### Evidence Report/Technology Assessment: Number 7

# Treatment of Depression—Newer Pharmacotherapies

## Summary

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Under its Evidence-based Practice Program, the Agency for Health Care Policy and Research (AHCPR) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities. 

Overview / Reporting the Evidence / Methodology / Findings / Summary Implications / Future Research / Availability of Full Report

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## Overview

Depressive disorders, including major depression and dysthymia, are serious, disabling illnesses. It is estimated that one in five individuals is affected by a mood disorder in his or her lifetime. The economic costs to society and personal costs to individuals and families are enormous. In the U.S. alone, the estimated monetary costs for depression exceeded $44 billion in 1990. The personal costs are reflected by higher mortality and impairment in multiple areas of functioning. The World Health Organization estimates that major depression is the fourth most important cause worldwide of loss in disability-adjusted life years, and will be the second most important cause by 2020.

In the late 80s, the U.S. Department of Health and Human Services sponsored the development of standard treatment guidelines for major depression. The guidelines advanced knowledge substantially, but available evidence was insufficient to address many clinically important questions. Since publication of the guidelines, a widely publicized emphasis on recognizing and treating depression as well as the development of many new antidepressants have contributed to explosive growth in antidepressant prescribing and increasing pharmacy costs for health plans. Newer antidepressants and readily available herbal remedies have led to wider but sometimes confusing choices for clinicians.

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## Reporting the Evidence

The ultimate purpose of this report is to help clinicians make informed choices about newer antidepressant drugs and herbal therapies, and to aid organizations developing clinical guidelines for the treatment of depression. The report provides a comprehensive evaluation of the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and children. The report focuses on 29 newer antidepressant drugs and 3 herbal remedies. Older antidepressants and psychosocial therapies are considered only when they are compared directly to a newer antidepressant.

An expert multidisciplinary panel formulated 24 specific questions, guided by 2 key principles: the potential to summarize new information not addressed in previous literature synthesis, and relevance to clinicians making treatment decisions and policymakers developing guidelines.

Questions address the efficacy of newer pharmacotherapies for the most prevalent forms of depression and for individuals with recurrent or refractory depression. Additional questions involve the relative efficacy of newer agents compared to psychosocial therapies and the efficacy of herbal remedies. The primary outcomes of interest for these questions were depressive symptoms as assessed by a rating scale or a clinical diagnosis, total dropouts, and dropouts due to adverse effects. Secondary outcomes were health-related quality of life, functional status, and suicides. The report also focuses on specific patient populations (e.g., children and adolescents) and specific settings (e.g., primary care). Issues involving combination treatments with other psychotropics, psychosocial therapies, and augmenting agents are addressed. The important question of long-term efficacy is examined through relapse prevention studies. Finally, the report addresses a group of questions related to adherence, common adverse effects, and rare but serious adverse effects.

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## Methodology

English and non-English literature was identified from a specialized registry of 8,451 clinical trial articles, as well as references from pertinent meta-analyses and experts. The specialized registry contained trials addressing depression identified from multiple sources, including: electronic databases such as MEDLINE, EMBASE, PsycLIT, LILACS, Psyndex, SIGLE, CINAHL, Biological Abstracts, and The Cochrane Library; hand searches of 69 psychiatry-related journals; and contacts with 30 pharmaceutical companies.

Sources were searched from 1980 to January 1998 to capture literature relevant to newly released antidepressants. The terms "depression," "depressive disorder," or "dysthymic disorder" were combined with a list of 32 specific "newer" antidepressants and herbal treatments to yield 1,277 relevant records. The study reviewed randomized controlled trials that: lasted at least 6 weeks; compared a "newer" antidepressant to another antidepressant (newer or older), placebo, or psychosocial intervention; involved participants with depressive disorders; and had a clinical outcome. Two or more independent reviewers identified 315 such trials. (Continuing searches of MEDLINE and PubMed were conducted from January 1998 through August 1998 while this report was being prepared and peer reviewed. Twenty-three additional trials were found; pertinent additional trials are noted in each section.)

A separate search strategy identified reports of serious but rare adverse drug effects. The databases MEDLINE, EMBASE, and PyscLIT were searched for articles of any study design (including case reports) that were original reports of serious adverse effects thought to be secondary to any of eight newer FDA-approved antidepressants or hypericum (St. John's wort). Specific keywords for adverse effects defined by MedWatch, nonspecific keywords, and text words such as "adverse," "serious," "severe," or "poisoning" were combined with the list of selected newer antidepressants and hypericum to yield 12,374 potentially relevant articles. Of these, 674 were reports of serious adverse effects.

