo for depression in people with ischemic heart disease Setting: Any Bibliography: Ostuzzi G, Turrini G, Gastaldon C, Papola D, Rayner L, Caruso R, Grassi L, Hotopf M, Barbui C. “Efficacy and acceptability of antidepressants in people with ischemic heart disease: systematic review and meta-analsyis.” International Clinical Psychopharmacology. [In Press].

Certainty assessment № of patients Effect

Other № of Study Risk of Indirect- Im- Anti- Relative Absolute Certainty Importance Inconsistency consider- Placebo studies design bias ness precision depress. (95% CI) (95% CI) ations

ESCITALOPRAM - ACCEPTABILITY (assessed with: total dropouts)

3 random- not not serious not serious a none 117/333 111/334 RR 1.05 17 more ⨁⨁⨁◯ IMPORTANT ised serious serious (35.1%) (33.2%) (0.86 to per MODERATE trials 1.28) 1,000 (from 47 fewer to 93 more)

Citalopram - ACCEPTABILITY (assessed with: total dropouts)

2 random- not not serious very not serious none 18/142 36/142 RR 0.49 129 ⨁⨁◯◯ IMPORTANT ised serious serious b (12.7%) (25.4%) (0.29 to fewer LOW trials 0.82) per 1,000 (from 46 fewer to 180 fewer) Certainty assessment № of patients Effect

Other № of Study Risk of Indirect- Im- Anti- Relative Absolute Certainty Importance Inconsistency consider- Placebo studies design bias ness precision depress. (95% CI) (95% CI) ations

Sertraline - ACCEPTABILITY (assessed with: total dropouts)

4 random- not not serious not serious a none 66/294 54/277 RR 1.18 35 more ⨁⨁⨁◯ IMPORTANT ised serious serious (22.4%) (19.5%) (0.86 to per MODERATE trials 1.61) 1,000 (from 27 fewer to 119 more)

Fluoxetine - ACCEPTABILITY (assessed with: total dropouts)

1 random- not not serious not very none 5/27 9/27 RR 0.56 147 ⨁⨁◯◯ IMPORTANT ised serious serious serious a,c (18.5%) (33.3%) (0.21 to fewer LOW trials 1.44) per 1,000 (from 147 more to 263 fewer)

CI: Confidence interval; RR: Risk ratio

Explanations a. The 95% CI crosses both no difference (1) and an appreciable harm related to the antidepressant (relative risk increased more than 25%). b. The two comparisons included in the analysis are from the same study where citalopram and psychological interventions are administered together; therefore we cannot rule out the effect of citalopram only (downgraded of -2). c. Only 54 patients were included.