A Systematic Review of Newer Pharmacotherapies for Depression in Adults: Evidence Report Summary: Clinical Guideline, Part 2

Depressive disorders, including major depression and dysthymia, are serious disabling illnesses. Approximately one in five persons is affected by a mood disorder at some point (1, 2). The attendant economic costs to society and personal burden to patients and families are enormous. In the United States, the estimated costs of treating depression and the costs incurred by lost productivity exceeded $44 billion in 1990 (3). The personal burden of depression includes higher mortality and impairment in multiple areas of functioning. The World Health Organization estimates that major depression is now the fourth most important cause worldwide of loss in disability-adjusted life-years and will be the second most important cause by 2020 (4, 5). In the late 1980s, the U.S. Department of Health and Human Services sponsored the development of standard treatment guidelines for major depression (6, 7). Since publication of the guidelines, widely publicized emphasis on recognizing and treating depression and development of many new pharmacotherapies 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. The purpose of this paper is to help clinicians make informed choices about antidepressants and herbal therapies for the treatment of depression. Because previous reviews have conclusively demonstrated the efficacy of older antidepressants, this paper focuses on 29 newer antidepressants and 3 herbal remedies (6, 8-11). Older antidepressants and psychosocial therapies are considered only when they are compared directly with a newer antidepressant. Our goal was to summarize data on the efficacy of newer antidepressants and herbal treatments compared with placebo, older antidepressants, and each other for a broad spectrum of depressive disorders. 1.0 Methods English-language and non-English-language literature was identified by using the Cochrane Collaboration Depression, Anxiety and Neurosis Group's specialized registry of 8451 clinical trial articles and from references of pertinent meta-analyses and consultation with experts (1, 6-8, 10, 12-54). The specialized registry contained trials addressing depression identified from multiple sources, including electronic databases, such as MEDLINE, EMBASE, PsychLIT, 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 1277 relevant records. The newer antidepressants are selective serotonin reuptake inhibitors (SSRIs); serotonin and noradrenaline reuptake inhibitors; selective norepinephrine reuptake inhibitors; reversible inhibitors of monoamine oxidase; 5-hydroxy-tryptophan (5-HT2) receptor antagonists; 5-HT1a receptor agonists; -aminobutyric acid (GABA) mimetics; dopamine reuptake inhibitors and antagonists; and herbal remedies, such as hypericum (Table 1). 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. Table 1. Classification and Dosage Range of Antidepressants Two persons independently abstracted data from each trial. Data were synthesized descriptively, with attention to participant and diagnostic descriptors; study design, including randomization method and blinding; intervention characteristics; and clinical outcomes. When the studies were conceptually homogenous, quantitative analyses were done by using an empirical Bayes random-effects estimator method. Conceptual homogeneity required similar trial design, comparison of similar drug classes, diagnostic homogeneity, and adequate numbers of trials to justify pooling. Statistical heterogeneity was evaluated by using the chi-square test for homogeneity and Galbraith plots to identify outliers. When statistical heterogeneity was identified, outlier studies were reviewed to identify possible reasons for heterogeneity and studies were reanalyzed without the outliers. Primary outcomes were symptomatic response rate, total discontinuation rates (dropouts), and rates of discontinuation because of adverse events. Secondary outcomes were health-related quality-of-life, functional status, and suicide. Response rates were defined as a 50% 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 by 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 of randomly assigned patients. The modified intention-to-treat analysis produces an estimate of treatment effect that is conservative because it assumes that all persons who drop out of the study early receive no benefit. A sensitivity analysis was based on an end point method. In this method, the denominator for the risk ratio was the number of participants who completed follow-up or whose last observation was carried forward. Funnel plots with the Beggs rank-order correlation test and the Egger regression approach were used to estimate the possibility of publication bias whenever a quantitative meta-analysis was performed (54). Publication bias is the tendency of published studies to have different results (usually positive findings) from studies rejected from publication or never submitted for review (usually negative findings). More detailed methods and updates through September 1998 are available in the report on which this manuscript is based (55, 56). This study was funded by the Agency for Healthcare Research and Quality, which specified certain aspects of the study, such as a technical advisory panel and the report format. 2.0 Data Synthesis 2.1 Literature on Newer Antidepressants Three hundred fifteen randomized trials evaluated newer pharmacotherapies for depression. Because some trials had multiple treatment arms, the 315 trials yielded 355 pairwise comparisons. More than 90% of the trials focused on major depression (Table 2). Nine studies focused on dysthymia, a chronic mood disorder characterized by depressed mood for at least 2 years accompanied by two or more vegetative or psychological symptoms. Three studies each examined mixed-anxiety depression and subsyndromal depression, a less symptomatic, acute depression that causes less impairment in social or occupational functioning than major depression. Forty-four trials involved participants with heterogeneous groups of depressive disorders. Most studies (n =206) compared newer and older antidepressants. Serotonin reuptake inhibitors have been the most widely tested; 60 comparisons have been made with placebo, 123 with older antidepressants, and 36 with an SSRI or other newer agent. Table 2. Treatment Trials of Newer Antidepressants and Herbal Remedies More than 90% of the included trials were of short duration (6 to 8 weeks). Among trials reporting visit frequency, patients were seen weekly (62%), every other week (23%), monthly (5%), or on a schedule that varied over time. 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% described ethnic background or socioeconomic status of the participants. Of studies that described the study setting, 77 were based in mental health specialty practices and 27 were exclusively in primary care settings. Most studies reported whether recruitment involved inpatient or outpatient settings, and most (160 studies) were based in outpatient practices. Secondary outcomes (health-related quality-of-life, functional status, and suicide) were reported too infrequently for analysis. More than 90% of the randomized trials used double-blinded methods, but fewer than 5% reported whether blinding was successful. Few studies described the method of randomization or allocation and concealment. Approximately 30% of studies had relatively low dropout rates ( 20%), and approximately 20% reported dropout rates exceeding 40%. Analysis of adverse events was complicated by variability in data collection, including voluntary reporting, generic questioning, and standardized scales that may differ and affect the reliability of the overall estimates. 2.2 Major Depression: Newer Antidepressants for Initial Treatment The lifetime risk for major depressive disorder ranges from 10% to 25% for women and 5% to 12% for men, with a point prevalence rate of 5% to 9% for women and 2% to 3% for men (2, 6, 57). It affects persons of all ages, ethnicities, and socioeconomic circumstances. Major depression is characterized by at least 2 weeks of depressed mood or loss of interest or pleasure in nearly all activities (58). The person must experience at least four additional symptoms drawn from a list of vegetative (for example, loss of appetite) and psychological (for example, difficulty concentrating or making decisions) symptoms. In addition, the symptoms must cause clinically significant distress or impairment in social, occupational, or other areas of functioning. In the trials that we reviewed, the average severity of depression was moderate to moderately severe, as measured by a standard symptom rating scale (mean score, 24 [range, 14 to 32], stand