Two persons independently abstracted data from each trial. Data was synthesized descriptively, with attention given to participant and diagnostic descriptors, intervention characteristics, study designs, and clinical outcomes. Some data were analyzed quantitatively using an empirical Bayes random-effects estimator method. Primary outcomes were symptomatic response rate, total discontinuation rates (dropouts), and discontinuation rates due to adverse events. Response rates were defined as a 50 percent or greater improvement in symptoms as assessed by a depression symptoms rating scale or a rating of much or very much improved as assessed by a global assessment method. Response rates were computed using a modified intention-to-treat approach. This approach computes response rates as the number of patients who stay in treatment and get better divided by the total number randomized. Given that some patients who left treatment may have responded, the modified intention-to-treat analysis produces a conservative estimate of treatment effect. A sensitivity analysis was done based on an endpoint method. In this method, the denominator for the risk ratio was the number of participants who completed followup or whose last observation was carried forward.

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## Findings

More than 300 randomized trials evaluated newer pharmacotherapies for depression. For most of these (>90 percent), the focus was major depression. Nine studies focused on dysthymia and three studies each examined subsyndromal and mixed anxiety depression. The largest number of comparisons (n=206) were between newer and older antidepressants. Over 100 studies compared the efficacy of newer antidepressants to placebo.

More than 90 percent of the included trials were short duration (6-8 weeks) and used double-blind methodology. Trial reporting was often incomplete. Less than one-third of studies described study settings, few studies described the nature and content of clinical interactions between providers and patients, and fewer than 10 percent described ethnic background or socioeconomic status of the participants. Secondary outcomes (health-related quality of life, functional status, suicides) were reported too infrequently for analysis.

Summary results follow for specific disorders and groups. Key findings are presented first. They are followed by gaps in knowledge which could not be answered by the available evidence.

### Major depression

More than 80 studies prove newer antidepressant drugs are more efficacious than placebo for treating adults with major depression. Response rates were 50 percent for active treatment compared to 32 percent for placebo.

Newer antidepressants are equally efficacious compared to first and second generation tricyclic antidepressants. The number of studies comparing different classes of newer antidepressants is relatively small but the studies show no difference in overall efficacy. For patients who have recovered from major depression, continued treatment with a newer antidepressant for at least 6 months decreases the risk of relapse by 70 percent. The large protective effect is best established for patients recruited from mental health settings or who have recurrent depression.

**Gaps in knowledge.** A number of important questions could not be answered with available evidence. No studies compared combinations of newer antidepressants or newer antidepressants plus another psychotropic (e.g., an anxiolytic) to a single antidepressant. Data were insufficient to determine if the combination of newer antidepressants with psychosocial therapies is more effective than antidepressants alone. Data also were insufficient to determine if augmenting agents (e.g., pindolol, lithium) in combination with a newer antidepressant quicken or improve response rates in patients with resistant depression. Whether particular antidepressant agents are more effective than others could not be determined for patients with resistant or refractory depression. Finally, the need for and efficacy of long-term antidepressant therapy needs to be evaluated in more representative populations.

### Other depressive disorders

Two selective serotonin reuptake inhibitors (fluoxetine, sertraline) and amisulpride are efficacious for treating adults with dysthymia. Response rates for active treatment were 59 percent compared to 37 percent for placebo. There is no evidence suggesting that particular agents are more effective than others, including first generation tricyclic antidepressants.

**Gaps in knowledge.** There is insufficient evidence to establish whether newer antidepressants are effective for subsyndromal (minor) depression or mixed anxiety depression.

### Herbal remedies

Hypericum (St. John's wort) appears more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. Adverse effects occur significantly less frequently with hypericum compared to first generation tricyclic antidepressants. These findings are tempered by the relatively small number of trials and evidence of publication bias favoring positive trials.

**Gaps in Knowledge.** It is not clear if hypericum (St. John's wort) is as effective as standard antidepressive agents. No trial data for two other herbal remedies (valeriana and kava kava) were found. (1)

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(1) Editor's note: The National Institutes of Health (NIMH/NCCAM/ODS) is sponsoring a placebo controlled, blinded clinical trial comparing St. John's wort to a selective serotonin reuptake inhibitor.

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### Newer antidepressants compared to psychosocial therapies

**Gaps in Knowledge.** There were no trials comparing newer agents to educational or supportive counseling. Only one small trial compared psychotherapy directly to a newer agent in adults. These data were too limited to determine if newer antidepressants are more or less effective than psychosocial therapies.

### Newer antidepressants in children, older adults, and other special populations

Multiple antidepressants proved to be better than placebo in treating major depression in older adults. Antidepressants appear equally effective. Dropouts overall and due to adverse effects do not differ significantly between older and newer antidepressants.

