Standard approaches to analyzing psychotropic drug trials rely on the "average patient" model
which relies on a number of assumptions: (1) illness-specific drug effects eliminate the target
syndromes; (2) every patient equally benefits from treatment — or at least a significant
proportion of patients benefits; and (3) drug effects are additive to placebo effects. Given
these assumptions, patients who prematurely withdraw (typically, 20-35% of patients enrolling
in a drug trial will withdraw prior to the envisaged end of study) are treated by means of the
"last observation carry on forward method" (LOCF), thereby implicitly biasing data in favor of
active compounds, as premature withdrawals occur earlier under placebo,
when depression scores are still high. Specifically, standard approaches to analyzing psychotropic
drug trials apparently amalgamate (1) patients with rapid sustained improvement and subsequent
remission, (2) patients with an irregular, fluctuating course of recovery where improvement gets
"stuck" at some point, (3) patients who show no improvement at all under all kinds of treatment,
and (4) patients who do not complete treatment for various reasons, among which lack of beneficial
effects and serious side effects are prominent.
Empirical data from typical drug trials suggest that the "average patient" is rarely observed in
clinical practice (Figure). Rather, one gets the impression that there are as many different
time courses of recovery as patients, thus suggesting that the clinically defined entity "major
depressive disorder" (MDD) may not constitute an etiologic entity. If there were etiologic
heterogeneity, the "average patient" approch could actually be misleading, or obscure the existence
of etiologically relevant subgroups among the patients.
Assessing the time course of recovery under antidepressants separately for each individual
patient has several methodological advantages over the "average patient" model. In particular,
the "individual patient" approach offers a way to disentangle the inter-individual diversity of
antidepressant drug response as well as to assess the "speed" of response under the various
treatments at a much better resolution.
The two central aspects of psychotropic drug response, the proportion of patients in whom a
therapeutic response is induced ("incidence") and the time to onset of improvement ("latency"),
can be separated through a 2-dimensional cure model, thus enabling quantitative approaches
to disentangling the inter-individual diversity of psychotropic drug response. In particular,
tests become available [Kolmogorov-Smirnov, Cramer-von Mises] to explicitly compare the speed
of improvement between treatments among improvers.
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