Guideline: Acute Phase 4 Management with Medication Indications for Acute Phase Medication Guideline: Medications have been shown to be effective in all forms of major depressive disorder. Barring contraindications to these agents, antidepressant medications are first-line treatments for major depressive disorder when: ■The depression is moderate to severe. ■There are psychotic, melancholic, or atypical (overeating, oversleeping, weight gain) symptom features. ■ The patient requests medication. ■ Psychotherapy by a trained, competent psychotherapist is not available. ■ The patient has shown a prior positive response to medication. ■ Maintenance treatment is planned. Absence of these indicators does not predict medication failure. However, when these indications are present, there is high likelihood of a beneficial response to medication. (Strength of Evidence = A.) Individual patient considerations for acute phase medication are summarized in Table 3. The rationale for these recommendations is as follows: ■ For severe and psychotic depressions, there is strong evidence for the efficacy of medication and little or none for the efficacy of psychotherapy alone. There have been no randomized controlled trials of psychotherapy in patients with major depressive disorder with atypical symptom features, but placebo-controlled randomized controlled trials do indicate that antidepressant medications are effective (especially the monoamine oxidase inhibitors [MAOIS]). ■ Maintenance medication clearly prevents recurrences, while, to date, maintenance psychotherapy does not (Frank, Kupfer, Perel, et al., 1990). For virtually all patients, the practitioner who provides the medication also provides support, advice, reassurance, and hope, as well as monitoring side-effects (including monitoring of vital signs), adjusting the dosage, or switching the medication, if needed. This "clinical management" is critical with depressed patients, whose pessimism, low motivation, low energy, and sense of social isolation or guilt may lead them to give up, not adhere to treatment, or drop out of treatment. Clinical management of medication has been detailed in the form of a manual (Fawcett, Scheftner, Clark, 1Because a recurrent form of depression is likely (and, therefore, the need for maintenance medication). 2Because there are several randomized controlled trials indicating medication is more effective than placebo, but psychotherapy has not been studied to date by such a trial in this group. et al., 1987) and may well be effective, either alone or with a placebo, in mildly to moderately depressed outpatients with major depressive disorder. For this reason, clinical management is viewed not only as a method to optimize dosage and patient adherence to medication, but also as a treatment, albeit nonspecific, in its own right. Common sense and a body of studies on adherence suggest that appropriate clinical management improves adherence and, therefore, patient response. In addition to routine clinical management, specific sessions aimed at increasing adherence (adherence counseling) may be indicated in the situations noted in Chapter 2. Evidence for Efficacy The search for randomized controlled trials evaluating the efficacy of medication treatment for adult and geriatric patients with major depressive disorder was restricted to English language literature published from 1975 to the present, as the diagnostic taxonomies in use before that time are incompatible with the present system. However, studies of MAOIs carried out between 1960 and 1975 were included because they represent an important body of work and used sufficiently well defined patient groups to make inferences to the present system. The vast majority of studies were conducted on outpatients with moderate to severe, nonpsychotic major depressive disorder seen in non-primary care settings. Table 4 shows the number of randomized controlled trials for each medication in adult and geriatric patients with major depressive disorder. The largest number of randomized controlled trials is found for acute phase treatment. Studies of anxiolytic medications are included because these drugs are sometimes used for patients with milder forms of depression, for patients with both anxiety and depressive symptoms, and for depressed patients with complex associated medical conditions that make standard antidepressants risky to use. (Only acute phase studies were available for anxiolytic medications.) Unstudied treatments are, by definition, neither effective nor ineffective. Intent-to-treat meta-analyses for acute phase treatment indicate that, in general, most antidepressant medications have comparable efficacy (Table 5). The drug-placebo comparisons are relatively equivalent across medications. Most reports focus on those with adequate treatment exposure (3 to 4 weeks of medication), an experimental condition that favors a higher response rate (65 to 70 percent) than that found with an intent-totreat sample (50 percent), because patients unable to take medication because of the side effects or who decide to discontinue treatment often do so early in the course of treatment. In general, the