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

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 55 lacking—a viable alternative theory against which the DHS has had to compete. Thus, one potential lesson from Kuhn for the DHS is a negative one: it persisted because no sufficiently prominent and more successful alternative theory ever developed, in tandem with which the burgeoning empirical anomalies of the DHS could generate a true crisis leading to a subsequent revolution. At present, there is still no consensus on an alternative theory to the DHS, although most speculation seems to focus on multi-neurotransmitter neurocircuitry, in which glutamate may play a prominent role (Harrison and Weinberger 2005). Imre Lakatos In an attempt to synergize Popper’s falsifiability approach with Kuhnian insights, Lakatos (1970) developed what he termed “a methodology of research programs.” Research programs, he suggested, typically responded to problems of falsifying experiments, not with wholesale rejection of their theory, but rather with modifications of its peripheral elements, leaving intact what he called its “hard core.” Furthermore, in contrast with Kuhn, Lakatos suggested that proponents of different programs could communicate with each other and assess the relative strengths of different “programs.” Lakatos was particularly interested in distinguishing two kinds of programs. Progressive research programs confronted difficult empirical facts, explained them using their theories, and generated novel predictions that were subsequently empirically confirmed. Einstein’s theory of general relativity is an exemplar of a progressive research program. It predicted the unexpected “bending” of light around the sun observed by Eddington in 1919 and continues to be verified by increasingly accurate physical measures of our universe (Bennett 2005). By contrast, degenerating research programs confront empirical difficulties with ad hoc alterations to their hypotheses that explain the individual anomaly, but do not account for new facts. A classical example of a degenerating research program is the Ptolemaic astronomic system that, when confronted with increasingly accurate measures of planetary motion, simply added more epicycles. Which of these systems does the DHS most closely resemble? The DHS did generate a few novel findings such as the association between schizophrenia and the Cys311Ser polymorphism in the D2 gene. However, this result must be set against the many failed predictions of the theory, many of which were accompanied by post hoc rationalizations about the source of the failure. Although the picture is mixed, in general, the DHS has more closely resembled a degenerating than a progressive research program. Bayesian Approaches One difficulty with Lakatos’s vision of scientific progress is the lack of both a general measure to assess how well a program is faring and a system by which to determine how experimental successes or failures incrementally impact on the validity of an underlying theory. Several philosophers of science have developed an approach to these problems utilizing a Bayesian model of scientific reasoning (Dorling 1979; Howson and Urbach 2005; Schaffner 1993). From a Bayesian perspective, the DHS began as a theory with a reasonable prior probability of being true. The relationship between DA blockade and antipsychotic drug action had been well supported and consistent evidence indicated that DA agonist drugs could produce psychotic-like pictures. A Bayesian model allows each new experiment to impact on the posterior probability that a theory is true. A verification of the predictions of the theory makes it more likely to be true. A failure of verification makes it less likely to be true. The size of the change in this probability relates to the quality of the test. The better the test, the bigger is the change in either direction. So, when Eddington showed that light from a distant star was really bent when it passed by the sun, this had a big impact on the probability that Einstein’s theory of general relatively was true. It was a powerful test and the prediction of the theory was validated. How has the DHS fared from a Bayesian viewpoint? It has had many tests, most of them of only modest quality. However, a high proportion of them were disconfirming—the prediction of the DHS was not verified. Therefore, in aggregate, although the DHS started with a reasonable prior
56 ■ PPP / Vol. 18, No. 1 / March 2011 probability of being true, this probability has declined over the years as non-verifications have substantially outnumbered verifications. However, it is possible that further advances in genetics or imaging that confirm predictions of the DHS could reverse this trend. The Bayesian viewpoint—one strength of which is its ability to be consistently updated as new information becomes available—can also incorporate evolution of the theory itself. That is, we could see the “revised” DHS articulated by Davis et al. (Figure 2) as a new theory that might have stronger support from a Bayesian viewpoint. Other Accounts of Scientific Progress and the Issues of Theory Identity and Theory Substructure Other philosophers of science have grappled with the issues of scientific progress, including Laudan (1977), Shapere and Dordrecht (1984), and Kitcher (1993). These philosophers have additional suggestions that, although possibly useful for the DHS, cannot be reviewed in the space available. It might be of interest, however, to note yet another problem for the DHS that would be raised by Laudan’s analysis. In his Progress and Its Problems, Laudan set out a problem-solving model of progress in which quite disparate “research traditions” could compete with each other by attempting to solve their own key problems more efficiently and completely. Applying this commonsensical approach to the evaluation of scientific progress, we can simply ask—Did the DHS achieve its main aim of solving the problem of the etiology of schizophrenia? The answer, we would suggest, is no. However, we are aware that this is a high standard especially for the young field of psychiatry. The history of DHS’s attempted verifications and apparent falsifications reviewed above highlights the changing character of the assumptions of the DHS over time. This is a feature of what Kuhn termed paradigms and Lakatos referred to as research programs, and an adaptation and elaboration of Lakatos’ distinction between the hard core and the peripheral hypotheses of a theory might shed some additional light on this history. One of us (KFS) has developed a relevant philosophical account of scientific progress that incorporates these themes from both Kuhn and Lakatos (Schaffner 1993), the elements of which were introduced above and represented graphically in an atemporal manner in Figures 1 and 2 (that is, we are not showing temporal progression of the changing theories over time, but only the alternatives at a given time). That analysis, extensively applied to a research program in immunology in (Schaffner 1992), suggests that a research program is best analyzed as a temporally extended theory (TET), which is in turn partitioned into high-level central hypotheses and a temporal series of more specific mechanisms that embody the central hypothesis. If the specific mechanisms, which instantiate the central high level hypothesis and are empirically testable, fail tests of verification, and these mechanisms become patched up in ad hoc ways, then any competing account with a distinctly different central high-level hypothesis becomes significantly more attractive. On the other hand, if a TET is successful, investigators working with it will develop a series of rigorous experimental tests that cannot be accounted for by other competing mechanisms. When that situation occurs, the TET account suggests that we have attained “direct evidence” for the high-level central hypothesis. Viewed from this perspective, the DHS would have the central high-level hypothesis of excess DA activity contributing to the etiology of schizophrenia. The specific mechanisms (and their related tests of CSF, endocrine measures, post-mortem DA levels) have generally faired poorly in empirical tests and thereby reflected poorly on the attractiveness of the central hypothesis. The search for such “direct evidence” was a “holy grail” of DHS research, and, alas, like the grail, it has not yet been found. This TET analysis also suggests that only by stretching the original central or core abstract hypothesis was the theory significantly modified as in Davis et al.’s 1991 revised DHS. It is possible that the central or core hypothesis could be still further abstracted from the original DHS formulation, namely to the even more unspecific claim that “dopamine must have something to do with schizophrenia” or the problem is with DA “dysregulation.” However, such an additional
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