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

John W. Williams Jr., MD, MHS; Cynthia D. Mulrow, MD, MSc; Elaine Chiquette, PharmD; Polly Hitchcock Noël, PhD; Christine Aguilar, MD, MPH; and John Cornell, PhD
[+] Article and Author Information

From the South Texas Veterans Health Care System, Audie Murphy Division and the San Antonio Evidence-based Practice Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.


For other ACP-ASIM Clinical Practice Guidelines, see http://www.acponline.org/sci-policy/guidelines.

Grant Support: By the Agency for Healthcare Research and Quality, contract #290-97-0012. Dr. Williams is a recipient of a Veterans Affairs Health Services Research Career Development Award.

Acknowledgments: The authors thank Drs. Robert Badgett, Valerie Lawrence, W. Scott Richardson, and Madhukar Tirvedi, who contributed content to the original report on which this manuscript is based; the project staff with the San Antonio Evidence-based Practice Center; the 11-member technical advisory panel; and the peer reviewers who provided helpful suggestions that improved the manuscript.

Requests for Single Reprints: John W. Williams Jr., MD, MHS, Department of Medicine, Mail Code 7879, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900.

Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints@mail.acponline.org.

Current Author Addresses: Drs. Williams, Mulrow, Aguilar, and Cornell: Department of Medicine, Mail Code 7879, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900.

Dr. Chiquette: 8000 Oakdell Way, #1508-3, San Antonio, TX 78240.


Ann Intern Med. 2000;132(9):743-756. doi:10.7326/0003-4819-132-9-200005020-00011
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Background: Depressive disorders are persistent, recurring illnesses that cause great suffering for patients and their families.

Purpose: To evaluate the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and adolescents.

Data Sources: English-language and non-English-language literature from 1980 to January 1998 was identified from a specialized registry of controlled trials, meta-analyses, and experts.

Study Selection: Randomized trials evaluating newer antidepressants (such as serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and St. John's wort) that reported clinical outcomes were selected.

Data Extraction: Two persons independently abstracted data that were then synthesized descriptively; some data were pooled by using a random-effects model.

Data Synthesis: Of 315 eligible trials, most evaluated antidepressants in adults with major depression, were conducted among outpatients, and examined acute-phase treatment. Newer antidepressants were more effective than placebo for major depression (relative benefit, 1.6 [95% CI, 1.5 to 1.7]) and dysthymia (relative benefit, 1.7 [CI, 1.3 to 2.3]). They were effective among older adults and primary care patients. Efficacy did not differ among newer agents or between newer and older agents. Hypericum (St. John's wort) was more effective than placebo for mild to moderate depression (risk ratio, 1.9 [CI, 1.2 to 2.8]), but publication bias may have inflated the estimate of benefit. Newer and older antidepressants did not differ for overall discontinuation rates, but side effect profiles varied significantly. Data were insufficient for determining the efficacy of newer antidepressants for subsyndromal depression, depression with coexisting medical or psychiatric illness, or depression in adolescents.

Conclusions: Newer antidepressants are clearly effective in treating depressive disorders in diverse settings. Because of similar efficacy, both newer and older antidepressants should be considered when making treatment decisions. Better information is urgently needed on the efficacy of newer antidepressants in patients with nonmajor depression and in special populations, including adolescents.

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 (12). 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 (45).

In the late 1980s, the U.S. Department of Health and Human Services sponsored the development of standard treatment guidelines for major depression (67). 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, 811). 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.

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, 68, 10, 1254). 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; γ-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 Jump PlaceholderTable 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 (5556).

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.

2.1 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 Jump PlaceholderTable 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], standardized to the 17-item Hamilton Depression Rating Scale). Epidemiologic studies in primary care settings have usually shown that patients with major depression have less severe symptoms than do patients in these trials (5961).

Three types of therapy for major depressive disorder have proven efficacy: pharmacotherapy, psychotherapy, and electroconvulsive therapy (6, 12, 55, 6266). Pharmacotherapy is the therapy most often given directly by internists [67]. To aid selection from the large number of pharmacotherapies available, we review 1) the efficacy of newer pharmacotherapies compared with placebo and 2) the relative efficacy and rates of adverse effects of newer and older antidepressants and of different classes of newer antidepressants.

