Martin M. Katz: Clinical Trials of Antidepressants:
How Changing the Model Can Uncover New, More Effective Molecules

Comment by Per Bech

Although the pharmacological industries have doubled their research funds since 1991 for identifying new drugs with an antidepressant action more efficacious than the existing antidepressants, no such new drugs have been marketed. This is the background for Martin Katz’ description of how his model can uncover new, more effective molecules.

The FDA requirements focusing on optimal dosage and marketability are referred to by Katz as an applied science, whereas his new model is a component-specific model in which the clinical trial becomes a potential step in facilitating an advance to finding new and more effective treatments of major depression. Thus, according to Katz, antidepressants are not “diagnosis-specific”, but are in their modes of action “component-specific”. He refers, in this respect, to Hotelling’s principal component analysis by which he has identified such components as depressed mood, psychic anxiety, psychomotor retardation, psychomotor agitation, hostility, somatization, interpersonal sensitivity, sleep, or cognitive impairment. These components can then be parts of specific dimensions, namely (1) anxiety-agitation-somatization-sleep; (2) depressed mood-retardation; and (3) hostility-interpersonal sensitivity. At the item level of these dimensions, Katz predominantly refers to the Hamilton Depression Scale (HAM-D) and the Symptom Checklist (SCL-90).

From a clinimetric point of view, it is indeed valid to have these two rating scales as the platform for the component/dimensional specific approach. The time has come to use both the HAM-D and the SCL-90 as multidimensional scales and not within the concept of the traditional FDA guided trials where these scales are “bureaucratically” considered as unidimensional. The total scores of the HAM-D or the SCL-90 are not sufficient statistics when using Katz’ model for the identification of new, more effective molecules.

Throughout his new book, Katz has used his previous placebo-controlled trials with desipramine versus paroxetine to demonstrate the onset of action for the componential approach, illustrating the superiority of desipramine on the dimension of depressed mood- retardation, with an onset of action already after 3 days compared to 13 days for paroxetine and 21 days for placebo. From an economic standpoint, when performing clinical trials of antidepressants, Katz recommends such intensive assessments of specific drug-induced changes. He concludes that the field of neuropsychopharmacology stands to gain new knowledge of importance to both basic and clinical research.

We all must read Martin Katz’ attempt to educate us about his very impressive work on going beyond the FDA model of applied science to the basic science of clinical psychopharmacology.

Per Bech

May 26, 2016