Friday, 22.10.2021

Reply (Martin M. Katz)

Martin M. Katz’s reply to Donald F. Klein’s third comment/question on his book Depression and Drugs

The questions:

In Katz’s view, do the several component neurotransmitter systems vary independently producing all possible combinations and manifestations? In that case, there should be no recognizable syndromes or courses. Alternatively, are   certain neurotransmitter deviation   combinations   particularly   likely, thus giving the appearance of syndromes?

But if certain   combinations   of deviances are somehow favored, how does that differ from the diagnostic syndrome formulation which accepts multi-causal impairments of a particular evolved adaptive function, as modified by adaptive backups, yielding a  particular somewhat variable, syndrome?

Dr. Klein raises basic questions concerning the neural mechanisms underlying the mental disorders, e.g., specifically, the depressive disorders, and their relationships to our system of diagnosis. In responding, one has to acknowledge that such an analysis at this point in our progress, is required at two levels, one, the presumed neurochemical basis for the mechanisms involved, and two, the observable behavioral and somatic manifestations of the disorders, which represent the sole indicators of the presence of the clinical syndromes. We understand that at this point in time, despite our knowledge of the role of genetics in the susceptibility to certain of these disorders, e.g., the bipolar disorder, we still have no “biological markers” for the diagnosis of any of the mental disorders.

Regarding the interaction of the central neurotransmitter systems at the first level, raised in Klein’s opening questions, there is evidence of strong linking in functioning among the dopaminergic, serotonergic and adrenergic systems, described earlier by Sulzer (1985) and later demonstrated in several studies, including in our own collaborative research program (Maas et al 1991). The intercorrelations are substantial, but do not approach unity, indicating that they do not vary togetheror completely independently, and thus, are not likely to “produce all possible combinations”.Evidence also exists that in attempting to link the dysfunction in the neurotransmitter systems to specific behaviors, that as reported in the book by Katz (Katz 2013) and as summarized in the review by Morilak and Frazer (2005), the functioning of the serotonin system is significantly associated with “impulsive aggression” and anxiety, the norepinephrine system with motor retardation and depressed mood. There is no evidence that we are aware of that links a specific pattern of neurotransmitter dysfunction to a specific diagnosis. Progress along this line must await further advance in the capacity to link “diagnosis” on one side, to patterns of neurotransmitter dysfunction, on the other. Until then, Carlsson (2013) summed up our dilemma with his classic comment “drugs don’t care about the boundaries between one diagnosis and another.”

I cannot adequately answer Klein’s second question, except to indicate that at present we do not appear to have the proper capacity. We are not able to link the two levels, that is, the neurochemical basis and an overt syndrome, directly. We are, however, part of the way, having established that the various neurotransmitter systems have distinct patterns of relationships with behavioral variables such as anxiety, that are core aspects of most syndromes. .

Basic clinical research that will adopt this behavioral componential approach in parallel with the elemental neurotransmitter systems, an approach discussed in detail in the “Depression” book requires abandoning in this critical search, the established DSM diagnostic system. It is, however, more likely to enhance progress in uncovering the underlying biological patterns of the major dimensions of psychopathology.



Carlsson A. (2011) In Katz MM (ed) History of the ACNP[vol 10 Oral History of Neuropsychopharmacology (ed: Ban TA)}, Brentwood TN: ACNP, pg 90.istory of Neuropsychopharmacolgoy.

Katz MM. Depression and Drugs: The Neurobehavioral structure of a Psychological Storm, NY:Springer, 2013.

Maas JW, Katz MM, Frazer A, Stokes PE, Swann AC, Davis JM, Casper R, Berman, N. (1991) 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, 7, 155-169.

Morilak D, Frazer A. (2004) Antidepreessant brain monoaminergic systems: a dimensional approach to understanding their effects in depression and anxiety disorders. InternationalJournal of Neuropsychopharmacology, 7, 193-218.

Sulzer F. (1985) The “serotonin-norepinephrine link hypothesis” of affective disorders. In: Proceedings of the III World Congress of Psychiatry, ed. P. Pichot, P Berner, K Thau. NY: Plenum Press, pp.411-416


Martin M. Katz

July 17, 2014