2.2.1 Newer Antidepressants Compared with Placebo

Eighty-one trials involving more than 10 000 adults with major depression compared newer antidepressant drugs with placebo. In most trials, more than 50% of participants had histories of previous depressive episodes. Selective serotonin reuptake inhibitors are the best studied agents (43 studies), followed by serotonin norepinephrine reuptake inhibitors (12 studies), reversible inhibitors of monoamine oxidase A (10 studies), 5-HT2 receptor antagonists (9 studies), 5-HT1a receptor agonists (3 studies), and dopamine reuptake inhibitors (3 studies) (Figure 1). No studies that compared combinations of newer antidepressants plus another antidepressant or an anxiolytic were identified. Trials were conducted in 15 countries, and most participants were recruited from outpatient mental health settings. Overall, 51% of participants randomly assigned to active treatment and 32% of participants who received placebo experienced at least a 50% improvement in depressive symptoms.

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Figure 1.
Meta-analysis of placebo compared with newer antidepressants for major depression in adults.Nn

indicates number of participants; indicates number of studies. GABA = γ-aminobutyric acid; HT = hydroxy-tryptophan; RIMA = reversible inhibitor of monoamine oxidase A; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and noradrenaline reuptake inhibitor.

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As a group, newer antidepressants were significantly more efficacious than placebo (relative benefit, 1.6 [CI, 1.5 to 1.7]). Except for the GABAmimetic fengabine, the efficacy of different antidepressant classes was similar (Figure 1). Within classes, individual agents had similar efficacy. Funnel plots constructed by using the Beggs rank-order correlation test were statistically significant (P = 0.002), indicating possible publication bias (68). These data prove that newer antidepressants are more efficacious than placebo for treatment of major depression in adults, although the magnitude of the effect may be somewhat overestimated because of publication bias.

2.2.2 Newer Antidepressants Compared with Older Antidepressants

In 150 studies involving more than 16 000 participants, newer antidepressants were compared with older antidepressants. More than half of the studies were conducted in Europe. Among newer agents, SSRIs were the most extensively tested; they have been compared with older agents (97 studies), serotonin norepinephrine reuptake inhibitors (14 studies), reversible inhibitor of monoamine oxidase A (26 studies), norepinephrine reuptake inhibitors (2 studies), 5-HT2 receptor antagonists (6 studies), and dopamine reuptake inhibitor (5 studies). Comparisons with first-generation tricyclic antidepressants were most frequent (122 studies), followed by comparisons with tetracyclic antidepressants (14 studies), second-generation tricyclic antidepressants, trazodone (8 studies), and monoamine oxidase inhibitors (2 studies). The outpatient mental health setting was most common: Seventeen studies recruited participants from primary care settings.

As a group, 54% of patients randomly assigned to receive a newer antidepressant and 54% of those assigned to receive an older antidepressant experienced at least a 50% improvement in depressive symptoms (relative benefit, 1.0 [CI, 0.97 to 1.06]). Comparisons within individual classes of newer and older antidepressants (Figure 2) showed no significant differences, except for three studies comparing a serotonin norepinephrine reuptake inhibitor with trazodone that showed a modestly greater effect for the serotonin norepinephrine reuptake inhibitor (relative benefit, 1.2 [CI, 1.0 to 1.4]).

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Figure 2.
Meta-analysis of older antidepressants compared with newer antidepressants for major depression in adultsNn

. indicates number of participants; indicates number of studies. HT = hydroxy-tryptophan; MAOI = monoamine oxidase inhibitor; NRI = norepinephrine reuptake inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and noradrenaline reuptake inhibitor; TCA1 = first-generation tricyclic antidepressant; TCA2 = second-generation tricyclic antidepressant.

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2.2.3 Comparisons between Newer Antidepressants

Newer antidepressants have been compared directly in 32 studies involving more than 4000 participants. Studies were conducted predominantly in Europe. Participants were recruited primarily from inpatient settings; no study reported recruitment from primary care settings. Comparisons were made between an SSRI and another newer agent (17 studies), two SSRIs (14 studies), and a reversible inhibitor of monoamine oxidase A and norepinephrine reuptake inhibitor (1 study).

