Walter Brown’s final comment

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

            Establishing the efficacy of an antidepressant is a perilous business. In the conventional antidepressant clinical trial, drug placebo differences are vanishingly small (effect sizes average about 0.3), fewer  than half the clinical trials of approved antidepressants show the antidepressant to have an advantage over placebo and even when an antidepressant proves better than placebo it’s not at all clear that the drug will be useful in a clinical situation; the sorts of depressed patients who make up the subjects of contemporary clinical trials bear little resemblance to those seen in clinical practice.

            Martin Katz, in the book reviewed here, tackles some of the problematic features of antidepressant trials and, focusing on measurement issues, offers some solutions.  His comments about his book and the comments of others provide a reasonably thorough and balanced assessment of the book’s main thrust, which is that the sorts of outcome measures used in clinical trials need an overhaul and that assessment of depressive components would be more informative than the global appraisals now in vogue. Katz may be right. Clearly anything that can be done to improve the efficiency of and knowledge gained from clinical trials is welcome.

            Still, the dearth of treatment innovation pointed to in these exchanges will not be resolved by tweaking clinical trials. Clinical trials are not meant as a route to discovery. When something new comes out of a formal trial it’s strictly by accident. As William Thomas  Beaver, a clinical pharmacologist credited with drafting the initial FDA regulations defining adequate and controlled clinical studies said: “The function of the controlled clinical trial is not the “discovery” of a new drug or therapy. Discoveries are made in the animal laboratory, by chance observation, or at the bedside by an acute clinician. The function of the formal controlled clinical trial is to separate the relative handful of discoveries which prove to be true advances in therapy from a legion of false leads and unverifiable clinical impressions, and to delineate in a scientific way the extent of and  the limitations which attend the effectiveness of drugs.”

            In trying to understand why nothing new has come along, we need to ask ourselves why the 1950s saw a flood of novel psychotropic drugs that hasn’t been equaled since. The far more sophisticated research methods of today have brought us, by contrast, a trickle of me-too drugs which offer a minuscule, if any, advantage over the older agents. Current research methods certainly have their advantages. Placebo control groups, randomization to treatment arms and standard rating instruments help prevent the misleading conclusions that can be drawn from clinical impression alone. Yet, unfettered, open-minded, clinical observation, unconstrained by regulatory requirements, was the “method” which allowed Roland Kuhn and Nathan Kline to detect the healing power of the first antidepressants. Perhaps their experiences can inform the search for better approaches to drug discovery.


Affidavit of William Thomas Beaver, M.D. (personal  correspondence, Peter Barton Hutt Esq. and Dr Robert Temple, FDA, December 2007, FDA History Office Files). In: White Junod, S. FDA and Clinical Drug Trials: A Short History. Available at:


August 3, 2017