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When starting an , try either of these 2 drugs fi rst Most patients fi nd that ertralines and are more effective and better tolerated than other

Meta-analysis of 117 high-quality studies found Gail L. Patrick, MD, MPP that sertraline and escitalopram are superior to Dr. Patrick is Assistant Professor of Family and Community Medicine, other “new-generation” antidepressants.1 Northwestern University, Feinberg ® Dowden Health MediaSchool of Medicine, Chicago. Gene N. Combs, MD Copyright Dr. Combs is Clinical Associate IN THIS For personal use only Professor in the Department A woman with diabetes who is fatigued but cannot sleep of Family Medicine, University ARTICLE Mrs. D., 45 years old, has been your patient for several years. of Chicago (NorthShore). Antidepressants are She has type 2 diabetes. On her latest visit, she reports a Thomas F. Gavagan, not all equivalent loss of energy and diffi culty sleeping, and wonders if these MD, MPH symptoms could be related to the diabetes. Dr. Gavagan is Vice Chair of the page 32 Department of Family Medicine, As you explore further and question Mrs. D. about her University of Chicago (NorthShore). symptoms, she becomes tearful, and tells you she has epi- “Acceptability” and sodes of sadness and no longer enjoys things the way she The authors report no fi nancial effi cacy of 10 drugs relationships relevant to this article. used to. Although she has no history of depression, when page 35 you suggest that her symptoms may be an indication of depression, she readily agrees. What this evidence Acknowledgment You discuss treatment options, including antidepres- Sofi a Medvedev, PhD, of the University means for practice sants and . Mrs. D. decides to try medication. HealthSystem Consortium, Oak Brook, Ill., analyzed data from the National Ambulatory page 36 But with so many antidepressants on the market, how do Medical Care Survey and the UHC Clinical you choose one? Database as part of the development of the manuscript of this article.

ajor depression is the fourth leading cause of dis- Mease globally, according to the World Health Orga- nization.2 Depression is common in the United States as well, and primary care physicians, including ObGyns, are often the ones who are diagnosing and treating it. In fact, ›› SHARE YOUR EXPERIENCE! the US Preventive Services Task Force recently expanded Does your practice afford time its recommendation that primary care providers screen for managing depression? adults for depression, to include adolescents 12 to 18 years E-MAIL [email protected] FAX 201-391-2778 old.3 When depression is diagnosed, physicians must help patients decide on an initial treatment plan. CONTINUED ON PAGE 32

