Martin M. Katz: Onset of Clinical Action of Antidepressants

Martin M. Katz’s response to Donald F. Klein’s reply to Leslie Morey’s comment

 Drs. Klein and Morey have subjected our small study (Katz et al 2011) to very careful analysis and disagree on the results. Klein questions Morey’s relying exclusively on the Hamilton Rating Scale to support the conclusion that 90% of patients who show no response to antidepressants within the first two weeks, will not respond to treatment at outcome. Morey has, therefore, supported the position that that drug treatment can be discontinued at the two week point. Although I agree with Klein that further evidence from clinical methods other than the Hamilton Rating Scale, as we have applied them in these trials (see e.g. Katz 2016), would be desirable before making such an important decision, we note that the 90% figure for the Hamilton has been replicated in several large sample studies involving thousands of patients. In view of the Hamilton method’s status as the established efficacy measure in the field, the evidence would support Morey’s and my conclusion that stopping the treatment at that two week point is well justified.

Regarding the other points in Klein’s comment, I have responded in a detailed manner previously. As for the issue of our combining the two drug groups, my co-investigators and I viewed that small step as justified for the 2011 analysis since that small study was a pilot. We, therefore, recommended that it be replicated in a prospective design with a more substantially sized patient sample. In view of this disagreement over the approach to analysis, we still recommend that route to resolving the issue.

More important, however, it is necessary to restate that the study they reanalyzed was on a relatively small patient sample and dealt with a very small piece of the overall problem. The main issue, the subject of this controversy, is whether the onset of clinical actions of efficacious antidepressant drugs lag several weeks beyond the almost immediate drug neurochemical effects in patients, or that those clinical actions begin to occur within the first two weeks of treatment. In reviewing the evidence, as pointed out previously, we turned to both independent studies (e.g., Coryell et al 1982, Katz et al 1987, 2004) which first reported significant early clinical actions and the later, more definitive large sample studies that included a range of antidepressants, such as those of Stassen et al (1993) and Szegedi et al (2009), for the answers. These methodologically sound studies provide uniform results. They establish that significant, clinically observable actions of the drugs when administered in the proper dosages in treatment-responsive patients are detected as early as the first week of treatment and on average within the first two weeks.

We believe this exchange on follow up analyses and views on these studies by several leaders in the field, most prominently by D. Klein, have served to further clarify the soundness of these results, and hopefully resolved the controversy on the main issue. The sooner these findings become accepted by the field at large, the sooner hundreds of patients already in severe pain, can be relieved of having to suffer through many weeks of ineffective treatments. The sooner, also, researchers can intensify their focus on the nature of these early, diverse clinical actions. This investigative approach should enhance our capacity to develop novel agents that hopefully, can act even more rapidly and be more broadly effective than the currently established antidepressant drugs.



Coryell W, Coppen A, Zeigler VE, Briggs J. Early improvement as a predictor of response to amitriptyline and nortryptyline: a comparison of patient samples. Psychological Medicine 1982; 12: 135-39.

Katz MM. Clinical Trials of Antidepressants: How Changing the Model Can Uncover New, More Effective Molecules.New York: Springer; 2016

Katz MM, Berman N, Bowden CL, Frazer A. The componential approach enhances the effectiveness of 2-week trials for antidepressants. J Clin Psychopharmacology 2011; 31: 253-4.

Katz MM, Koslow SH, Maas JW, Frazer A, Bowden CL, Casper R, Croughan J, Kocsis J, Redmond E. The timing, specificity, and clinical prediction of tricyclic drug effects in depression. Psychol Med 1987; 17: 297-309.

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. Time course of improvement under antidepressant treatment: a survival–analytic approach. Eur Neuropsychopharmacol 1993; 3: 127-35.

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.



Martin M. Katz

June 9, 2016