Martin M. Katz:  Onset of clinical action of antidepressants

Donald F. Klein’s reply to Martin M. Katz’s comment on Klein’s response to Carlos Morra’s response to Klein’s reply to Morra’s comment


Our previous discussions were about drugs whose clinical actions seem somehow related to the fast blockade of reuptake mechanisms for norepinephrine and serotonin. The interesting fast effects of ketamine are still poorly understood. Comparing the various aspects of the ketamine response to our older antidepressants seems premature

However, Katz and I agree that the Zarate et al (2006) study, which showed ketamine’s rapid onset of antidepressant actions in some patients  was irrelevant  to Katz’ claim  that response during the first two weeks was predictive of a positive outcome in trials of putative antidepressants.

            Katz argues, “Morra’s earlier comment about Kasper et al’s (2006) evidence regarding onset within the first week, however, supports one of the basic issues in this controversy, i.e., that clinical onset in treatment-responsive patients occurs early within the first two weeks of treatment.”

This is difficult to follow. Kasper et al’s abstract begins, “In general, antidepressant drugs are regarded as too slow acting. Most patients who benefit from treatment require more than 2 weeks of therapy to respond to treatment. An efficacious and well-tolerated antidepressant drug with an earlier onset of effect would be of greater interest to clinicians and patients.”

Clearly Kasper does not agree with Katz. His study was about whether escitalopram’s effect (undefined) had a faster onset than other SSRIs. The key finding was, “The mean change in MADRS total scores was significantly higher for escitalopram-treated patients than for patients treated with the comparators on day 7 (-3.9 versus -3.4, respectively, P = 0.029).”  This indicates a difference (0.5), implicitly considered by Katz as a measure of depression alleviation occurring within the first week, thus supporting his claim.

However is that accurate? Item analysis revealed “that … inner tension was significantly decreased”in the escitalopram group compared to the all comparators group as early as week 1 … also at week  2.

Reduced sleep was similarly affected as early as week 2 …This difference remained significant until the end of the trial.”

Are these clear indicators of an antidepressant effect?  An alternative conclusion is that escitalopram is on average, a better faster acting sedative than the other SSRIs. However, without a placebo contrast even this is obscure. Perhaps the pooled SSRIs had an anti-sedation effect, muffled by a positive placebo effect and escitalopram was simply a placebo.

In any case, strong support for Katz’s hypothesis of antidepressant effect occurring within the first two weeks receive no support. The other hypothesis that early improvement was predictive of positive outcome was not even alluded to. It it is difficult to understand why this article is considered supportive of Katz’s views.

Marty sees me as “reluctant to accept, despite strong accumulating evidence… (e.g., Stassen et al 1997, Szegedi et al 2009, Katz et al 2004), … that early reactivity or non-reactivity to the drugs, i.e., within two weeks of treatment, will predict at a high level of confidence, which patients will respond to the treatment at outcome of a 6 to 12 week trial.”

Right, reluctance puts it mildly. In my comments every single one of the articles that Katz cites as supportive were found irrelevant or non-supportive. This 4 year discussion might be shortened by direct confrontations over the specific data and analyses that Katz and I disagree about.  The grounds for reluctance are not obscure.



Kasper S, Spadone C, Verpillat P, Angst J. Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharmacol. 20062; 1:105-10.

Katz MM, Tekell J, Bowden CL Brannan S,Houston JP, Berman N, Frazer A. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 2004; 29: 566-79.

Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of recent results. Eur Psychiatry 1997: 12: 166-76.

 Szegedi A, Jansen WT, van Wugenburg AP. Early improvement in the first two weeks as predictors of treatment outcome in patients with major depressive disorder: a meta-analysis including 6,562 patients. J Clin Psychiatry 2009; 70: 344-53.

Zarate CA Jr, Singh JB, Carlson PJ, Brutshe NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methlyl-D-asparate antagonist in treatment –resistant onaldF. Kleinmajor depression. Arch Gen Psychiatry 2006; 63: 856-64.


Donald F. Klein

September 8, 2016