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Not all antidepressants are equal analysis were all RCTs in which one of these Options for initial treatment of unipolar ma- 12 antidepressants was tested against one, or jor depression include psychotherapy and several, other second-generation antidepres- the use of an antidepressant. For mild and sants as monotherapy for the acute treatment moderate depression, psychotherapy alone phase of unipolar major depression. Th e au- is as eff ective as medication. Combined psy- thors excluded -controlled trials in chotherapy and antidepressants are more order to evaluate effi cacy and acceptability of eff ective than either treatment alone for all the study medications relative to other com- degrees of depression.4 monly used antidepressants. Th ey defi ned Th e ideal medication for depression acute treatment as 8 weeks of antidepressant would be a drug with a high level of eff ec- therapy, with a range of 6 to 12 weeks. Th e tiveness and a low side-eff ect profi le; until primary outcomes studied were response to now, however, there has been little evidence treatment and dropout rate. to support one antidepressant over another. Response to treatment (effi cacy) was con- Previous meta-analyses have concluded that structed as a Yes or No variable; a positive there are no signifi cant diff erences in either response was defi ned as a reduction of ≥50% effi cacy or acceptability among the various in symptom score on either the Hamilton second-generation antidepressants on the Depression Rating Scale or the Montgomery- market.5,6 Th erefore, physicians have histori- Asberg Rating Scale, or a rating of “improved” cally made initial monotherapy treatment or “very much improved” on the Clinical decisions based on side eff ects and cost.7,8 Global Impression scale at 8 weeks. Effi cacy Th e meta-analysis we report here tells a dif- was calculated on an intention-to-treat ba- ferent story, providing strong evidence that sis; if data were missing for a participant, that some antidepressants are more eff ective and person was classifi ed as a nonresponder. better tolerated than others. Dropout rate was used to represent accept- ability, because the authors believed it to Combined be a more clinically meaningful measure psychotherapy Two “best” drugs revealed than either side eff ects or symptom scores. 1 and antidepressants Cipriani and colleagues conducted a system- Comparative effi cacy and acceptability were are more effective atic review and multiple-treatments meta- analyzed. —the fi rst of the second- than either analysis of 117 prospective randomized, generation antidepressants—was used as the controlled trials (RCTs). Taken together, the reference medication. Th e FIGURE (page 35) treatment alone RCTs evaluated the comparative effi cacy and shows the outcomes for nine of the antide- for all degrees acceptability of 12 second-generation anti- pressants, compared with those of fl uoxetine. of depression depressants: , , dulox- Th e other two antidepressants, etine, escitalopram, fl uoxetine, fl uvoxamine, and , were omitted because they milnacipran, , , rebox- are not available in the United States. etine, sertraline, and . Th e overall meta-analysis included Th e methodology of this meta-analysis 25,928 individuals, with 24,595 in the effi - diff ered from that of traditional meta-analy- cacy analysis and 24,693 in the acceptability ses by allowing the integration of data from analysis. Nearly two thirds (64%) of the par- both direct and indirect comparisons. (An in- ticipants were women. Th e mean duration of direct comparison is one in which drugs from follow-up was 8.1 weeks. Th e mean sample diff erent trials are assessed by combining the size per study was 110. results of their eff ectiveness and comparing Studies of women with postpartum de- the combined fi nding with the eff ectiveness pression were excluded. of a drug that all the trials have in common.) Escitalopram and sertraline stand out. Previous studies, based only on direct com- Overall, escitalopram, mirtazapine, ser- parison, yielded inconsistent results. traline, and venlafaxine were signifi cantly Th e studies included in this meta- more effi cacious than fl uoxetine or the other

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medications. Bupropion, citalopram, escital- FIGURE Sertraline and escitalopram come out on top in opram, and sertraline were better tolerated acceptability and effi cacy than the other antidepressants. Escitalopram and sertraline were found to have the best 1.25

combination of effi cacy and acceptability. 1.20 escitalopramescitalopraam Effi cacy results. Fifty-nine percent of partici- 1.15 sertrsertralinerraline pants responded to sertraline, versus a 52% re- bbupropion sponse rate for fl uoxetine (number needed to 1.10 citalopramit l treat [NNT]=14). Similarly, 52% of participants 1.05 fl uoxetine responded to escitalopram, compared with 1.00 mirtazapine 47% of those taking fl uoxetine (NNT=20). 0.95 venlafaxinevenlafaxine Acceptability results. In terms of the dropout paroxetinen 0.90

