Reply by Donald F.Klein


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

Dr. Morra believes that our stand regarding antidepressant onset rules out evidence of first week effect. Not so, our general point is, even if first week anti-depressant effect is actually detected (given the ample opportunity for misleading  early drug vs placebo effects in the first week that have no relation to later clinically documented effects at 6 weeks), the central issue is that most substantial onsets of antidepressant effects occur later than one week. Is that a factual issue?  I think no one has denied that.

The heuristic importance is that we agree that the drug effect on reuptake blockade is immediate, causing greater synaptic neurotransmitter concentration.The issue is whether this is sufficient for clinical benefit or is at best the first domino. If sufficient, the quest for better anti-depressants should hover about reuptake blockade, synaptic concentration, immediate receptor stimulation, etc. In fact, this is the accepted model for drug development, but clinical outcomes over forty years have not improved and no new class of antidepressant has been discovered… 

If the drug's immediate synaptic effects are usually at some distance from anti-depressant onset then the simple model fails. It also fails since anti-depressants with the same immediate synaptic effects do not make normal subjects happier.   Evidently, the drug is in some fashion neutralizing the pathophysiology and clinical benefit depending on the extent of the neutralization.

Unfortunately models that incorporate the drug effect over time with the still unknown pathophysiology of the manifest illness, (my guess is an adaptive hedonic mechanism that requires remedy of damaged stabilizing negative feedback loops), have not testably replaced the simplistic model. I attempted from Marty Katz's report to elicit, by reconstruction, the data relating the week two effect to the six week outcome.  Marty says my algebra was cockeyed and he may well be correct. Fortunately, this is beside the point. My data reconstruction may well be wrong. This lacks importance when the real actual data is in Marty's data bank. My substantial point is that if Marty revealed the actual data in 2 X 2 form, relating two week effects to six week outcome, the discrepancy from his theories would be glaring.  Also, it would make evident that consideration of the placebo effect was missing. Fortunately, Marty has the opportunity to demonstrate the correctness, or not, of his theories by this simple data demonstration. Let's see it


Donald F. Klein

July 23, 2015