Response (Martin M. Katz)

Martin M. Katz’s response to Donald F. Klein’s response to Katz’s reply to Klein’s fourth comment (Mental Syndromes and Neurotransmitters) on his book Depression and Drugs


D. Klein states that we agree about “the need to defer judgment on syndromes, neurotransmitters and distinct behavioral effects while awaiting relevant findings.” We agree to a point. I, however, believe that we are further along on these issues than Don Klein may be ready to accept. The evidence is stronger regarding the differential associations the neurotransmitter systems have with behavior than many investigators acknowledge. Specific relationships of the functioning of the serotonin system and the regulation of anxiety and of “impulsive aggression” are strong, as are the norepinephrine system and its association with “arousal” and dopamine with motor activity. (see Morilak, Frazer’s 2004 summary of this basic research)  True, the interaction among these neurotransmitter systems are, in themselves, complicated, so that there is still much to learn about how the regulatory activities on various moods and behaviors play out in the functioning organism. But I believe, that one aspect of the issue is very clear and that is that decades of attempting to find direct, straightforward linkages of neurochemical systems with classical mental disorders, as defined in the DSM, or even with syndromes as more commonly defined, has been unsuccessful, leading to many blind alleys. As Arvid Carlsson put it earlier in another investigatory framework: “Drugs don’t care about the boundaries between one diagnosis and another”

 This is not to deny the values of the diagnostic system or that such disorders as schizophrenia or the affective disorders are not real. Decades of study make clear that these syndromes clearly exist in much the same form as they are described in the established literature. The problem is that they are as conceptions, too complex in nature, and too difficult to quantitate reliably to be of any great value in uncovering the neurobehavioral mechanisms underlying abnormal behavior and the impact of drugs on these mechanisms. The late James Maas and I encountered this “diagnostic” obstacle in early work on the psychobiology of depression attempting to relate drug- induced neurochemical changes to changes in the composition of the disorders (Maas et al. 1991). Our solution then, when seeking to uncover underlying neurobehavioral mechanisms, was to adopt a more elemental approach in measuring the behavioral side, i.e., to substitute the use of behavioral components and the dimensions that structured the disorders, for the disorders themselves, rather than attempting to find links between the neurochemical systems and the “whole” disorders. This line of thinking and the evidence for it was elaborated in more detail in my book.

So Klein is correct that I feel strongly that a major “drag” on progress is our over reliance on diagnosis and syndromes in clinical investigations as against improving the precision of our measures of anxiety, anger, apathy in order to further chart the network of associations of the neurotransmitter systems and behavior. Uncovering parts of this network has already improved our capacity to resolve issues about the underlying mechanisms of psychopathology and broadening our knowledge about the nature and timing of specific actions of antidepressants. It is the evidence utilizing this dimensional approach that has stimulated new thinking and theory about how the depressive disorders are structured and how the drugs work to achieve clinical response.   That evidence supports my view that efforts should continue to be concentrated on further elaborating the characteristics of these all important neurochemical-behavioral networks and their functions in the various mental disorders.

Katz MM, Depression and Drugs: The Neurobehavioral Structure of a Psychological Storm.  NewYork: Springer; 2013.

Maas JW, Katz MM, Frazer A et al. Current evidence regarding biological hypotheses of depression and accompanying pathophysiological processes: A critique and synthesis of results using clinical and basic research results. Integrative Psychiatry 1991; 7:155-69. 

MorilakD, FrazerA. Antidepressant brain monoaminergic mechanisms: A dimensional approach to understanding their effects in depression and anxiety disorders.  International Journal of Neuropsychopharmacology 2004; 7: 193-218.


Martin M. Katz

December 11, 2015