Martin M. Katz:  Onset of clinical action of antidepressants

Donald F. Klein’s response to Carlos Morra’s response to Klein’s reply to Morra’s comment

 You state, "one can predict whether a patient will respond to antidepressant treatment within the time frame Marty Katz suggests, even if Dr. Klein’s argument is correct that the substantial response to treatment takes place later" and cite 3 articles in support.

Maeng and Zarate (2007) appear to agree with me about  the irrelevance of week one findings in the sort of antidepressants Katz had studied, by stating, " Although most anti- depressants exert their initial effects by increasing the intrasynaptic levels of serotonin and/or norepinephrine, the resolution of core depressive symptoms becomes manifest only after weeks of administration". They hypothesize the acute and maintained effect of ketamine infusion, “are due to an increase in AMPA relative to NMDA glutamatergic throughput, which results in increased synaptic potentiation." In their cited Berman pilot study, using their 50% HAMD decrement criterion, 4/7 subjects had this immediate response. There is no prediction of this benefit or of any degree of maintained benefit.

Zarate et al (2003) simply suggest that glutamatergic mechanisms may be of anti-depressant relevance. 

Zarate et al (2006) describe a crossover study of IV ketamine vs placebo, two weeks apart. Using the 50% fall in HDRS as criterion, about 55% of the ketamine treated group achieved this during the first post-infusion day.

Again there was no outcome predictability evident

Of interest, although not strictly relevant to this discussion, "The earliest improvements were at 40 minutes for depressed mood and guilt. Depersonalization or derealization was worse from 40 to 110 minutes. Motor retardation and gastrointestinal symptoms were worse at 40 minutes, but at day 1, motor retardation was better for participants receiving ketamine than those receiving placebo." 

This review does not agree with your statement, "one can predict whether patient will respond to antidepressant treatment within the time frame Marty Katz suggests".  That ketamine is having quick acute benefits is not to the point.  That neither these acute or maintained  benefits, due to ketamine, have been predictable  is interesting but also irrelevant to the discussion that Katz and I had.



Zarate CA Jr, Du J, Quiroz J, Gray NA, Denicoff KD, Singh J, Charney DS, Manji HK. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann N Y Acad Sci. 2003;1003: 273-91.

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


Donald F. Klein

July 7, 2016