Pharmacologic Treatment of Acute Major Depression and Dysthymia: Clinical Guideline, Part 1

The numbers in square brackets are cross-references to the numbered sections in the accompanying background paper, A Systematic Review of Newer Pharmacotherapies for Depression in Adults: Evidence Report Summary, which is part 2 of this guideline (see pages 743-756). Major depression and dysthymia are two of the most common and debilitating illnesses. The World Health Organization estimates that worldwide, major depression is the fourth leading cause of loss of disability-adjusted life-years. Major depression is a clinical syndrome lasting at least 2 weeks, during which the patient experiences either depressed mood or anhedonia plus at least five of the following symptoms: depressed mood most of the day, nearly every day; markedly diminished interest or pleasure in most activities most of the day; significant weight loss or gain or appetite disturbance; insomnia or hypersomnia; psychomotor agitation or retardation; inappropriate guilt; diminished ability to think or concentrate, or indecisiveness; or recurring thoughts of death, including suicidal ideation. Dysthymia, by contrast, is a chronic but mild depressive disorder found in approximately 3% of community populations. It also causes significant impairment and is characterized by depressed mood, less severe than that in major depression, that is present on more days than not for 2 years. During this period, two of the following symptoms must also be present: appetite disturbance, insomnia or hypersomnia, decreased energy or fatigue, low self-esteem, decreased concentration or difficulty making decisions, or feelings of hopelessness. This guideline is based on an evidence report on pharmacotherapies for depression from the San Antonio Evidence-based Practice Center that was commissioned by the Agency for Healthcare Research and Quality (1). It answers the following questions: What is the evidence supporting the benefits of pharmacologic treatment? What are the data on the efficacy and side effect profiles of newer compared with older pharmacotherapies? How can the evidence assist physicians and patients in making informed decisions about treatment options? 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. Persons of all ages, ethnicities, and socioeconomic status experience the burden of depression. The prevalence of depressive disorders varies; it is lowest in community samples, intermediate in outpatient populations, and highest in inpatient settings. Because of the increasing prevalence of depression worldwide, especially in elderly persons, primary care physicians can expect to encounter and screen more patients with this condition (2) [2.2]. Three types of therapies have proven efficacy for depressive disorders: pharmacotherapy, psychotherapy, and electroconvulsive therapy. Because pharmacotherapy is the main tool of the primary care physician, it forms the focus of this guideline. Clinicians are faced with a multitude of antidepressants to choose from. These include older agents, such as the first- and second-generation tricyclic antidepressants, heterocyclics, and monoamine oxidase inhibitors. During the past decade, several newer classes of antidepressants have become available. The most notable of these is selective serotonin reuptake inhibitors (SSRIs). Lesser-known new agents include serotonin and noradrenaline reuptake inhibitors; selective norepinephrine reuptake inhibitors; reversible inhibitors of monoamine oxidase; 5-hydroxy-tryptophan2 (5-HT2) receptor antagonists; 5-HT1a receptor agonists; -aminobutyric acid mimetic agents; dopamine reuptake inhibitors; dopamine antagonists; and herbal remedies, such as hypericum (St. John's wort). In general, clinicians believe that the newer antidepressants, particularly SSRIs, are more efficacious, have a more benign side effect profile, and are better tolerated by patients. The San Antonio Evidence-based Practice Center found a sufficient number of randomized, controlled clinical trials and meta-analyses to evaluate the efficacy of treatment of acute major depression and dysthymia. The researchers systematically reviewed the literature and gathered evidence from 315 trials selected from 1277 relevant citations. The evidence was sufficient to evaluate treatment in adult primary care settings and in elderly patients with no comorbid conditions, but it was insufficient to evaluate treatments of other depressive disorders, such as subsyndromal depression and refractory depression. Similarly, evidence was insufficient to evaluate the treatment of depression in adolescents or patients with comorbid psychiatric conditions [1]. The primary outcome measures used in the clinical trials to assess drug efficacy were scores on the Hamilton Rating Scale for Depression, the Montgomery Asberg Depression Rating Scale, or the Clinical Global Impression Scale. These scales provide valid and reliable assessment