rate, 28% of participants discontinued fl uox- Acceptability (odds ratio) 0.85 etine, versus 24% of patients taking sertraline. fl vuvoxamine Th is means that 25 patients would need to be 0.80 0.80 0.90 1.00 1.10 1.20 1.30 1.40 treated with sertraline, rather than fl uoxetine, to avoid one discontinuation. In the compar- Effi cacy (odds ratio) ison of fl uoxetine versus escitalopram, 25% discontinued fl uoxetine, compared with 24% Researchers analyzed a number of second-generation antidepressants, using fl uoxetine as the reference medication. Sertraline and escitalopram provided the who discontinued escitalopram. best combination of effi cacy and acceptability.1 Th e effi cacy and acceptability of sertra- line and escitalopram compared with other second-generation antidepressant medica- tions follow similar trends. Our fi nding? An estimated 4 million pa- Generic advantage. Th e investigators recom- tients 18 years and older given a diagnosis of mend sertraline as the best choice for an ini- depression in the course of the study year re- tial antidepressant because it is available in ceived new prescriptions for a single antide- Sertraline is the generic form and is therefore lower in cost. pressant. Six medications accounted for 90% best choice for Th ey further recommend that sertraline, in- of prescriptions, in this order: an initial stead of fl uoxetine or placebo, be the new • fl uoxetine (Prozac) antidepressant standard against which other antidepres- • duloxetine (Cymbalta) because it is sants are compared. • escitalopram (Lexapro) available in generic • paroxetine (Paxil) form • venlafaxine (Eff exor) Choice is now evidence-based • sertraline (Zoloft). We now have solid evidence for choosing ser- Sertraline and escitalopram, the drugs traline or escitalopram as the fi rst medication shown to be most eff ective and acceptable in to use when treating a patient with newly di- the Cipriani meta-analysis, accounted for 11.8% agnosed depression. This represents a prac- and 14.5% of the prescriptions, respectively. tice change because antidepressants that are less effective and less acceptable have been chosen more frequently than either of these Caveats medications. Th at conclusion is based on our This meta-analysis looked at the analysis of the National Ambulatory Medical acute phase of treatment only Care Survey database for outpatient and ambu- Th e results of this study are limited to initial latory clinic visits in 2005-2006 (the most recent therapy as measured at 8 weeks. Few long- data available). We conducted this analysis to term outcome data are available; response determine which of the second-generation an- to initial therapy may not be a predictor of tidepressants were prescribed more often for full remission or long-term success. Current initial monotherapy of major depression. guidelines suggest maintenance of the initial

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may limit the overall generalizability of the WHAT THIS EVIDENCE MEANS study results to a primary care population. FOR PRACTICE Studies included in this meta-analysis were selected exclusively from published When you initiate an antidepressant literature. Th ere is some evidence of a bias for a patient who has not been treated toward the publication of studies that have for depression in the past, select either yielded positive results, which may have the sertraline (Zoloft) or escitalopram eff ect of overstating the eff ectiveness of a (Lexapro). given antidepressant.13 However, we have no reason to believe that this bias would favor successful therapy, often with increasing in- any particular drug. tervals between visits, to prevent relapse.9 Most of the included studies were spon- Th is study does not add new insight into sored by drug companies. Notably, phar- long-term response rates. Nor does it deal maceutical companies have the option of with choice of a replacement or second an- continuing to conduct trials of medications tidepressant for nonresponders or those who until a study results in a positive fi nding for cannot tolerate the initial drug. their medication, with no penalty for the What’s more, the study covers drug treat- suppression of equivocal or negative results ment alone, which may not be the best initial (negative publication bias). Under current treatment for depression. Psychotherapy, FDA guidelines, there is little transparency in the form of cognitive behavioral therapy for the consumer as to how many trials have or interpersonal therapy, when available, is been undertaken and the direction of the re- equally eff ective, has fewer potential physi- sults, published or unpublished.14 ologic side eff ects, and may produce longer- We doubt that either publication bias lasting results.10,11 or the design and sponsorship of the stud- ies included in this meta-analysis present Drug therapy may Little is known about study design signifi cant threats to the validity of these not be the best Th e authors of this study had access only fi ndings over other sources upon which initial treatment for to limited information about inclusion cri- guidelines rely, given that these issues are depression. Psycho- teria and the composition of initial study common to much of the research on phar- therapy is equally populations or settings. Th ere is a diff erence macotherapy. We also doubt that the com- between a trial designed to evaluate the “effi - pensation of the authors by pharmaceutical effective, has fewer cacy” of an intervention (i.e., “the benefi cial companies would bias the outcome of the potential side and harmful eff ects of an intervention under study, in this instance. One of the authors effects, and may controlled circumstances”) and the “eff ec- (Furukawa) received compensation from produce longer- tiveness” of an intervention (i.e., the “benefi - Pfi zer, the maker of Zoloft, which is also lasting results cial and harmful eff ects of the intervention available as generic sertraline. None of the under usual circumstances”).12 It is not clear authors received compensation from For- which of the 117 studies were effi cacy studies est Pharmaceuticals, the maker of Lexapro and which were eff ectiveness studies. Th is (escitalopram).

