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Assessing and Enhancing the Effectiveness of Antidepressants

Assessing and Enhancing the Effectiveness of Antidepressants

With over 2 dozen FDA-approved antidepressants on the market, it is reasonable to ask: which antidepressants are most effective? After decades of clinical experience and literally millions of prescriptions written over the years, it stands to reason that 1 or 2 agents have risen from the pack to outshine the rest.

Unfortunately, clinical experience shows this not to be the case. The general consensus is that despite their different mechanisms of action, all current antidepressants seem to have more or less the same effect. The functional equivalency of antidepressants is highlighted in practice guidelines and, understandably, serves as justification for restricted formulary access to more expensive agents.1 As a result, most psychiatrists choose antidepressants not on the basis of efficacy, but rather on the basis of insurance coverage, adverse-effect profiles, or particular clinical features of depression (eg, melancholic, atypical, anxious features), for which some differences in efficacy do exist.

Efficacy vs effectiveness

The question of how well antidepressants work for the routine treatment of depression can be answered in terms of efficacy or effectiveness. An efficacy trial asks the question, Does the drug work under ideal circumstances? Although such trials are usually brief (6 to 8 weeks) and interventions are standardized and rarely flexible, they serve as the basis for the FDA’s approval of drugs.

“Effectiveness” concerns the success or failure of drugs in the real world. A true effectiveness study asks the question, Does the drug work under usual conditions? Effectiveness trials enroll a more heterogeneous population, often with comorbid mental illness, substance abuse, or other psychiatric diagnoses, and health care professionals are often free to offer concurrent therapies. As a result, effectiveness trials tend to have more generalizability, or external validity, to real patient populations.

Effectiveness trials help clinicians and policymakers select which medications work best for a given indication in real-world conditions. Surprisingly, despite decades of experience with antidepressants, information on their relative effective-ness is lacking, while health care costs continue to escalate. As a result, more emphasis is being placed on comparative effectiveness research, in which alternative treatments are compared under real-world conditions, and costs and adverse effects are measured in addition to clinical outcomes.

Effectiveness studies

Effectiveness trials are often large, expensive, and time-consuming. They sometimes take the form of a practical clinical trial in which multiple clinically relevant treatment regimens are compared across a large population of subjects. One such landmark study is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. In this NIMH-funded study, more than 4000 depressed patients in outpatient psychiatry and primary care practices received citalopram for up to 12 weeks; those who did not improve advanced to later phases that offered augmentation with, or a switch to, a second antidepressant or psychotherapy.2

Remission rates in step 1 were low (28%) and decreased further with additional steps. Cumulatively, two-thirds of patients entered remission after 4 steps.3 Direct comparison of the effectiveness of antidepressants was not possible because of the overall lack of randomization and poor statistical power.4 Despite the scope and initial aims of the study, no single antidepressant strategy or combination appeared more advantageous than any other.

Other effectiveness trials have yielded similar results. A 24-week trial that randomized patients to sertraline or citalopram found no significant difference between groups.5 Another 24-week trial of 234 patients randomized to receive sertraline or fluoxetine also found no significant difference.6 In a 2001 study, 573 patients were randomized to 1 of 3 SSRIs for 9 months; sertraline, paroxetine, and fluoxetine were equally effective.7 Patients admitted to a German psychiatric hospital for treatment of depression were followed up for 10 weeks, and response and remission rates were 68.9% and 51.9%, respectively, again with no difference among individual antidepressant agents.8 Effectiveness trials, therefore, seem to confirm the conventional wisdom that no single antidepressant works better than—or worse than—any other.


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