Reply to Elemer Szabadi by Martin M. Katz

Martin M. Katz: Onset of Antidepressant Effect 

Martin M. Katz’s reply to Elemer Szabadi’s comment

Dr. Szabadi is responding to the question of whether the findings from controlled clinical studies that show the large majority of treatment-responsive patients to significantly improve within the first two weeks of antidepressant treatment applies to individual patients. Don Klein raised that question in his earlier critique. Dr. Szabadi summarizes results from studies conducted by several investigators, using an innovative method of determining onset, i.e., associated speech pause time, to show that in many cases, patients who improve on this measure early, go on to recover with treatment. He makes a good case for early onset but one would have to examine these studies to ensure that his studies cover a significant number of cases.

Nevertheless, these results are certainly in accord with Kuhn’s initial report identifying imipramine as an ”antidepressant”, in which he, as other well-known clinicians, have been quick to report that when a patient responds to six weeks of treatment, early improvement within the first week of treatment, was a frequent occurrence.

More telling from the scientific vantage is that finding that “early response” is a highly frequent occurrence, significantly greater than occurs with placebo or non-effective drugs, is not simply a statistic. It is a finding that could only occur if significantly more patients demonstrated this response than those who did not. The studies by Stassen et al (1996) and Szegedi et al (2009) report significant results on this issue based on samples which number in the thousands.

On the issue of the possible association with severity of the disorder that Dr. Szabadi raises, my own experience in our Collaborative program (Maas et al 1980.1984) with this issue provides very relevant results. In that study, 100+ severely depressed patients, all severe enough to be hospitalized, were assembled.  Each patient was individually examined by an experienced clinician, rated weekly, then categorized on the basis of all behavioral measures, as to whether he/she was “fully recovered” through “no change”. The final results of treatment showed 65% of patients “markedly improved”.

This finding on “individual patients” was to be expected. What was surprising was that by the end of two weeks of treatment, 50% of patients were categorically judged by experienced clinicians, as “recovered”.  This helps to explain our reported results on early onset (Katz et al 1987) and clearly demonstrates that it was based not simply on average response during the first two weeks, but on marked change toward recovery at this early point, by no less than 50% of the sample of patients.




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.

Kielholz P, Poldinger W. Die behandlung endogener depressionen mit psychopharmaka. Dt med Wschr 1968; 93:701-4.

Maas JW, Koslow S, Davis J, KatzMM, Mendels J, Robins E, Stokes P, Bowden C.  Biological component of the NIMH-Clinical Research Branch Collaborative Program on the Psychobiology Depression. Psychological Medicine 1989; 10:759-76.

Maas JW, Koslow S, Katz MM, Gibbons RL, Bowden CL, Robins E, Davis JM.  Pretreatment neurotransmitter metabolites and tricyclic antidepressant drug response. Am J Psychiatry1984; 141:1159-71.

Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of recent results. Eur Psychiatry 1996; 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.


Martin M. Katz

October 29, 2015