of severity of depression and treatment-associated variations in severity. Most studies did not assess functional status or quality of life. Clinical improvement was defined as a 50% or greater improvement in score on the Hamilton Rating Scale for Depression or Montgomery Asberg Depression Rating Scale or much to very improved on the Clinical Global Impression Scale. The Evidence-based Practice Center computed response rates by using a modified intention-to-treat approach, in which the number of patients who continued treatment and got better was divided by the total number of patients who were randomly allocated. This method produces a conservative estimate of treatment effect because some patients who discontinued treatment may have improved. Is Pharmacologic Treatment of Depression Beneficial? Previous systematic reviews of the literature have shown that first- and second-generation tricyclic antidepressants are more efficacious than placebo for treating mood disorders (3). The Evidence-based Practice Center report found evidence that valid conclusions could be drawn about the comparative efficacy of SSRIs, serotonin and noradrenaline reuptake inhibitors, reversible inhibitors of monoamine oxidase, 5-HT2 receptor antagonists, and St. John's wort. Compared with placebo, treatment with these classes of drugs resulted in clinically and statistically significant improvement of acute major depression [2.2. 1, 2.5. 1]. In primary care settings, the average treatment response difference was 25%, and in elderly persons without comorbid conditions, the difference was 20%. The combined average treatment response difference was approximately 20%. In addition, for treating dysthymia, the effect difference of SSRIs compared with that of placebo (59% and 37%) was clinically and statistically significant [2.4. 1]. Are Newer Drugs or Herbs Better Than Older Drugs in Treating Depression? In 150 clinical trials involving more than 16 000 participants, 154 comparisons were made between newer and older antidepressants [2.2.2]. Fifty of these studies compared SSRIs with first- and second-generation tricyclic antidepressants [2.2.2], 14 studies compared two SSRIs [2.2. 3], and 14 studies involving more than 1400 patients compared St. John's wort with placebo and first-generation tricyclic antidepressants [2.5. 1]. No clinically or statistically significant differences in efficacy were found within SSRIs or between SSRIs and tricyclic antidepressants for treatment of major depression. However, for treating dysthymia, sufficient evidence was available for evaluation of only two SSRIsfluoxetine and sertralineand for ritanserin, a 5-HT2 receptor antagonist that is not available in the United States [2.4. 1]. St. John's wort has been shown to be more efficacious than placebo; whether it is as efficacious as tricyclic antidepressants given in adequate doses has not been established. Dosages of tricyclic antidepressants may have been subtherapeutic, and statistical evidence indicated publication bias in the St. John's wort studies. Side Effect Profiles and Patient Preference Selection of antidepressant agents is based in part on such criteria as anticipated tolerance and adverse effects. In the clinical trials, overall dropout rates did not differ significantly between active treatments. The rate of dropout due to adverse effects was slightly higher (and statistically significant) for first-generation tricyclic antidepressants than for SSRIs (16% compared with 11%; difference, 5 percentage points [95% CI, 2 to 6 percentage points]). No differences in adverse effect-related dropout rates were found between second-generation tricyclic antidepressants and SSRIs. Only 1.5% of persons taking St. John's wort discontinued use because of adverse effects, which were not well described. In this review, adverse effects were assessed and reported by using different methods, and few trials differentiated emergent from preexisting symptoms [2.2.4]. The Table lists the 11 most common adverse effects found for SSRIs and tricyclic antidepressants. Table. The 11 Most Common Adverse Effects of Selective Serotonin Reuptake Inhibitors and Tricyclic Antidepressants Rates of blurred vision, constipation, dizziness, dry mouth, and tremors were significantly higher with use of tricyclic antidepressants. Rates of diarrhea, headache, insomnia, and nausea were significantly higher with use of SSRIs (Figure). Evidence indicates that some adaptation to nausea and dizziness occurs after 4 to 6 weeks of treatment with SSRIs (4). In clinical practice, patients report that sedation is also a common side effect, but it was not mentioned in the studies [2.2.4]. Figure. Adverse effects of selective serotonin reuptake inhibitors ( striped bars ) and tricyclic antidepressants ( white bars ). Other important side effects of both classes of drug include sexual dysfunction and suicide attempts. Fewer than 10% of the trials explicitly reported suicide attempts an