The Dopamine Hypothesis of Schizophrenia: An Historical and ...

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 57 abstraction makes the hypothesis more vague and harder to test empirically. Similarly, the very broad extension of the theory summarized in the quote from Stahl suggests a violation of a core hypothesis of the original DHS, and in point of fact, a replacement by a more complex theory that is actually a competitor of the original DHS. In addition, and somewhat similar to the Kuhnian point about the need for a competing paradigm as a condition for a scientific revolution, from the TET perspective, a scientific field would not be ready to abandon a central hypothesis in the absence of an alternative. In the Stahl quote, and much of the recent literature on the DHS, this emerging multi-transmitter hypothesis may be paving the way for an ultimate rejection of any simple DHS. How Might We Have Done Better? Although we can be justly criticized as passing judgment from a position of hindsight, it is nonetheless worthwhile to ask how the DHS might have done better and been made more falsifiable and progressive. Psychiatric researchers might have emulated the molecular biology that was a model for them during the period that the DHS was developed, and attempted to follow a Popperlike methodology of “strong inference.” Such an approach was articulated by Platt, who in 1964 attempted to summarize the methods then used by the stunningly successful discipline of molecular genetics. Platt suggested that rapid scientific progress could be made only if well-formulated alternative hypotheses were subjected to crucial experiments designed to eliminate most of the alternatives. He characterized this approach as involving the following steps: 1. Devise alternative hypotheses. 2. Devise one or more crucial experiments with alternative possible outcomes, each of which will, as nearly as possible, exclude one or more of the hypotheses. 3. Carrying out the experiment so as to get a clean result. 1’.Recycle the procedure, making subhypotheses or sequential hypotheses to refine the possibilities that remain; and so on. Closely integrated with this attempt at strong tests whose goal was disproof was the need to simultaneously entertain multiple hypotheses. It was critical, he argued, for the working scientist to avoid being wedded to one favorite, and thus look for ad hoc excuses to save the preferred hypothesis. In this line of argument, Platt drew on Chamberlin’s 1897 methodological caution which we quote in extenso: The moment one has offered an original explanation for a phenomenon which seems satisfactory, that moment affection for his intellectual child springs into existence, and as the explanation grows into a definite theory his parental affections cluster about his offspring and it grows more and more dear to him. . . . There springs up also unwittingly a pressing of the theory to make it fit the facts and a pressing of the facts to make them fit the theory. . . . To avoid this grave danger, the method of multiple working hypotheses is urged. It differs from the simple working hypothesis in that it distributes the effort and divides the affections. . . . Each hypothesis suggests its own criteria, its own method of proof, its own method of developing the truth, and if a group of hypotheses encompass the subject on all sides, the total outcome of means and of methods is full and rich. The lack of a genuine alternative to the DHS facilitated Kuhnian resistance prevented a robust competition between alternative research programs, and militated against strong tests from both a Popperean and Bayesian perspective. This paper is not the place to speculate on what genuine alternatives might have emerged or what types of alternatives might best be now developed. The currently fashionable glutamate/ NMDA hypothesis may have similar defects to the DHS. We suspect that successful candidates will be multi-systems models incorporating both multiple explanatory levels as well as incorporating aspects of neurodevelopment (Kendler and Parnas 2008). Future research might also succeed in efforts begun in the days of Kraepelin and Bleuler to subdivide the syndrome of schizophrenia into more discrete etiologic subtypes. The Persistence of the DHS When viewed from the perspective of these four major theories of scientific progress, the DHS has performed relatively poorly. Yet it has remained a
58 ■ PPP / Vol. 18, No. 1 / March 2011 major theory in psychiatry for over four decades and still has a prominent place in many textbooks (e.g., Buchanan and Carpenter, Jr. 2005; Cohen 2003 Gazzaniga 2004; Kandel et al. 2000;). How can we account for its tenacity? Addressing this question requires us to segue from philosophical analyses of science to a sketch of the sociological factors that have impacted on the development and persistence of the DHS. Of these, the most important was surely the rise of the biological psychiatry movement. Psychiatry has long sought for simple etiologic explanations of the complex clinical syndromes that it describes and treats. The dramatic successes with General Paresis of the Insane and Pellagra held out the promise that similar advances would be possible for other syndromes. Beginning in the early twentieth century, an etiological approach based on increased understanding of physiology and biochemistry began to have success in general medicine (Schaffner 2002). Psychoanalysis, which held a dominant position in mid-twentieth century American psychiatry, had, however, little interest in these developments, believing that the causes of psychiatric disorder lay in the mental realm. Led by a few key individuals, especially Kety, the nascent biological psychiatry movement began in the 1950s to seek physiological explanations for major psychiatric disorders, especially schizophrenia. However, a number of their early efforts (e.g., ceruloplasman, taraxein, the “pink spot” and transmethylation theories [Kety 1959, 1966; Predescu et al. 1968]) went nowhere—an embarrassing situation for a young field seeking to legitimize itself. Snyder et al. summed up this situation: Innumerable “discoveries” of the biochemical abnormality in one or another body fluid of schizophrenics have relentlessly been followed by failures of confirmation in other laboratories. (1974, 1243). We suggest that the DHS was grasped with avidity by the nascent biological psychiatry movement for three reasons. First, the DHS was grounded in two inter-related “new” basic sciences—neurochemistry and psychopharmacology. By linking etiologic theories to these high-prestige, “hard-science” disciplines, biological psychiatry could obtain legitimization and be seen as applying to psychiatry the biological etiologic approach that had proved increasingly successful in the rest of medicine. This fulfilled one central goal of the movement—to bring psychiatry back into the medical mainstream. The history of medicine provides other examples of groups of physicians attempting to ground their theories in new scientific advances, in part to bolster their professional status (e.g., Brown 1970). Second, the stunning success with Parkinson’s disease, where all the features of the illness could be apparently traced to a single neurotransmitter deficit, suggested the viability of the tempting “one transmitter, one disease” model for neuropsychiatric disorders (Shorter 1997). This model fit very well with the reductive zeitgeist of the biological psychiatry movement that sought to continue in the tradition of the stories of GPI and pellagra. Third, the DHS tied the etiologic theory of schizophrenia to the increasingly unassailable evidence of the efficacy of antipsychotic drugs for the treatment of schizophrenia. Thus, the DHS could, at least in this indirect manner, be anchored in the practical world of psychiatric therapy. Relatedly, Shorter has suggested that a “one transmitter one-disease hypothesis” was “a perfect marketing concept for the drug companies” (1997, 267). The DHS has also been sustained over time by increasing evidence that the therapeutic effect of antipsychotic drugs correlates robustly with their capacity to block DA receptors. Such results are still commonly used as support for the DHS. In our view, this argument is logically flawed and results from a conflation of two distinct theories: The DHS, a theory of disease etiology, and the “dopamine hypothesis of antipsychotic drug action” (DHADA), a theory about pharmacologic mechanism. Information in support of the DHADA was clearly useful in supporting the plausibility of DHS at the time of its proposal. However, medicine has many examples in which the mechanism of action of a therapeutic drug is far removed from disease etiology, albeit perhaps not from its downstream pathophysiology. Diuretics are common treatments for congestive heart failure, yet the mode of action of these drugs in the kidney tell us little about the etiology of heart failure. Anti-inflammatory drugs reduce symptoms in a wide variety of conditions, but typically act on
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