**Gaps in Knowledge.** Gaps in knowledge for selected populations of special interest are substantial. Only two small studies evaluated newer agents in children or adolescents; data are insufficient to guide management of depression in children and adolescents. A small number of studies evaluated newer antidepressants in patients with depression and either alcoholism, chronic fatigue syndrome, HIV disease, ischemic heart disease, renal failure, or stroke. The results are conflicting and insufficient to reliably determine the efficacy of newer agents compared to placebo or older agents. Since fewer than 10 percent of trials reported data about participants' ethnic background, data are insufficient to determine whether efficacy differs across ethnic groups.

### Treatment in primary care and postpartum settings

Newer antidepressants are better than placebo in treating depressive disorders in adults in primary care settings. Response rates were 60 percent for active treatment compared to 35 percent for placebo. There is no evidence that particular agents are more effective than others.

**Gaps in Knowledge.** Only one small study with a high dropout rate evaluated newer pharmacotherapy in women with major or subsyndromal depression after childbirth. These data are insufficient to determine the efficacy of newer antidepressants in the postpartum setting.

### Treatment adherence and adverse effects

In general, participants discontinued treatment at similar rates for newer and older antidepressants due to lack of effect, adverse effects, or other reasons. However, fewer patients taking selective serotonin reuptake inhibitors or reversible inhibitors of monoamine oxidase A discontinued treatment due to adverse effects compared to patients taking first generation tricyclic antidepressants (rate differences 4 percent and 5 percent, respectively).

Compared to first generation tricyclic antidepressants, selective serotonin reuptake inhibitors had significantly higher rates of diarrhea (rate difference (RD) 10 percent), nausea (RD 10 percent), insomnia (RD 7 percent), and headache (RD 3 percent). Tricyclic antidepressants had significantly higher rates of dry mouth (RD 30 percent), constipation (RD 12 percent), dizziness (RD 11 percent), blurred vision (RD 4 percent), and tremors (RD 4 percent). Nine uncommon (<1 percent) but serious adverse effects were definitely associated with the selective serotonin reuptake inhibitors. They were: bradycardia, bleeding, granulocytopenia, seizures, hyponatremia, hepatotoxicity, serotonin syndrome, extrapyramidal effects, and mania in unipolar depression. Buproprion was associated with seizures. Hypericum (St. John's wort) was not associated with serious adverse effects.

**Gaps in Knowledge.** Marked variability in methods of ascertainment and reporting of common adverse effects makes interpretation difficult. Some adverse effects, such as sexual dysfunction and changes in weight, were reported too infrequently for reliable interpretation.

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## Summary Implications

This evidence report clearly shows newer antidepressants are effective treatments for major depression and dysthymia. They are efficacious in treating depressive disorders in mental health as well as primary care settings. Newer antidepressants have similar efficacy and total dropout rates compared to older antidepressants. Because of similar efficacy, both newer and older antidepressants should be considered when making treatment decisions. When selecting antidepressants, clinicians should consider costs, the small but statistically significant differences in dropouts due to adverse effects, the lack of information about relative benefits compared to alternative therapies (e.g., psychosocial and herbal), and the individual patient's preferences and tolerance for particular adverse effects. Health policy planners should consider these factors and advocate for cost-effectiveness studies to better guide the allocation of health care dollars.

For patients with other forms of depression, such as subsyndromal or mixed anxiety depression, and for special populations, such as children and adolescents, data on newer pharmacotherapies are insufficient to guide treatment decisions. Clinicians who choose to generalize efficacy data from adult patients with major depression to such patients should do so with care.

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## Future Research

Insufficient data left many of the 24 questions posed by the technical panel unanswered. Research priorities were identified based on these gaps in evidence. Global research priorities include: the need for better trial reporting; longer term trials that provide data on functional status, health-related quality of life; costs; and effectiveness studies that evaluate the relative benefits of treatments under usual clinical conditions.

There is an urgent need for better information about the efficacy of newer pharmacotherapies in patients with non-major depression and in a broad array of special populations, including children and adolescents. Clinicians need better data to guide treatment for patients with refractory depression. There is a critical gap in data on the comparative benefits of herbal treatments and various psychosocial therapies with newer pharmacotherapies. Combination treatments with other psychotropics and with various psychosocial therapies also need to be evaluated.

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## Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Health Care Policy and Research by the San Antonio Evidence-based Practice Center based at The University of Texas Health Science Center at San Antonio under contract  No. 290-97-0012. Printed copies may be obtained free of charge from the Agency Clearinghouse by calling 1-800-358-9295. Requesters should ask for Evidence Report/Technology Assessment  No. 7, *Treatment of Depression—Newer Pharmacotherapies* (AHCPR Publication  No. 99-E014). The Evidence Report is also available online on the National Library of Medicine Bookshelf.

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*AHCPR Publication Number 99-E013Current as of March 1999*

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**Internet Citation:**

*Treatment of Depression—Newer Pharmacotherapies*. Summary, Evidence Report/Technology Assessment: Number 7, March 1999. Agency for Health Care Policy and Research, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/deprsumm.htm

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