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Thursday, 20.07.2017

Response to Donald Klein’s response

ONSET OF ANTIDEPRESSANT EFFECT

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

 

This is a follow up to my earlier response to Don Klein’s reanalysis of our data from the 2011 paper on predicting positive outcome based on early improvement.

I wish to note at the beginning that the 2011 study (Katz et al) represented an attempt to demonstrate that prediction at two weeks is possible and that adopting the approach we outlined in that paper would be useful in any effort to shorten the length of clinical trials. I refer to the study as an example and acknowledge that it is based on a relatively small patient sample; so, it is obviously not the sole foundation for major prediction in this area. This small study, as noted in earlier papers, should be followed by a prospective study with a large and representative patient sample to establish the validity and practicality of this approach and to establish the notion that a two-week trial would be sufficient to determine whether a new, putative antidepressant will be efficacious.

My essay on onset of antidepressant action mainly refers to findings from independent and large sample multisite studies (e.g., Stassen et al 1996, Szegedi et al 2009, Katz et al 2004) that are relatively definitive in establishing that actions of efficacious drugs begin as early as 1 week. This is in contrast to the earlier textbook notion that the onset of clinical effects of these drugs lag several weeks after the almost immediate drug-induced actions on central neural transmitter systems. As an example of the process of prediction, the 2011 paper provides a test trial to demonstrate that significant prediction can be established at the two-week point.  To accomplish that goal we illustrated in Table 1 of that paper that combining the true positive predictors (TN) for DMI with the true negative predictors (TN) divided by N equals the percent of true predictors (C).

Klein apparently used the wrong definition of C in his equations and although the algebra is correct, the results lack meaning.  Also, under DMI in the first line in Table 1, by adding TP and TN for “depressed mood”, he gets a total of 1.62, which means more patients than we started with.  If you try using 0.68 for C, answers come out closer to Klein’s, but are not correct, e.g., if TN is equal to 1 then the cell for EI < .20 and outcome > .50 would be zero. So I am still not clear what he means by overshoot or undershoot.

Klein may have a point about the two-week results sometimes not being an accurate predictor. We have made the point in earlier papers that all could be clarified if the larger prospective study is eventually conducted. In sum, I think that Klein has not fully understood the results projected in Table 1, leading to some miscalculations in his algebra. That aside, however, his analysis does not negate our conclusions. More important, as noted, the 2011 study represents only a small aspect of the entire base of information that allows us to conclude that onset of efficacious agents occurs during the 1st two weeks. The test study merely represents an attempt to demonstrate how utilizing early improvement as a predictor and shortening the trial can lead to clinical benefits for the patient in reduced exposure to ineffective agents, and major cost reduction for the drug companies that develop and evaluate the new drugs. I appreciate Dr. Klein’s study of our work and that of the others who have carried out the multisite clinical trials on which these conclusions are based, but respectfully submit that his analysis of our small study does not in any way negate these important conclusions.

 

References

Katz MM, Berman N, Bowden CL, Frazer A. The componential approach enhances the effectiveness of 2-week trials of new antidepressants. J Clin Psychopharmacology 2011; 37:  193-218.

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

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.

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                   

April 2, 2015