Serotonin reuptake inhibitors and other newer antidepressants were equally efficacious; 53% of participants experienced at least a 50% improvement in depressive symptoms. Ten studies that reported response rates compared two SSRIs; 8 involved a comparison with fluoxetine. There was a trend for fluoxetine to be slightly less effective (relative benefit, 0.9 [CI, 0.8 to 1.0]) than the comparator SSRI (citalopram, sertraline, and paroxetine). However, analysis of the mean changes in depressive symptom scores showed no significant difference between fluoxetine and other SSRIs.

2.2.4 Dropout Rates and Symptom-Specific Adverse Effects

Patients may discontinue treatment for various reasons, including lack of effect, adverse effects, and the burden of complying with a study protocol. Overall dropout rates reflect these reasons in aggregate and may be lower in carefully controlled trials than in clinical practice. The rate of dropout due to adverse effects measures perceived intolerable adverse effects and represents a feasible method of comparing major adverse effects across drug classes. Another method of reporting adverse effects is overall rates of specific symptoms. Because trials differed greatly in their methods of collecting and reporting symptom-specific rates, these data should be interpreted with caution. For precision and feasibility reasons, we limited the analyses of dropout rates and adverse effects to trials that were 12 weeks or shorter and to drug classes for which dropout data from at least 10 trials were available.

Overall dropout rates did not differ significantly for any of the four drug classes being compared (Table 3). Dropout rates were higher in trials with weekly scheduled follow-up (31%) than in trials with follow-up conducted every other week (22%). Dropouts due to adverse effects were statistically significantly higher for first-generation tricyclic antidepressants than SSRIs (16% and 11%; difference, 5 percentage points [CI, 2 to 6 percentage points]) and for first-generation tricyclic antidepressants compared with reversible inhibitors of monoamine oxidase A (11% and 5%; difference, 6 percentage points [CI, 3 to 7 percentage points]). Significantly more participants taking an SSRI than those receiving placebo discontinued treatment because of adverse effects (risk difference, 5.5 percentage points more than placebo [CI, 3.4 to 7.6 percentage points]). Dropouts did not significantly differ for SSRIs compared with second-generation tricyclic antidepressants or tetracyclic antidepressants.

Adverse effects that were significantly more common with SSRIs than with tricyclic antidepressants were diarrhea (12% and 3%), headache (15% and 11%), insomnia (13% and 6%), and nausea (19% and 9%). Adverse effects that were significantly more common for tricyclic antidepressants than for SSRIs were blurred vision (10% and 6%), constipation (21% and 8%), dizziness (19% and 8%), dry mouth (48% and 18%), tremors (11% and 7%), and urinary disturbance (8% and 3%). Few trials (11%) gave rates of sexual dysfunction, and those that did reported diverse symptoms (for example, nonspecific sexual symptoms, ejaculatory abnormality, decreased libido, or anorgasmia). Realistic estimates of incidence rates and quantitative comparisons between antidepressants could not be made.

The potential for increased risk for suicide deserves special mention because of its seriousness. Two cohort studies and seven reviews of trials have shown a trend toward lower risk for suicide in patients treated with SSRIs (6977). This effect is presumably due to treatment of the underlying depression. In the event that depressed patients attempt suicide by drug overdose, the SSRIs are judged to be relatively less likely than other antidepressants to be lethal (7879). However, overdoses with any of these agents can be fatal.

2.2.5 Summary

In summary, substantial data prove the short-term efficacy of newer antidepressants for major depression in adults. Newer antidepressants are equally efficacious compared with first- and second-generation tricyclic antidepressants. Trials comparing different classes of newer antidepressants show no differences in efficacy. Overall dropouts do not differ between newer and older agents, but dropouts due to adverse effects are slightly higher for first-generation tricyclic antidepressants than for reversible inhibitors of monoamine oxidase A and SSRIs. Some specific adverse effects are more common with older agents, whereas others are more common with newer agents.

2.3 Major Depression: Newer Antidepressants for Relapse Prevention

If treatment is discontinued soon after recovery, approximately 25% of patients will experience relapse within 2 months. Because of the high rate of relapse, continued treatment is recommended beyond initial recovery (7). For treatments with established short-term efficacy, a critical test of overall efficacy is the ability to maintain remission in the long term. Six studies involving 910 adults with major depression who had responded to treatment compared an SSRI (citalopram, fluoxetine, paroxetine, or sertraline) with placebo. Two additional studies compared two SSRIs or an SSRI with lithium. In three studies, participants met criteria for recurrent major depression, which placed them at higher risk for relapse.

