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Early Onset of Improvement Predicts Later Response

Incidence and Latency

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"), are often combined into a single, 1-dimensional "cure" model by means of survival-analytical techniques. This cure model incorporates non-responders in addition to modeling the time to an a priori defined clinical response. Patients who dropped out of the trial prior to the envisaged observation period are treated as "censored" data under the assumption of random censoring. The non-parametric generalized maximum likelihood for the model is obtained from the Kaplan-Meier (KM) product limit estimator. By contrast, when separating incidence and latency through a 2-dimensional cure model, tests become available [Kolmogorov-Smirnov, Cramer-von Mises] to explicitly compare the speed of improvement between treatments among improvers.

Latency Explains No More than 5% of Variance

Among patients who meet improvement or response criteria, the distribution of the individual onsets is slightly left-skewed, yet approximately normal, covering a wide range from early to late improvement/response with mean values around day 12-14 (improvement) and day 18-20 (response). Unexpectedly, there are almost no differences between treatment modalities in this respect, with differences between active compounds, and between active compounds and placebo, being reflected only by the total number of improvers and responders. The subtle differences in the "average" onset are likely the effect of non-standardized placebo washouts which may explain a ±2 day shift of baseline, or may relate to the dose titration differences in the first days of treatment.

No Gender Differences

Analyses carried out separately for male and female patients did not reveal major gender differences, except for mirtazapine and paroxetine, where sample sizes were small.

⇒ Meeting improvement criteria is highly predictive of later outcome, as typically >70% of the patients who show sustained improvement within the first 10-14 days of treatment ("early improvement") later become sustained responders by the end of a typical six-week drug trial. Inversely, more than 80% of sustained responders at the end of a six-week drug trial show sustained improvement within the first 10-14 days of treatment, thus suggesting that in more than two thirds of the patients, the time course of improvement is sustained once the recovery has started.

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Response OR
Fig. 2: Sustained response is much more likely among early improvers independent of treatment modality as indicated by odds ratios that exceed 3 for all drugs and placebo. The estimates were derived by fitting a random-effects model which accounted for the between-study variation. The dotted line indicates an odds ratio of 1.
⇨ Please note: (1) patients showing no improvement throughout the first 2 weeks of treatment have a probability of <15% to later become responders; (2) this probability drops below 8% after 3 weeks without improvement.
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