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Thursday, 29.06.2017

Reply (Martin Katz)

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Don Klein’s comments on Per Bech’s book are helpful in advancing understanding of the author’s main points, and in focusing on some important issues regarding measurement and the manner in which we currently approach the evaluation of new drugs for the mental disorders. He raised at least three issues that currently obstruct longterm solutions to problems in clinical psychopharmacology, specifically in the conduct of clinical trials. He also alluded to points in which in my review of Bech’s book I differed with the author. I believe he agreed with my position that the multiple factor solution is the more effective use of factor analysis in extracting information about drug actions. At the same time, he is uncomfortable with the actual content of the factor measures, alluding to both Bech’s reservations about factor analysis, generally, his own prior work, and to the procedures applied in my “multivantaged” approach.  To further clarify my position, I respond to the issues raised as follows:

1.    It is important in all method development to be clear about what specifically, is to be measured. I believed the critical problem in current trials research is its almost exclusive focus on evaluation of change in the severity of the overall disorder, to the exclusion of evaluating drug effects on the major components of the disorder. When I proposed the multiple factor solution, it was because we first sought measures of the facets of psychopathology, measures that were essential to not only assess severity of the overall disorder, but the intensity of each of the major components of that multidimensional disorder. In that method work then, the target was valid measures of these facets, not of “change” due to a specific drug or drug class.  The componential approach applied affected how the rating scales were developed but also, highlighted the need to go beyond rating scales to achieve more “objective” measures. Klein refers, e.g., to the new DSM 5, to illustrate how “ambivalently” the concept of objectivity continues to be treated by the profession. We therefore, expanded the measurement approach through use of other psychological methods, e.g., self report inventories, measures of expression (through video), and psychomotor performance, in order to achieve more valid measures of the components.

2.    Klein points to the use of factor measures in drug trials in which the items in a given factor are differentially sensitive to change. He see this rightfully, as obscuring the drug-placebo differences; implying that the factor should only include items that are change sensitive. If the intention in creating the factor is to develop a “change” method specific to the measurement of the effects of that drug or like drugs, then, one might want to confine the factor items only to those that have been demonstrated to be change-sensitive. The method developed is then targeted to be more sensitive than existing methods, to the actions of that drug or like drugs. If, however, a new drug is tested that has different effects than the established ones, this particular method will be of limited use in detecting those effects.The prime intention when working in this sphere has, therefore, been to create measures of the facets of psychopathology of a given disorder or set of disorders, e.g., “anxiety”, that can be applied in the measurement of any type of treatment intervention. The position is that the “multivantaged” approach is what is most needed now in clinical trials of new agents and in clinical studies in psychopharmacology, generally. I believe that with colleagues, Alan Frazer and Charles Bowden, we have clearly demonstrated the advantages of that approach, its capacity, e.g., to provide information on the nature, timing, and sequence of actions of diverse antidepressants,in a series of studies. The results of these studies are summarized in my recent “Depression and Drugs” book (Springer, NY, 2013).

3.   On the third issue, Klein cites the limitation of drug-placebo comparisons by calling attention to the fact that finding a drug effect in a class of disorders, does not help with the prediction for any given patient. Separating the placebo from the drug effect in a patient is an important problem, particularly for clinicians trying to treat treatment-resistant patients. Klein raises this to initiate discussion of more precise methods for accomplishing that aim.The prediction literature on that problem for the depressive disorders indicates that for the most part, we do not have at treatment outset, any reliable specific symptom predictors of drug response. The work of Szegedi et al (2009) (Early improvement in the first two weeks. J Clin Psychiatry 2009; 70: 344-353), Stassen et al (1997) (Delayed onset of action of antidepressant drugs? Eur Psychiatry 1997; 12: 166-176), and Katz et al. (2011) (The componential approach. J Clin Psychopharmacology 2011; 31: 253-254) show that no improvement in the patient within the first two weeks of drug treatment in severity of the overall disorder or in levels of anxiety or hostility results in >90% of patients failing to respond positively at outcome. Whereas 70% of those having a positive treatment outcome will have shown significant improvement (>20%) by the end of the 2nd week of treatment.  These relatively new findings do not solve the problem Don Klein raises, but in utilizing “early response” to treatment as a predictor, it is an approach that can help reopen the issue.

 

Martin M. Katz

December 12, 2013