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Is There a Delayed Onset of Drug Action?

Onset of Improvement

Empirical data show considerable inter-individual variation in the times to onset of improvement under antidepressants, which vary from a few hours to several weeks. Specifically, one finds an approximately normal distribution with means around day 13 (20% sustained baseline score reduction: "improvement") and day 20 (50% sustained baseline score reduction: "response"). Differences between active compounds and placebo evolve from the very beginning of treatment, achieving over 65% of the maximal difference within the first two weeks, while differences between the various active compounds remain marginal throughout a typical drug trial of six weeks.

The Myth of a Delayed Onset

There is no distinct increase in the number of patients benefitting from treatment after 3-4 weeks as postulated by the "delayed onset-of-action hypothesis" but, rather, the probability of a patient to respond to treatment is as low as 15% if this patient does not display any sign of improvement throughout the first two weeks of treatment. And this probability even drops below 8% if there is no sign of improvement by the end of week three.

Statistical Artifact

Where does the myth of a "delayed onset-of-action" of psychotropic drugs comes from? In general, results from placebo-controlled, double-blind studies of antidepressants yield comparable "average" time courses of improvement under "effective" compounds, along with very similar drug-placebo differences. Figures 1a, b reveal the striking similarity in mean change in Hamilton Depression Score (HAM-D21) under 4 pharmacologically different compounds compared to placebo.

It is particularly worth noting that the differences between active compounds and placebo — as assessed for treatment groups by quantitative measures, such as the HAM-D rating scale — evolve over time in a very similar way from the very beginning of the drug trial, achieving over 65% of the final drug-placebo difference within the first two weeks of treatment, when drug-placebo differences reach statistical significance. ⇒ This statistical time lag has long been misinterpreted as indicating a delayed onset of action of antidepressants.

References

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Antidepressiva vs Placebo
Fig. 1a: Effect of treatment on mean change from baseline on the Hamilton Depression Scale HAM-D21 for patients with major depressive disorder. Comparisons are of imipramine (circles, n=506) or moclobemide (triangles, n=580) versus placebo (squares, n=191).
Fig. 1b: Effect of treatment on mean change from baseline on the Hamilton Depression Scale HAM-D21 for patients with major depressive disorder. Comparisons are of substance-P antagonist MK-869 (circles, n=66) or paroxetine (triangles, n=68) versus placebo (squares, n=64).
Please note: (1) differences between pharmacologically very different antidepressants (imipramine, moclobemide, paroxetine, substance-P) are marginal; (2) differences between placebo and active compounds whatsoever are virtually identical and emerge from the very beginning of treatment.
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