New Drugs for Old Folks: The Evidence‐Based Argument for Newer Antidepressants

QUESTION: What are the comparative benefits and drawbacks of the newer medicinal and botanical therapies for depression? BACKGROUND: Depressive symptoms and disorders are prevalent and one of the leading causes of disability worldwide. The first generation of antidepressants, the tricyclic agents and monoamine oxidase inhibitors, represented a major therapeutic advance. Nonetheless, dangerous side effects and potential lethality in overdose limited their use. Seniors with a clinically significant level of depressive symptoms were more likely to receive a benzodiazepine than an antidepressant. 1 Difficulty distinguishing depression from self‐limiting reactions to acute illness and injury also kept the generalist's threshold for prescribing an antidepressant high. The introduction and proliferation of selective serotonin reuptake inhibitors for the treatment of depression promised a golden era of psychopharmacology similar to that previously experienced with the pharmacotherapy of cardiovascular disease. However, further data on recurrence rates, the frequency with which patients discontinue treatment and greater experience with the newer agents have blunted the initial enthusiasm. The newer agents may be safer but they are not as easy to use as originally advertised, and there are so many of them. As a result, for generalists who prescribe the majority of antidepressants, the art of individualized treatment is stretched far beyond the science needed for an informed decision. This is even more the case for the youngest and oldest patients and those whose symptom presentation or physical conditions confound accepted diagnoses. Until large‐scale, multi‐site studies with representative rather than highly selected patient samples are completed, literature reviews such as Williams et al.'s will be crucial. DATA SOURCES: The authors review data from the Cochrane Collaboration Depression, Anxiety and Neurosis Group's specialized registry of 8451 clinical trials, meta‐analyses, and expert opinion in the English and non‐English language literature from 1980 to January 1998. STUDY SELECTION CRITERIA: Randomized trials of the selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and St. John's wort that reported clinical outcomes. DATA EXTRACTION: Two individuals independently abstracted the studies for descriptive synthesis in which some data were pooled using a random‐effects model. MAIN RESULTS: Most of the trials evaluated acute‐phase outpatient treatment of major depression in middle‐aged adults. Newer antidepressants were superior to placebo for major depression and dysthymia by a relative benefit factor of 1.6 to 1.7. Slightly more than half those receiving an antidepressant had a substantial reduction in symptoms compared with one‐third of patients who responded similarly to placebo. The new antidepressants were effective for both geriatric and primary care patients. No single agent or group emerged as preferred. Efficacy was nearly identical from one agent to another, whether old or new. Although adverse effect profiles differed substantially, overall discontinuation rates between the older and newer agents were comparable. St. John's wort was clearly superior to placebo but not to low‐dose first‐generation tricyclics (imipramine, amytriptyline, monoamine) in either efficacy or drop‐out rates. Data on the treatment of subsyndromal depression, depression in patients with comorbid physical or mental illness, and depression among adolescents were insufficient for a meaningful interpretation. CONCLUSION: The newer agents are safe and effective. The evidence does not support their absolute superiority over the second‐generation tricyclic nortriptyline, although they have supplanted the first‐generation antidepressants in clinical practice. Further information is needed regarding newer agents for the treatment of mood disorders beyond major depression and among more representative clinical populations. Data on the options for persons not responding to the initial prescription, those who will require concurrent psychotherapy, and the relative clinical and economic benefits of botanicals over the newer agents are insufficient. The treatment data deficiency is most striking among adolescents and ethnic minority groups.