Ten percent of participants randomly assigned to receive active treatment experienced a relapse within 24 weeks. The average relapse rate for participants given placebo antidepressants was 35%. Newer antidepressants were significantly more effective than placebo in preventing relapse (relative benefit, 0.3 [CI, 0.2 to 0.5]). In two placebo-controlled studies with extended follow-up, the advantage of antidepressants over placebo was maintained at 44 and 52 weeks. Relapse rates did not differ in the one study that compared two SSRIs (80). However, fluvoxamine was more effective than lithium in preventing relapse (13% and 25%; relative benefit, 0.5 [CI, 0.3 to 0.9]) (81). Among placebo-controlled trials, all but one study continued treatment at or above the dose to which the patient had initially responded. The one study in which treatment was continued at a lower dose had a higher but not statistically significantly different relapse rate (82).

These data show that SSRIs are efficacious for preventing relapse for up to 6 months. At least nine studies have shown similar results for the first-generation tricyclic antidepressants amitriptyline and imipramine (7). Few data are available on the efficacy of newer antidepressants for longer-term maintenance-phase treatment. No studies have compared newer antidepressants with older agents or psychosocial therapies.

2.4. Nonmajor Depression

Dysthymia, a chronic mood disorder associated with significant functional impairment, occurs in approximately 3% of persons (57). It is characterized by a chronically depressed mood that is present on more days than not for a period of at least 2 years. During periods of depressed mood, at least two of the following additional symptoms are present: appetite disturbance, insomnia or hypersomnia, decreased energy or fatigue, low self-esteem, decreased concentration or difficulty making decisions, or feelings of hopelessness.

Subsyndromal depression is an acute mood disorder that is less severe than major depression. It is associated with an increased risk for major depression, decreased functioning, and high use of health services. It is characterized by at least 2 weeks of depressed mood or loss of interest or pleasure in nearly all activities. In addition, the person must experience one to three of the vegetative or psychological symptoms used to diagnose major depression. Other commonly used names for subsyndromal depression are minor depression, subclinical depression, and subthreshold depression.

2.4.1. Newer Antidepressants for Dysthymia

Nine trials involving 1420 adults compared newer antidepressants with placebo (5 studies), first-generation tricyclic antidepressants (5 studies), an antipsychotic (1 study), or another newer antidepressant (1 study) (Figure 3). All studies were conducted in outpatient settings, and most recruited participants from mental health specialty clinics (6 studies). Selective serotonin reuptake inhibitors (3 studies), a dopamine antagonist (1 study), and a 5-HT2 receptor antagonist (1 study) were compared with placebo. Sertraline (an SSRI), ritanserin (a 5-HT2 receptor antagonist [2 studies]), amisulpride (a dopamine antagonist), and minaprine were compared with first-generation tricyclic antidepressants. No trials were longer than 12 weeks in duration.

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Figure 3.
Meta-analysis of newer antidepressants for dysthymia in adults.N

indicates number of participants. *Response rates not given. HT = hydroxy-tryptophan; SSRI = selective serotonin reuptake inhibitor.

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Among patients randomly assigned to receive a newer antidepressant, 59% experienced at least a 50% improvement in depressive symptoms. The respective response rates for participants given a first-generation tricyclic antidepressant or placebo were 59% and 37%. Newer antidepressants were significantly more efficacious than placebo (relative benefit, 1.7 [CI, 1.3 to 2.3]) but were similar to first-generation tricyclic antidepressants (relative benefit, 1.0 [CI, 0.9 to 1.2]) (Figure 3). Overall dropout rates were similar, but rates of dropout due to adverse effects were significantly lower for newer antidepressants (4%) than for first-generation tricyclic antidepressants (9%) (risk difference, 5 percentage points [CI, 0.1 to 10 percentage points]).

Relatively few trials have consistently shown a beneficial effect of newer antidepressants compared with placebo. Compared with older antidepressants, newer agents have similar efficacy and result in fewer dropouts due to adverse effects; the difference in dropout rates is small but statistically significant. These trials prove the short-term efficacy of newer antidepressants for improving depressive symptoms in patients with dysthymia. Effects on social functioning, work performance, or ability to carry out daily activities are not clear. Despite the chronic nature of this illness, the magnitude of the beneficial effects is similar to that seen for major depression.

