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Institute for Response-Genetics (e.V.)

Prof. Dr. Hans H. Stassen, Chairman

(Formerly Associated Institute of the University of Zurich)

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The "Average Patient" Approach

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.

The "Individual Patient" Approach

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.

Two-Dimensional Cure Models

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.

References

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scatter diagram
Time course of improvement under fluoxetine (SSRI): empirical HAMD depression scores of 440 patients are plotted (along the y-axis) as a function of observation time (x-axis). The solid line denotes the underlying regression curve, which displays quadratic characteristics.
Please note: (1) the "average patient" approach yields almost identical results for the two pharmacologically and biochemically very different antidepressants; (2) the "individual patient" approach reveals distinct inter-individual differences as to the time course of improvement.
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