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

More documents

Recommendations

Info

The Dopamine Hypothesis of Schizophrenia: An Historical and Philosophical Analysis Kenneth S. Kendler and Kenneth F. Schaffner Abstract: 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. Keywords: dopamine, schizophrenia, etiology, philosophy of science This essay selectively reviews, from an historical and philosophical perspective, the dopamine (DA) hypothesis of schizophrenia (DHS; Table 1 lists the abbreviations used in this essay). Our goal is not to adjudicate the validity of the theory—although we arrive at a generally skeptical conclusion—but to focus on the process whereby the DHS has evolved over time and been evaluated. Since its inception, the DHS has been the most prominent etiologic theory in psychiatry and is still referred to widely in current textbooks (e.g., Buchanan and Carpenter, Jr. 2005, 1336; Cohen 2003, 225; Gazzaniga 2004, © 2011 by The Johns Hopkins University Press
42 ■ PPP / Vol. 18, No. 1 / March 2011 1257; Kandel et al. 2000, 1200). Understanding its origins and evolution should help to clarify the nature of modern psychiatry. This essay has two parts. First, we review how the DHS emerged, how it was subsequently tested, and how well its predictions were verified. We are necessarily selective because the DHS has generated a huge literature. We concentrate on earlier episodes in its history where the results of empirical efforts at verification are relatively clear. We examine the modern areas of genetics and receptor imaging, but given the great flux these fields are now in, definitive conclusions about their ability to verify predictions of the DHS are not possible. Second, we evaluate the DHS from the perspective of prominent theories of the nature of scientific progress. (For most of this essay, we are forced by historical circumstance to make the unrealistic assumption that schizophrenia is an etiologically homogenous entity. This is because, despite huge amounts of effort and many proposed typologies, no broadly validated or deeply meaningfully method for subdividing schizophrenia has yet emerged that approaches the wide acceptance of the division of diabetes mellitus into types I and II (or even the lower standard of the division of affective illness into unipolar and bipolar). Although there are important exceptions, the large majority of the literature on the etiology of schizophrenia that we here review assumes etiologic homogeneity.) An Historical Sketch of the Dopamine Hypothesis of Schizophrenia Methodology For empirical questions in this selective review, we relied, whenever possible, on the most recent meta-analyses or reviews found through PubMed. Rise of the Dopamine Hypothesis of Schizophrenia To understand the development of the DHS requires an appreciation of the scientific context in which it arose (Baumeister and Francis 2002; Valenstein 1998). It is difficult to now recreate the excitement felt by the researchers who, in the 1950s and 1960s, were clarifying “the chemical language of the brain” (Carlsson 2001). Although chemical neurotransmission was demonstrated in the peripheral nervous system in the 1920s, debates about whether nerve cells in the brain communicated by chemical or electrical means raged well into the 1960s. In 1957, Montagu was the first to discover DA in brain tissue. This finding was quickly followed by the dramatic results from Ehringer and Hornykiewicz (Kopin 1993) of the lowered content of DA in post-mortem brains of patients dying with Parkinson’s disease. This finding led directly to the impressive treatment effects obtained by giving Parkinson patients L- dopa (Kopin 1993). A “paradigm shift” took place between 1960 and 1965 when the budding field of neuropharmacology went from skepticism to belief that the monoamines—particularly DA, norepinephrine, and serotonin—were chemical mediators between nerve cells in brain (Carlsson 2001). In the early to mid 1960s, histofluorescence stains were developed whereby the cell bodies and the neuronal pathways for the monoamine neurotransmitters DA, norepinephrine, and serotonin could be traced (e.g., Dahlstrom et al. 1962; Dahlstrom and Fuxe 1964; Falck et al. 1982; Fuxe et al. 1966). The first clear articulation of the DHS was made by van Rossum in 1967: When the hypothesis of the DA blockade by neuroleptic agents can be further substantiated it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of DA receptors could then be part of the etiology. (p. 327) As this quote indicates, a key early impetus for the DHS was the discovery by Carlsson and Lindqvist in 1963 that neuroleptic drugs effective in the treatment of schizophrenia increased DA turnover in rodent brain (that is, augmented the amount of DA being produced and degraded). However, research on the mechanism of action of stimulants also played an important role in van Rossum’s thinking (Baumeister and Francis 2002). (van Rossum’s work was not cited in early American papers on the DHS. Two of the early theorists [S. Matthysse and S. Snyder, written communication, July 2006] were not aware of it until years later.) Although hinted at in a lengthy
Page 1: The Dopamine Hypothesis of Schizoph
Page 5 and 6: 44 ■ PPP / Vol. 18, No. 1 / March

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

Create successful ePaper yourself

Delete template?

Save as template?