2.4.2 Newer Antidepressants for Subsyndromal Depression

Three trials involving 392 patients evaluated newer antidepressants in adults with subsyndromal depression. All were conducted in outpatient settings; one was a mental health specialty practice, one was a mixed primary care and mental health practice, and one was described as “outpatient.” A single placebo-controlled study was conducted in 130 patients 60 to 85 years of age (89). In this study, 60% of patients randomly assigned to receive minaprine (a miscellaneous antidepressant not available in the United States), 200 mg/d, showed global “improvement” compared with 39% of participants given placebo. Social functioning was also improved. There were no dropouts due to adverse effects. The largest trial (245 participants) compared paroxetine, 20 to 40 mg/d, with maprotiline, 100 to 150 mg/d (90). Response rates were high for both medications (77% for paroxetine and 69% for maprotiline) and did not differ significantly. A small trial (17 participants) with high dropout rates compared moclobemide (a reversible inhibitor of monoamine oxidase A) with low-dose (75 mg/d) amitriptyline (a tricyclic antidepressant) (91). This study was too small to detect clinically significant differences between treatment groups, and the dose of amitriptyline may have been inadequate.

Collectively, these few trials provide limited empirical data to guide management of patients with subsyndromal depression. Data are insufficient to determine whether therapy with newer antidepressant drugs is better than placebo. No trial has compared antidepressant drug therapy with psychosocial therapy, a reasonable alternative for some patients with milder forms of depression.

2.5 Herbal Remedies for Depressive Disorders

Some patients are reluctant to take traditional antidepressant medications or engage in psychotherapy. In such patients, herbal treatments are a potential alternative. Hypericum (St. John's wort), valeriana, and kava kava have all been proposed as therapy for depression. St. John's wort accounts for about 10% of all herbal medicine sales in the United States and has been dubbed by some as “nature's own Prozac” (92).

2.5.1 Hypericum (St. John's Wort)

Fourteen trials involving 1417 adults compared hypericum with placebo (8 studies) or first-generation tricyclic antidepressants (6 studies) (Figure 4). None compared hypericum with newer antidepressants. Dosages of hypericum extract varied from 300 mg/d to 1800 mg/d; three trials evaluated combinations of hypericum with other extracts, such as valeriana. First-generation tricyclic antidepressants compared with hypericum were amitriptyline (30 to 150 mg/d), desipramine (100 mg/d), and imipramine (75 mg/d). Psychiatrists and primary care physicians recruited participants, all of whom were outpatients. The trials involved multiple depressive disorders, including major depression (6 studies), dysthymia or minor depression (4 studies), “depressed mood” (2 studies), and a heterogeneous group of depressions (2 studies).

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Figure 4.
Meta-analysis of hypericum (St. John's wort) for depressive disorders in adults.N

indicates number of participants. The diamonds represent a summary estimate, derived from the individual studies listed above the diamonds. The center of each diamond is the point estimate, and the tails represent the 95% CIs.

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Sixty-two percent of participants given single preparations of hypericum extract experienced at least a 50% improvement in symptoms. Response rates for participants given placebo and older, low-dose tricyclic antidepressants were 38% and 61%, respectively. Hypericum extracts were significantly more effective than placebo (relative benefit, 1.9 [CI, 1.2 to 2.8]) but were similar to older tricyclic agents given in low doses (relative benefit, 1.2 [CI, 1.0 to 1.4]) (Figure 4). Tests indicated publication bias (P = 0.009), suggesting that positive results of hypericum therapy were systematically reported and that the treatment effect may be overestimated. Two trials of hypericum in combination with valeriana showed no significant difference from tricyclic antidepressants. Dropout rates due to adverse effects were 6% for hypericum and 7% for low-dose tricyclic antidepressants. Since these data were analyzed, a new study compared a standard preparation of hypericum (350 mg three times daily) with imipramine (100 mg/d) and placebo in 263 general practice patients with major depression (104). Hypericum was more effective than placebo and at least as effective as imipramine in improving mood and mental health functioning.

