Nuances of dose and placebo in the prescription of antidepressants for depression

Early studies of antidepressants have demonstrated clinical efficacy at doses much lower than those currently recommended. Even when deemed sub-therapeutic by modern standards, lower doses are often clinically effective – perhaps through a placebo effect. Emerging from clinical trial analyses, mounting data have cast doubt on the clinical superiority of antidepressants over placebos, for the treatment of mild-to-moderate depression. In studies of clinical practice, moreover, physicians appear to be using certain treatments devoid of demonstrated pharmacologic efficacy, one of which being sub-therapeutic doses of psychiatric medication. Administering a veridical drug at such a low dose raises interesting logistical and conceptual issues concerning placebo therapy in modern medicine, and, more particularly, in the treatment of depression. Until now, little research has focused on understanding the rationalizations behind sub-therapeutic doses, although the circumstances for using them appeared to differ between primary and specialty care physicians. Relying on insights gleaned from semi-structured interviews and a pan-Canadian physician survey, our research aims to review knowledge, attitudes and practices concerning the use of sub-therapeutic doses of antidepressants in the treatment of depression. Findings from interviews with 15 academic psychiatrists revealed that although psychiatrists do not report intentionally prescribing sub-therapeutic doses to elicit placebo effects, many forms of complex communication and expectation-shaping techniques relating to dose seem to permeate their use of such treatments. Through this investigation of intimate practice patterns, we were able to sketch conceptual challenges and uncover tacit attitudes in the contemporary treatment of depression. Based on the interview findings, we formulated a survey to investigate opinions and practices across a broader sample, one inclusive of physicians who treat depression in primary care. Among the 250 respondents who completed our online survey, 124 were psychiatrists and 126 were family physicians. Our comparisons revealed that psychiatrists had greater awareness than family physicians of the antidepressant-placebo literature; however, both groups acquiesced to the influence of non-pharmacologic effects in antidepressant therapy. Corroborating our interview findings, the majority of both psychiatrists and family physicians prescribe sub-therapeutic doses primarily to ease patients into a new drug regimen, rather than to elicit placebo effects. Approximately 80% of family physicians and 74% of psychiatrists, however, have witnessed clinical responses to sub-therapeutic antidepressants and less than 10% of each group did not believe such a response was likely. Counter to their rationalizations of prescription practices, physician explanations for responses to sub-therapeutic dose were founded largely in non-pharmacologic effects. Findings from both studies suggest a disconnect between sub-therapeutic dose rationalization and outcome, which, in turn, may signal a broader disconnect in the use of antidepressants at any dose. Through the exploration of dose related practices, the present thesis ventures into the interstices of evidence-based psychiatry: those that conflict with the standard of care, raise ethical conundrums, and question long-standing assumptions.

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