Efficacy of Antidepressants

Current knowledge about the mechanisms of action of antidepressants is rather limited. In consequence, it is not possible to make any predictions of whether or not a particular patient will respond to a particular treatment. The most puzzling point in the treatment of Major Depressive Disorder (MDD), however, is the observation that antidepressants which differ greatly in their biochemical design and primary site of pharmacological action display virtually the same efficacy, as measured by the proportion of patients in whom they induce a therapeutic response. Moreover, responder rates are modest, as revealed by recent meta-analyses of FDA data on 10,030 patients from 52 antidepressant drug trials, where active substances showed superiority to placebo in fewer than half of the studies [Khan et al. 2001, 2002]. And, what is particularly difficult to understand: while newer treatments have better tolerability and safety profiles, they do not offer any advantage in either efficacy or their ability to reduce residual symptoms.

Mechanisms of Action

What might explain the relative lack of progress in the field of antidepressant drug research over the past decades? Antidepressants are hypothesized to achieve their effect through modifications of single (or multiple) targets within the monoaminergic systems. However, a significant amount of clinical data suggest that effective antidepressants act in a rather unspecific and indirect way, that is, to merely trigger and maintain conditions necessary for recovery in a subgroup of patients who otherwise would remain nonresponders. Once triggered, the recovery of these patients follows its "natural" course as equally observed under placebo treatment. Indeed, antidepressants appear to be "polyvalent" in the sense that they induce a therapeutic response under various clinical indications. For example, antidepressants are also effective in anxiety disorders and antipsychotics are successfully used in the treatment of bipolar illness.

Advanced Approaches

It is quite unlikely that the observed inter-individual variation of antidepressant drug response "results" from one single factor or a few major factors, as single gene approaches typically "explain" no more than a small percentage <1.5% of observed variance. In consequence, advanced molecular-genetic approaches to psychotropic drug response involve (1) configurations of a larger number of interacting factors, and (2) quantitative phenotypes that assess more than just the rudimentary response-nonresponse dichotomy.

References