In summary, hypericum seems to be more effective than placebo for short-term treatment of mild to moderately severe depressive disorders. However, evidence on the efficacy of hypericum is incomplete. The preparations used in these trials may not be representative of the products currently being sold in the United States as dietary supplements, and data on the effectiveness of hypericum compared with newer agents are sparse. To address some of these issues, the National Institute of Mental Health is currently sponsoring a trial comparing St. John's wort with placebo and an SSRI.

2.6 Efficacy of Newer Antidepressants in Special Populations

Most antidepressants are evaluated in patient populations that may differ significantly from the patients encountered in internal medicine practices. These differences may affect treatment response, adherence to treatment, or rates of adverse effects. For example, many trials exclude patients with serious coexisting medical or psychiatric illnesses that may affect the course of depression. Most trials are limited to adults 18 to 65 years of age. Elderly persons, who may have more medical illness and greater risk for drug-drug and drug-disease interactions, are not often studied. Likewise, primary care patients, who may differ from patients recruited in mental health settings in their willingness to acknowledge depression, accept treatment, and tolerate adverse effects, are not often studied (Table 4).

Table Jump PlaceholderTable 4.  Treatment Trials of Newer Pharmacotherapies in Special Populations
2.6.1 Efficacy in Patients with Coexisting Medical or Psychiatric Illness

Ten trials involving 484 adults evaluated newer antidepressants for treatment of depression in patients with specific comorbid medical and psychiatric illnesses. Several conditions were examined, including alcoholism, the chronic fatigue syndrome, HIV infection, ischemic heart disease, renal failure, and stroke. Depressive disorders studied included major depression, dysthymia, adjustment disorder with depressed mood, atypical depression, and other, unspecified types of depression. Newer agents evaluated included SSRIs, reversible inhibitors of monamine oxidase, and selective norepinephrine reuptake inhibitors. Eight comparisons were made with placebo, four were made with older agents, and no direct comparisons were made with newer agents.

This heterogeneous group of studies with small sample sizes showed mixed effects. In placebo-controlled trials, four studies showed a greater response for the newer antidepressant and four showed no significant difference from placebo. Trials comparing newer and older antidepressants showed no significant difference in response rates. There were too few studies to determine the efficacy or superiority of particular antidepressant treatments in patients with serious coexisting medical or psychiatric conditions or whether efficacy varies for different coexisting illnesses.

2.6.2 Efficacy in Elderly Persons

Twenty-seven trials involved 3929 persons older than 60 years of age. Most participants were outpatients with major depression. Two small trials involved physically ill inpatients; 1 included 46 physically frail elderly persons receiving nursing home care. Ten comparisons were made between newer agents and placebo; most other comparisons were between a newer agent (10 studies of an SSRI, 4 studies of a reversible inhibitor of monoamine oxidase A, and 2 studies of a serotonin norepinephrine reuptake inhibitor) and a first-generation tricyclic antidepressant.

Approximately 50% of elderly persons receiving newer antidepressants had at least a 50% improvement in depressive symptoms. The average response rate for older patients given placebo was 30%; the average response rate to older agents was 54%. Newer antidepressants were significantly more efficacious than placebo (relative benefit, 1.4 [CI, 1.2 to 1.6]) and had efficacy similar to that of older agents (relative benefit, 1.0 [CI, 0.9 to 1.1]). No specific class of newer agents, including SSRIs, reversible inhibitors of monoamine oxidase A, and norepinephrine reuptake inhibitors, were superior to tricyclic agents. Overall dropout rates and rates of dropout due to adverse effects did not differ significantly between newer and older antidepressants. The three small trials in physically frail elderly persons compared fluoxetine (an SSRI), 20 mg/d, with placebo; sulpiride (a dopamine antagonist), 200 mg/d, with placebo; and fluvoxamine (an SSRI), 150 mg/d, with dothiepin (a tricyclic antidepressant), 150 mg/d. None of these trials showed significant differences between groups.

These data show that newer antidepressant drugs are better than placebo in treating major depression in relatively healthy older adults. The magnitude of effect is similar to that seen in younger populations. Newer agents are not associated with greater effect, fewer total dropouts, or fewer dropouts due to adverse effects than are older tricyclic antidepressants.