CONTINUED ON PAGE 39

About the source of this review selected and evaluated using FPIN’s PURL to the University of Chicago. The content of this This article is one of a series of “Priority Up- Surveillance System methodology. The cri- article is solely the responsibility of the authors dates from the Research Literature” (PURLs), teria and fi ndings that led to the selection and does not necessarily represent the offi cial a program of the Family Physicians Inquiries of this study as a PURL can be found at views of the National Center for Research Re- Network (FPIN). It is republished here from www.jfponline.com/purls. sources or the National Institutes of Health. the July 2009 issue (volume 58, number 7) of The PURLs Surveillance System is sup- The PURLs editor for The Journal of The Journal of Family Practice, a Dowden ported in part by Grant Number UL1RR02499 Family Practice is John Hickner, MD, MSc, Health Media publication. from the National Center for Research Re- Chair of the Department of Family Medicine at The study1 analyzed in this article was sources, a Clinical Translational Science Award the Cleveland Clinic, Cleveland, Ohio.

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36_OBGM1109 36 10/22/09 8:17:47 AM 5. Impaired glucose tolerance. acetate were reported to have a two-fold increase in the risk of developing probable The following additional adverse reactions have been reported with estrogen and or . Alzheimer’s disease was the most common classification of probable estrogen/progestin therapy: 6. Reduced response to metyrapone test. dementia in both the conjugated estrogens plus medroxyprogesterone acetate 1. Genitourinary system E. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women who were older than 70. (See WARNINGS, Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; break- Long-term continuous administration of estrogen, with and without progestin, in Dementia.) through bleeding, spotting, dysmenorrhea, increase in size of uterine leiomyomata, women with and without a uterus, has shown an increased risk of endometrial vaginitis, including vaginal , change in amount of cervical secretion, cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS ADVERSE REACTIONS changes in cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial and PRECAUTIONS.) See BOXED WARNINGS, WARNINGS, AND PRECAUTIONS. cancer. Long-term continuous administration of natural and synthetic estrogens in certain Because clinical trials are conducted under widely varying conditions, adverse reaction 2. Breasts animal species increases the frequency of carcinomas of the breast, uterus, cervix, rates observed in the clinical trials of a drug cannot be directly compared to rates vagina, testis, and . (See BOXED WARNINGS, CONTRAINDICATIONS, and Tenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic breast in the clinical trials of another drug and may not reflect the rates observed in practice. changes, breast cancer. WARNINGS sections.) The adverse reaction information from clinical trials does, however, provide a basis In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day for identifying the adverse events that appear to be related to drug use and for 3. Cardiovascular drospirenone alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of drospirenone approximating rates. Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, and ethinyl , 0.24 to 10.3 times the exposure (AUC of drospirenone) of The following are adverse events reported with ANGELIQ occurring in >5% of subjects: myocardial infarction, stroke, increase in pressure. women taking a 1 mg dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of drospirenone alone. In a similar Table 4: Adverse Events Regardless of Drug Relationship Reported at a 4. Gastrointestinal study in rats given 10 mg/kg/day drospirenone alone or 0.3 + 0.003, 3 + 0.03 and Frequency of >5% in a 1-year Double-blind Nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice, increased incidence of gall bladder disease, pancreatitis, enlargement of hepatic . 