percentage of responders expected for each drug (drug efficacy) for outpatients is larger than that for inpatients—a finding that appears to result from a greater placebo response in outpatients. The drug-placebo differences often appear larger for inpatients than for outpatients, which may result from both lower attrition and lower placebo response rates for inpatients. Other highlights of Table 5 include the following: ■ The oldest tricyclic medications are the most extensively studied, largely as a result of industry-sponsored studies that use older drugs as standards. In general, medications with the largest number of randomized controlled trials have efficacy equal to those with fewer studies. The efficacy of medications studied to date in geriatric patients is similar to that seen in younger adults (nearly all geriatric patient studies have been conducted on depressed, but otherwise medically fit, patients with major depressive disorder). ■The MAOIS have a larger number of studies reported, in part because of the longer period of research reviewed compared to that of other compounds. Over 30 randomized controlled trials of antianxiety agents used for patients with depression were found to fulfill the panel's inclusion/ exclusion criteria. Of these, 22 investigated alprazolam; 11, diazepam; and 4, chlordiazepoxide. Two additional studies of the non-benzodiazepine anxiolytic, buspirone, were also found. Diazepam, alprazolam, and chlordiazepoxide are not FDA-approved as antidepressant medications, although they are occasionally used in patients whose general medical conditions represent a special risk for the use of FDA-approved antidepressant medications. Most of the 22 studies with alprazolam showed it to be more effective than a placebo or as effective as an established TCA. However, 3 studies in the more severely depressed patients failed to support this finding. Half of the studies examining diazepam alone showed it to be worse than another active standard antidepressant or no better than a placebo. Of the 4 studies reporting on antidepressant effects of chlordiazepoxide, 2 showed it to be superior to a placebo or equivalent to an antidepressant, while 2 did not. Table 5 shows that by meta-analysis of the drug-placebo differences, the anxiolytics differ in their comparative antidepressant efficacy. A few studies that were not included in the evidence table merit comment. Several studies performed about 20 years ago using the combination of chlordiazepoxide and amitriptyline (Limbitrol, an FDAapproved antidepressant) suggested a faster onset of action, but no greater overall efficacy than amitriptyline alone (Feighner, Brauzer, Gelenberg, et al., 1979; Rickels, Gordon, Jenkins, et al., 1970). These studies were suggestive, but generally did not use sufficiently rigorous methodology or sufficiently high medication dosages to be clearly interpretable. Two recent studies, however, have addressed the issue of combining an anxiolytic and an antidepressant (Feet, Larsen, and Robak, 1985; Kravitz, Fogg, Fawcett, et al., 1990.) A double-blind comparison of imipramine and the combination of imipramine plus 10 mg of diazepam per day in outpatients with nonagitated depression did not demonstrate any benefit from the addition of diazepam to imipramine (Feet, Larsen, and Robak, 1985). One study found that the combination of desipramine and alprazolam was associated with a more rapid response than was desipramine alone (Kravitz, Fogg, Fawcett, et al., 1990). In fact, this study, as well as several studies of alprazolam alone in the treatment of depressed outpatients, suggests that most of the clinical benefit derived in depressed patients who respond at all to alprazolam occurs during the initial 7 to 14 days of treatment (Overall, Biggs, Jacobs, et al. 1987; Rush, Erman, Schlesser, et al., 1985). Whether this finding applies to other benzodiazepines is unstudied. In summary, these data suggest that benzodiazepines, with the exception of the triazolo-benzodiazepine, alprazolam, should generally not be used to treat major depressive disorder, even in combination with other antidepressants. Moreover, alprazolam is not recommended for routine clinical use because no continuation or maintenance phase trials have been published and because problems associated with discontinuing this compound in remitted, depressed patients have not been fully studied. However, the presence of certain concurrent general medical conditions for which standard antidepressants are contraindicated may necessitate consideration of this agent in selected patients because of its cardiovascular safety, quick onset of action, and generally low side-effect profile. Table 4. Number of randomized controlled trials of medication in patients with major depressive disorder1,2 'Numbers in brackets show the number of cells that were meta-analyzed for each drug. 2Numbers in parentheses indicate the number of double-blind, nonrandomized, extension trials within continuation or maintenance phases. 3Not FDA-approved for use in the United States. *Completed after 1990. "Not FDA-approved as an antidepressant medication. Note: Cont = Continuation. Maint = Maintenance. |