2.6.3 Efficacy in Children and Adolescents

Three trials evaluated the efficacy of newer antidepressants in children or adolescents (or both) with major depression. All examined acute-phase (6- to 8-week) treatment in participants who, on average, were 14 years of age; 43% of participants were female. One trial (40 participants) compared fluoxetine (20 to 60 mg) with placebo (105). At follow-up, the groups did not significantly differ in mean number of depression symptoms or psychosocial functioning. A second trial compared fluoxetine (20 mg/d) with placebo in 96 patients with severe, persistent major depression (106). Significantly more patients assigned to fluoxetine were much or very much improved (56%) compared with those assigned to placebo (33%). Overall discontinuation rates and rates of dropout because of lack of efficacy were significantly lower for the fluoxetine group. The third trial (40 participants) compared a combination of venlafaxine (a serotonin norepinephrine reuptake inhibitor) and psychotherapy with a combination of placebo and psychotherapy (107). Both treatments improved depressive symptoms, but the groups did not significantly differ with regard to improvement.

In summary, few trials have examined the efficacy of newer antidepressants in children and adolescents, providing only limited data to help clinical decision making (108).

2.6.4 Efficacy in Primary Care Patients

Twenty-seven trials evaluating newer agents involved 5540 adult primary care patients. Most compared newer agents (SSRIs, serotonin norepinephrine reuptake inhibitors, reversible inhibitors of monoamine oxidase A, and dopamine antagonists) with first- or second-generation tricyclic agents. Multiple depressive disorders were studied: major depression (12 studies); “depression requiring treatment,” as judged by the primary care provider (4 studies); mixed-anxiety depression (3 studies); dysthymia (2 studies); endogenous depression (1 study); and heterogeneous patient groups with depressive illness that included more than one disorder (4 studies). Except in a large trial from a U.S. staff-model health maintenance organization and two trials in frail elderly persons, patients with “serious” concomitant medical illnesses were excluded.

Approximately 60% of the primary care participants who received newer antidepressants had at least a 50% improvement in symptoms. Response rates did not differ significantly between newer agents except for minaprine, for which two studies showed lower response rates of approximately 34%. The average response rate for patients given placebo was 35%; average response rates for patients given tricyclic antidepressants was 60%. Newer antidepressants were significantly more efficacious than placebo (relative benefit, 1.6 [CI, 1.2 to 2.1]) but similar to tricyclic antidepressants (relative benefit, 1.0 [CI, 0.9 to 1.1]). Dropouts due to adverse effects occurred in 2%, 8%, and 13% of patients given placebo, newer agents, and tricyclic antidepressants, respectively. In the 6-month U.S. health maintenance organization trial, patients assigned to receive fluoxetine (an SSRI) reported fewer adverse events, were more likely to continue taking their original medication, and were more likely to reach adequate doses than were patients assigned to desipramine (a second-generation tricyclic) or imipramine (a first-generation tricyclic). Depressive symptoms, quality of life, and total health care costs did not differ significantly between groups.

These data show that newer antidepressants are more efficacious than placebo in treating depressive disorders in adults in primary care settings. For adults without serious concomitant medical illness, the efficacy of antidepressants is as good or better in patients recruited from primary care settings compared with those recruited from mental health settings. Multiple agents are effective.

Many trials have evaluated the efficacy of newer pharmacotherapies for depressive disorders. Information is most thorough for major depression, an illness with substantial personal and societal costs. Trials show that newer antidepressants are more efficacious than placebo and have efficacy similar to that of older agents. Treatments are effective in primary care patients and in older persons. For patients with recurrent depression and those with moderately severe major depression, continued treatment after recovery decreases short-term relapse rates. Fewer trials show efficacy for newer antidepressants in treating dysthymia, a more chronic, less symptomatic depression.

These data are clearly useful for guiding selection of antidepressant treatment. However, the effective use of antidepressants involves consideration of several pragmatic issues. First, the high dropout rates observed in these studies (30% on average) are paralleled by high rates of therapy discontinuation in naturalistic studies. Frequent in-person or telephone follow-up visits to titrate medication, monitor symptoms, and address adverse effects have been a common component of interventions shown to improve medication adherence and patient outcomes (109112). Education about the following factors may improve adherence: taking medication daily, expecting the medication to take 2 to 4 weeks to produce a noticeable effect, continuing therapy even when feeling better, not stopping therapy without checking with a physician, and what to do if questions arise (113). A second issue is antidepressant dosing. Studies have shown that underdosing of antidepressants is common, particularly for tricyclic antidepressants (114116). To replicate the benefits of antidepressant medication observed in clinical trials, physicians need to work with their patients to achieve therapeutic doses. For some drugs, this will involve dose titration. Finally, adherence to therapy is related to adverse medication effects. Although the rate of dropout due to adverse effects differed only slightly between some drug classes, specific adverse effects differed between older and newer agents. The consequences of specific adverse effects for individual patients (for example, dizziness in an elderly patient with poor balance or nausea in a patient with dyspepsia) may aid drug selection.

