Delayed Onset of Action of Antidepressant Drugs? Survey of Results of Zurich Meta-Analyses

Abstract

The onset of action of antidepressant drugs was investigated on the basis of two independent, multicenter, double-blind studies, comparing amitriptyline (N = 120), oxaprotiline (N = 120), imipramine (N = 506) and moclobemide (N = 580) with placebo (N = 189/+191). Highly significant differences between the active drugs and placebo were found with respect to the total number of improvers and the total number of responders. In addition, significant differences between treatment modalities showed up in both the percentage rate and the time distribution of premature withdrawals. However, among improvers, the distribution of time spans to onset of improvement was found to be independent of treatment modality, indicated by virtually identical cumulative percentages of improvers over the whole observation period. This picture of treatment-independent improvement rates was essentially the same for the HAMD, HAMA and ZUNG assessments, except for a significant time lag between observerratings and self-ratings. Specifically, our analyses revealed no evidence for a delayed onset of action of various antidepressants with large biochemical and pharmacological differences when compared to placebo. The early onset of improvement was highly predictive of later outcome: on average, 70% of patients showing improvement within the first 14 days became responders. Differences between active treatments and placebo emerged within the first five days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. Not more than 20-25% of patients were, on average, "true" drug responders, thus suggesting that the therapeutic qualities of antidepressants do not lie in the suppression of symptoms, but rather relate to their ability to elicit and maintain certain conditions which enable recovery in a subgroup of patients who would otherwise remain nonresponders.

Changes in rat hippocampal CA1 synapses following imipramine treatment

“…Clinical studies about imipramine indicate that most patients show some response within the first 1-3 weeks of therapy (Blier, 2001;Jain, 2004) and onset benefits of imipramine can be seen after 2 weeks, but its greater efficacy may take up to 4-8 weeks to observe (Stassen et al, 1996). Rogoz et al reported increased BDNF gene expression in hippocampus in normal rat brains after 14 days of imipramine administration (Rogoz and Legutko, 2005).…”

Criteria for early onset of action of an antidepressant from the clinical trial logistics point of view – methodological considerations

“…This general opinion on the sensitivity of the self-rating scales, especially during the early treatment period, is supported by findings of clinical trials (Müller, Müller and Volz, 1996;Stassen et al 1996). Stassen et al 1996 have found that, on the 20% reduction from the baseline score criterion of the Hamilton Anxiety Scale (HAMA), on day 6, for both active treatment groups (oxaprotiline and amitriptyline), 12.3% and 12.5% of patients respectively showed an onset of improvement, whereas on the Zung self rating scale these values were 2.3% and 5.2%, respectively. Similar findings were obtained for day 7 (HAMA: oxaprotiline 26%, amitryptiline 37.5%, Zung: oxaprotiline 4.5%, amitryptiline 20.7%).…”

“…On the basis of all 429 cases they determined the 'natural variability' of HAMD and HAMA scores (spontaneous fluctuations and error variation due to instrument and observer). Later, they found that the change of 15-25% in relation to the corresponding initial values 'over the first 3 days' (Stassen, Angst and Delini-Stula, 1996) represents a suitable threshold for a response definition of onset of improvement. Taking some other considerations into account, they proposed a 20% decrease in the initial HAMD score as the threshold that defines onset of action.…”

“…Response to treatment is Niklson defined as 50% decrease from baseline score with no subsequent increase beyond 20% of response deterioration. In their subsequent article, Stassen et al (1996) further specified the 20% criterion as a condition to be 'sustained' -once reached there should be no subsequent deterioration from it. The 20% decrease in the initial HAMD total score from the baseline appeared to predict the response in patients who were going to respond (where response is defined in terms of a 50% decrease from baseline criterion).…”

Hamilton depression rating subscales to predict antidepressant treatment outcome in the early course of treatment

“…Additionally, the sum score reduction of Z20%, which is commonly used to define EI for the HAMD 17 scale (Lam, 2012;Stassen et al, 1996;Szegedi et al, 2003Szegedi et al, , 2009, is not yet validated for the HAMD subscales. Compared to the HAMD 17 , the score variability of the subscales is limited due to fewer items; therefore, a cut-off which is lower than 20% might apply, because the total score is not biased by items which are insensitive to depressive change (e.g., insight, loss of weight).…”