THIS EVIDENCE REPORT IS OUTDATED AND IS NO LONGER VIEWED AS GUIDANCE FOR CURRENT MEDICAL PRACTICE. IT IS MAINTAINED FOR ARCHIVAL PURPOSES ONLY.

Evidence Report/Technology Assessment

Number 7

Prepared for:
Agency for Health Care Policy and Research

U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852
http://www.ahcpr.gov

Contract No. 290-97-0012

Prepared by:
San Antonio Evidence-based Practice Center based at
The University of Texas Health Science Center at San Antonio
The Veterans Evidence-based Research, Dissemination,
and Implementation Center (VERDICT),
a VA health services and development Center of Excellence at the
Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX

Cynthia D. Mulrow, MD, MSc
EPC Project Director

John W. Williams, Jr., MD, MHS
Madhukar Trivedi, MD
Elaine Chiquette, PharmD
Christine Aguilar, MD, MPH
John E. Cornell, PhD
Robert Badgett, MD
Polly Hitchcock Noel, PhD
Valerie Lawrence, MD, Msc
Shuko Lee, MS
Michael Luther, MS
Gilbert Ramirez, DrPH
W. Scott Richardson, MD
Karen Stamm, BA
Investigators

AHCPR Publication No. 99-E014

February 1999

The Agency for Health Care Policy and Research (AHCPR), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHCPR and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHCPR encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the nation. The reports undergo peer review prior to their release.

AHCPR expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Health Care Policy and Research, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

John M. Eisenberg, M.D. Administrator Agency for Health Care Policy and Research	Douglas B. Kamerow, M.D. Director, Center for Practice and Technology Assessment Agency for Health Care Policy and Research

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Health Care Policy and Research or the U.S. Department of Health and Human Services of a particular drug, device, test treatment, or other clinical service.

Depressive disorders are persistent, recurring illnesses that impose enormous personal suffering on individuals and their families. Major depression alone is estimated as the fourth most important cause of worldwide loss in disability-adjusted life years and is likely to become the second most important within 20 years. A continued quest for more effective treatments has spawned newer antidepressants and herbal treatments, which have contributed to explosive growth in the prescribing of antidepressants, increasing pharmacy costs, and wider but sometimes confusing choices for clinicians and patients. This evidence report provides a comprehensive evaluation of the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and children.

Pertinent literature from 1980 to January 1998 was identified from a specialized registry of controlled trials, meta-analyses, and experts. The registry contained trials addressing depression that had been identified from multiple electronic bibliographic databases, handsearching of journals, and pharmaceutical companies. The search, which yielded 1,277 records, combined terms "depression," "depressive disorder," or "dysthymic disorder" with a list of 32 specific "newer" antidepressant and herbal treatments.

Randomized controlled trials that were at least 6 weeks in duration; compared a "newer" antidepressant with another antidepressant (newer or older), placebo, or psychosocial intervention; involved participants with depressive disorders; and had a clinical outcome were reviewed. Two or more independent reviewers identified 315 trials that met these criteria.

Two persons independently abstracted data from each trial. Data were synthesized descriptively; attention was paid to participant and diagnostic descriptors, intervention characteristics, study designs, and clinical outcomes. Some data were analyzed quantitatively through the use of an empirical Bayes random-effects estimator method. Primary outcomes were 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.

There were 264 trials that evaluated antidepressants in patients, adults and children, with major depression. Of these, 81 compared newer agents with placebo, 150 newer to older agents, 32 newer to newer agents, and 1 newer agent to psychotherapy. There were 14 trials evaluating hypericum (St. John's wort), 27 trials each in primary care patients and older adults, 10 trials limited to patients with specific concomitant illnesses, 9 trials in patients with dysthymia, 3 trials each in patients with mixed anxiety depression and subsyndromal depression, 2 trials in adolescents, and 1 in the postpartum setting. Most trials were conducted in outpatients and only examined acute phase treatment lasting less than 12 weeks.

Newer antidepressants were more effective than placebo in treating major depression (risk ratio [RR] 1.6, 95 percent confidence interval [CI] 1.5 to 1.7) and dysthymia (RR 1.7, 95 percent CI 1.3 to 2.3). They were effective in older adults and in primary care patients. In general, there were no significant differences in efficacy among individual newer agents or between newer and older agents. Hypericum (St. John's wort) was more effective than placebo in treating mild to moderately severe depressive disorders (RR 1.9, 95 percent CI 1.2 to 2.8). Whether hypericum (St. John's wort) is as effective as standard antidepressant agents given in adequate doses was not established.

