Martin M. Katz:  Onset of clinical action of antidepressants

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


 Morra found results of the Zarate et al (2006) study, which showed ketamine to effect rapid onset of antidepressant actions in some patients within the first day of treatment, to support soundness of the earlier finding that response during the first two weeks was predictive of a positive outcome in trials of putative antidepressants. Klein is right to question whether the Zarate study provides any evidence in support of this predictive hypothesis. Zarate et al’s conclusion (2006) refers to an onset achieved through a single intravenous dose of ketamine within two hours, “the effects remaining significant for one week”, and does not deal, as Klein points out, with the outcome issue.

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.

The bottom line here, which Klein still seems reluctant to accept, despite strong accumulating evidence from studies that investigated multiple antidepressants across thousands of soundly diagnosed depressive disorders (e.g., Stassen et al 1997, Szegedi et al 2009, Katz et al 2004), is 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.



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 2

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 major depression. Arch Gen Psychiatry 2006; 63: 856-64.

Martin M Katz

July 14, 2016