10 + 0.1 mg/kg/day drospirenone and ethinyl estradiol, 2.3 to 51.2 times the exposure E2 1 MG ANGELIQ of women taking a 1 mg dose, there was an increased incidence of benign and total 5. Skin (benign and malignant) adrenal gland pheochromocytomas in the group receiving ADVERSE EVENT (N=226) (N=227) the high dose of drospirenone. Drospirenone was not mutagenic in a number of in n (%) n (%) Chloasma or melasma, which may persist when drug is discontinued, multiforme, , hemorrhagic eruption, loss of scalp hair, hirsutism, vitro (Ames, Chinese Hamster Lung gene mutation and chromosomal damage in BODY AS A WHOLE human lymphocytes) and (mouse micronucleus) genotoxicity tests. pruritus, . Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed Abdominal pain 29 (12.8) 25 (11) 6. Eyes adducts with rodent liver DNA but not with human liver DNA. (See WARNINGS Pain in extremity 15 (6.6) 19 (8.4) Retinal vascular thrombosis, intolerance to contact lenses. section.) Back pain 11 (4.9) 16 (7) 7. Central F. Flu syndrome 15 (6.6) 16 (7) Headache, migraine, dizziness, mental depression, chorea, nervousness, mood ANGELIQ should not be used during pregnancy. (See CONTRAINDICATIONS.) disturbances, , exacerbation of epilepsy, dementia. Accidental injury 15 (6.6) 13 (5.7) G. NURSING 8. Miscellaneous Abdomen enlarged 17 (7.5) 16 (7) Estrogen administration to nursing mothers has been shown to decrease the quantity Increase or decrease in weight, reduced carbohydrate tolerance, aggravation of por- and quality of the milk. Detectable amounts of estrogens have been identified in the Surgery 6 (2.7) 12 (5.3) phyria, , arthralgias, leg cramps, changes in , anaphylactoid/anaphylactic milk of mothers receiving this drug. Caution should be exercised when ANGELIQ is METABOLIC & NUTRITIONAL DISORDERS reactions including urticaria and angioedema, hypocalcemia, exacerbation of asthma, administered to a nursing woman. increased triglycerides. Peripheral edema 12 (5.3) 4 (1.8) After administration of an oral contraceptive containing drospirenone about 0.02% of the drospirenone dose was excreted into the breast milk of postpartum women NERVOUS SYSTEM within 24 hours. This results in a maximal daily dose of about 3 mcg drospirenone Headache 26 (11.5) 22 (9.7) in an . Manufactured for: RESPIRATORY SYSTEM H. PEDIATRIC USE Upper respiratory infection 40 (17.7) 43 (18.9) ANGELIQ is not indicated in children. Sinusitis 8 (3.5) 12(5.3) I. GERIATRIC USE SKIN AND APPENDAGES There have not been sufficient numbers of geriatric patients involved in clinical Bayer HealthCare Pharmaceuticals Inc. studies utilizing ANGELIQ to determine whether those over 65 years of age differ Breast pain 34 (15.0) 43 (18.9) from younger subjects in their response to ANGELIQ. UROGENITAL Wayne, NJ 07470 In the Women’s Health Initiative Memory Study, including 4,532 women 65 years Vaginal hemorrhage 43 (19.0) 21 (9.3) Manufactured in Germany of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to Endometrial disorder 22 (9.7) 4 (1.8) 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone ©2008 Bayer HealthCare Pharmaceuticals Inc., All rights reserved. therapy use. Women treated with conjugated estrogens plus medroxyprogesterone Leukorrhea 14 ()(6.2) 3 ()(1.3) 6702400BS US 80621990 March 2008

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No major barriers anticipated tion for a 3-month supply of Lexapro (10 mg) Both sertraline and escitalopram are cov- costs about $250. A 3-month supply of gener- ered by most health insurers. As noted, ser- ic sertraline (100 mg) from the same sources traline is available in a generic formulation costs approximately $35. Pfi zer, maker of and is therefore much less expensive than Zoloft, and Forest Pharmaceuticals, maker of escitalopram. Lexapro, both administer patient assistance In a review of drug prices at www.phar- programs to make these medications avail- macychecker.com, we found that a prescrip- able to low-income, uninsured patients.

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