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.
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.
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.
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