The Dopamine Hypothesis of Schizophrenia: An Historical and Philosophical Analysis

The dopamine (DA) hypothesis of schizophrenia (DHS) has, since its inception over 30 years ago, been among the most prominent etiologic theories in psychiatry. This essay begins by summarizing the history of its emergence and efforts to empirically test it through the examination of (i) cerebrospinal fluid DA metabolites, (ii) neuroendocrine measures, (iii) clinical response to psychostimulants, (iv) brain levels of DA and its metabolites, (v) brain studies of DA receptors, and (vi) genetic association studies. We then examine how successful the DHS has been and by what criteria its performance should be evaluated. In this process, it is critical to distinguish the etiological DHS from the pharmacological DA hypothesis of neuroleptic action. Although the DHS stimulated much science, most efforts to empirically validate it have failed, in contrast with the well-supported pharmacological DA hypothesis of neuroleptic action. Nonetheless, the DHS has held the status of a scientific paradigm defended by some with great avidity. Like other temporally extended theories, the DHS in its most general form is relatively nonspecific and protean in nature. In its evolution through successive more specific forms, often embodying ad hoc modifications of subsidiary hypotheses, it became very difficult to falsify. Although stimulating much research, it has not produced a progressive research program generating various novel and confirmed predictions about schizophrenia. For most of its history, the DHS has lacked a viable competing alternative theory against which it could be incisively compared. Sociological factors, especially the rise to prominence of the biological psychiatry movement, and the conflation of the DHS and the DA theory of antipsychotic drug action have probably played an important role in its persistence. Psychiatry needs theories with higher levels of specificity and falsifiability. As the science of psychiatry matures, the field needs to become more self-critical about the validity of its theories.