Despite the large number of clinical trials, clinically important questions remain. For major depression, most studies were short-term, focused exclusively on relief of depressive symptoms, and were conducted under rigorously controlled conditions necessary to evaluate efficacy. Longer-term trials that could provide more informative data on adverse effects and the sustainability of beneficial effects are lacking. Although effects on depressive symptoms are clear, effects on functional status and health-related quality-of-life outcomes are not well described. “Effectiveness” studies are needed to evaluate the relative benefits of treatments under usual clinical conditions. This may be particularly true for persons in ethnic minority groups, who may have different beliefs about depression and its treatment. In addition, several pragmatic issues need further study. Data are insufficient to determine whether combinations of antidepressants or antidepressants plus psychosocial treatments are more effective than treatment with an antidepressant alone. The relative benefits of St. John's wort compared with newer antidepressants need to be evaluated further. There are too few studies to guide selection of antidepressants for patients in whom an initial course of treatment fails. We need better data on the efficacy of antidepressants in patients with chronic coexisting illness, such as cardiovascular disease or alcohol abuse, that may alter response to treatment. Ideally, drug selection would be tailored to individual patients to maximize benefit and minimize harm on the basis of clinical and demographic information. Currently, data are insufficient to allow this informed decision making, in part because reporting of patient characteristics from clinical trials is incomplete.

Research priorities for nonmajor depression and herbal therapies are equally important. In primary care settings, the prevalence of subsyndromal depression and dysthymia is high. Large, high-quality treatment trials are needed to better evaluate the effects of antidepressants for these illnesses. Finally, the paucity of trials in children and adolescents is a particularly important gap in evidence. Suicide is one of the most common causes of death in late adolescence and is frequently related to depression. Treatment trials in these groups are urgently needed.

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Figures

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Figure 1.
Meta-analysis of placebo compared with newer antidepressants for major depression in adults.Nn

indicates number of participants; indicates number of studies. GABA = γ-aminobutyric acid; HT = hydroxy-tryptophan; RIMA = reversible inhibitor of monoamine oxidase A; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and noradrenaline reuptake inhibitor.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Meta-analysis of older antidepressants compared with newer antidepressants for major depression in adultsNn

. indicates number of participants; indicates number of studies. HT = hydroxy-tryptophan; MAOI = monoamine oxidase inhibitor; NRI = norepinephrine reuptake inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin and noradrenaline reuptake inhibitor; TCA1 = first-generation tricyclic antidepressant; TCA2 = second-generation tricyclic antidepressant.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Meta-analysis of newer antidepressants for dysthymia in adults.N

indicates number of participants. *Response rates not given. HT = hydroxy-tryptophan; SSRI = selective serotonin reuptake inhibitor.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Meta-analysis of hypericum (St. John's wort) for depressive disorders in adults.N

indicates number of participants. The diamonds represent a summary estimate, derived from the individual studies listed above the diamonds. The center of each diamond is the point estimate, and the tails represent the 95% CIs.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Classification and Dosage Range of Antidepressants
Table Jump PlaceholderTable 2.  Treatment Trials of Newer Antidepressants and Herbal Remedies
Table Jump PlaceholderTable 4.  Treatment Trials of Newer Pharmacotherapies in Special Populations

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Simon GE, VonKorff M, Heiligenstein JH, Revicki DA, Grothaus L, Katon W, et al..  Initial antidepressant choice in primary care. Effectiveness and cost of fluoxetine vs tricyclic antidepressants. JAMA. 1996; 275.1897-902
 
Rost K, Nutting P, Smith J, Werner J.  Primary care intervention improves depression outcomes. Int J Psychiatry Med. 1998; 28.398-9
 
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Katon W, von Korff M, Lin E, Bush T, Ormel J.  Adequacy and duration of antidepressant treatment in primary care. Med Care. 1992; 30.67-76
 

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NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

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