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

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 59 physiological processes remote from those which cause the disorder. For this reason, we suggest that further evidence supporting the DHADA is of minimal relevance to the validity of the DHS. Although one can justly claim from the DHADA that “dopamine must have something to do with schizophrenia,” this is a weak argument because the mode of action of drugs can be so far removed from basic disease etiology as to be largely uninformative about etiologic processes. We suggest that, in their enthusiasm for this theory, the biological psychiatry movement was, initially and for many subsequent years, willing to overlook the substantial limitations of the DHS that we have reviewed above and conflate the DHS and DHADA. Although a further explication of this part of the story lies outside the bounds of this review, a full historical understanding of the DHS would require consideration both of scientific and extra-scientific forces. Concluding Thoughts In conclusion, we want to be clear about what we are and are not saying. We do not claim that DA is unrelated to the etiology of schizophrenia or that DA does not explain a lot about the action of antipsychotic drugs. Furthermore, we recognize that theories can be useful in guiding treatment even if they are etiologically incomplete or wrong (Schaffner 2002). Many hypotheses in medicine that were not based on deep etiological understanding have produced practical therapeutic benefits. This is likely the case for the DHS. By contrast, we do conclude that, as a scientific theory, the DHS has to date performed relatively poorly and has, from the perspective of leading models of science, important deficiencies. Furthermore, we suggest that the story of the DHS has at least four important lessons for our field. First, psychiatry needs theories with higher levels of specificity and falsifiability. Global, nonspecific theories like the DHS have heuristic value and can play an important role in stimulating research in the short run. However, such theories are less effective at guiding research in the long run in fruitful and progressive directions. Several of the etiologic theories for schizophrenia that compete with the DA hypothesis, including those focusing on glutamate or NMDA receptors, probably also suffer from lows levels of specificity and falsifiability. Other leading “neurochemical” theories in psychiatry, such as the serotonin hypothesis of depression, may be similar (Lacasse and Leo 2005). Second, science works best when diverse theories with distinct predictions compete with one another. This has been hard to implement in the field of mental health research for many reasons. Third, it has been common in the history of science in general and the medical and social sciences in particular for theories to be defended with a fervor that cannot be justified by the available evidence. More than we may wish to admit, this has been the case with the DHS. As our science and field matures beyond ideologically driven controversy, it would be wise and mature for all of us, regardless of whether we see ourselves as biological, social or psychodynamic, to be more self-critical about the theories we adopt and as more tolerant of diversity in theory articulation. Finally, psychiatry is probably not ready for “big” unitary theories like the DHS. Although very tempting, it will likely be more realistic and productive for us to focus on smaller questions, and to settle for “bit-by-bit” progress as we clarify, in a piecemeal manner, the immensely complex web of causes that contribute to disorders like schizophrenia (Kendler 2005; Schaffner 1994). Acknowledgments This work is supported in part by the Rachael Banks Endowment Fund (KSK) and the National Science Foundation under Grant Nos. 0324367 and 0628825 (KFS). Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. Helpful comments on earlier versions of this essay were kindly provided by Joel Kleinman, MD, Steven Matthysse, PhD, Solomon Snyder, MD, Carl Craver, PhD, Robert Malenka, MD, PhD, Karoly Mirnics, MD, John Bickle, PhD, James Bogen, PhD, Peter Machamer, PhD, Edouard Machery, PhD, Robert C. Olby, PhD, and Carol Tamminga, MD.
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