No significant differences were found between newer and older antidepressants in overall discontinuation rates. Administration of selective serotonin reuptake inhibitors (SSRIs), reversible inhibitors of monoamine oxidase A (RIMAs), and hypericum (St. John's wort) resulted in fewer dropouts due to adverse effects than administration of first generation tricyclic agents (TCAs). When compared with first generation TCAs, SSRIs resulted in higher rates of diarrhea, headache, insomnia, and nausea. SSRIs resulted in lower rates of blurred vision, constipation, dizziness, dry mouth, tremors, and urinary disturbances.

Newer antidepressants are clearly effective in treating depressive disorders in a variety of settings. Multiple agents are effective. In general, there are no significant differences in efficacy between newer antidepressants and first and second generation tricyclic antidepressants nor among different classes of newer antidepressants. Newer antidepressants have similar overall discontinuation rates as do older antidepressants but have varying side effect profiles. Some newer agents, such as RIMAs and SSRIs, have fewer dropout rates due to adverse events compared with first generation tricyclic agents.

Available trial data have several limitations. Most (74 percent) trials lasted 6 to 7 weeks; 81 percent reported dropout rates of greater than 20 percent. Fewer than 5 percent reported health-related quality-of-life outcomes. The actual treatment environment within which trials were carried out was rarely described. Few trials addressed effectiveness, and little information exists for children and adolescents, refractory depression, depression co-occurring with comorbid illness, and specific disorders such as mixed anxiety depression, subsyndromal depression, and depression in the postpartum setting.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibitied without the specific permission of the copyright holders.

Suggested citation:
Mulrow CD, Williams JW, Jr., Trivedi M, et al. Treatment of Depression: Newer Pharmacotherapies. Evidence Report/Technology Assessment No. 7. (Prepared by the San Antonio Evidence-based Practice Center based at The University of Texas Health Science Center at San Antonio under Contract 290-97-0012.) AHCPR Publication No. 99-E014. Rockville, MD: Agency for Health Care Policy and Research. February 1999.

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 United States 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 1980s, 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 salient questions. Since publication of the guidelines, a widely publicized emphasis on recognizing and treating depression and the development of many new antidepressants have contributed to explosive growth in the prescribing of antidepressants and in increasing pharmacy costs for health plans. Newer antidepressants and readily available herbal remedies have led to wider but sometimes confusing choices for clinicians.

The ultimate purpose of this report is to help clinicians make informed choices about newer antidepressant drugs and herbal therapies and to aid organizations in 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 with a newer antidepressant.

An expert multidisciplinary panel formulated 24 specific questions, guided by two 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 with 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.

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; handsearches 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. Randomized controlled trials that were at least 6 weeks in duration; compared a "newer" antidepressant with another antidepressant (newer or older), placebo, or psychosocial intervention; involved participants with depressive disorders; and had a clinical outcome were reviewed. 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 and 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 were synthesized descriptively; attention was paid to participant and diagnostic descriptors, intervention characteristics, study designs, and clinical outcomes. Some data were analyzed quantitatively through the use of 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.

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) was between newer and older antidepressants. Over 100 studies compared the efficacy of newer antidepressants with that of 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. Fewer 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 that could not be answered by the available evidence.

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

Newer antidepressants are equally efficacious compared with first and second generation tricyclic antidepressants. The number of studies comparing different classes of newer antidepressants is relatively small but 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.

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) with 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.

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 with 37 percent for placebo. No evidence suggests that particular agents are more effective than others, including first generation tricyclic antidepressants.

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

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 with first generation tricyclic antidepressants. These findings are tempered by the relatively small number of trials and evidence of publication bias favoring positive trials.

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 ^a .

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

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

Gaps in knowledge for selected populations of special interest are substantial. Only two small studies evaluated newer agents in children or adolescents; data were 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, human immunodeficiency virus (HIV) disease, ischemic heart disease, renal failure, or stroke. The results are conflicting and insufficient to reliably determine the efficacy of newer agents compared with that of 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.

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 with 35 percent for placebo. There is no evidence that particular agents are more effective than others.

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.

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 (SSRIs) or reversible inhibitors of monoamine oxidase A (RIMAs) discontinued treatment due to adverse effects compared with the number of those taking first generation tricyclic antidepressants (rate differences 4 percent and 5 percent, respectively).

Compared with first generation tricyclic antidepressants, SSRIs resulted in 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 resulted in 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. Bupropion was associated with seizures. Hypericum (St. John's wort) was not associated with serious adverse effects.

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.

This evidence report clearly shows that 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 as older antidepressants. Because of similar efficacy, both newer and older antidepressants should be considered when treatment decisions are made. 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 with alternative therapies (e.g., psychosocial and herbal), and 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.

Insufficient data left many of the 24 questions posed by the technical panel unanswered. Based on these gaps in evidence, research priorities were identified. Global research priorities include the need for better trial reporting; longer term trials that provide data on functional status, health-related quality of life, and 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 need to be evaluated.