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

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 51 al. (2005) performed a meta-analysis of six casecontrol studies that produced no evidence for association. They reviewed the known family-based association studies of this polymorphism, which were also all negative. We now turn to those genes for which no meta-analyses were available. For the D1 receptor, the most recent locatable report, which contains both new results and a literature review of several polymorphisms, finds no consistent evidence for association with schizophrenia (Kojima et al. 1999). For DOPA decarboxylase, we located two negative reports (Borglum et al. 2001; Zhang et al. 2004). For tyrosine hydroxylase, we found a recent negative report with a short literature review that indicated mixed prior results (Pae et al. 2003). Also noteworthy is a recent study that examined eighteen variants in twelve different key DA-related genes in 496 schizophrenic and matched control subjects (Hoogendoorn et al. 2005). None of these were associated. Although this review is not exhaustive, a general picture emerges. The large majority of genetic studies that have attempted to validate the DHS have produced negative results. Two positive findings emerge, the best validated of which is the Cys311Ser polymorphism in the D2 receptor. Less well studied is a promoter variant in the D4 gene. The effect sizes of these variants are, however, modest with ORs in the range of 1.2 to 1.4. A monozygotic twin of an individual with schizophrenia has a risk for schizophrenia that is increased 50- to 100-fold (Sullivan et al. 2003). If these gene effects are real, they account for very small proportions of the total genetic risk for schizophrenia. What do the findings from genetic association studies tell us about the DHS? The large majority of the data is inconsistent with the theory. But how strong are these tests? As pointed out by Talkowski et al. (2007), many of the association studies of DA-related genes in schizophrenia have been underpowered to detect modest effect sizes that are being seen in complex diseases. Furthermore, genomic coverage has also been far from ideal for most studies. The number of genetic variants that impact on DA function in the human brain may be very large. The field has focused to date on the obvious suspects, which together may constitute a small proportion of all genes influencing brain DA systems. Individual negative findings may therefore be of limited overall significance. In the next several years, multiple genome-wide association studies of schizophrenia will be published, further clarifying the relationship between DA-related genes and risk for schizophrenia. How are we to interpret the positive findings, especially given that variants at the D2 Cys311Ser polymorphism may make a small contribution to the genetic risk for schizophrenia? Do these results confirm the DHS? Is it significant that the leading susceptibility genes for schizophrenia do not seem to have a major impact on brain DA, but rather may alter glutamate functioning (Owen et al. 2004)? Reformulations of the DHS In its earliest phases, the DHS focused on the full syndrome of schizophrenia. However, on closer examination, the two major indirect supports for the DHS were not equally compelling for all aspects of schizophrenia. Neuroleptic drugs were more effective at treating positive symptoms of schizophrenia than the negative symptoms. Amphetamine-induced psychosis reflected much more the positive than the negative symptoms of schizophrenia (Connell 1958). In the 1980s, negative symptoms became more central to the conceptualization of schizophrenia (Andreasen 1981; Crow 1980). This led to a reevaluation of the DHS, which was also prompted by studies in Japan (reviewed in Meltzer and Stahl 1976) and later in the United States (e.g., Cutler et al. 1984; Tamminga et al. 1986), showing that DA agonist drugs improved the clinical picture in schizophrenia, particularly the negative features. Although this effect could result from DA autoreceptor stimulation, they raised the question of whether negative symptoms might actually be due to functional DA deficits. These and other results lead to an effort by Davis et al. to propose, in 1991, a major revision of the theory. Their formulation was that “schizophrenia can be characterized by hypodopaminergia in mesocortical and hyperdopaminergia in mesolimbic dopamine neurons” (Davis et al. 1991). Their proposal represents a modification
52 ■ PPP / Vol. 18, No. 1 / March 2011 of the original DHS in two major ways. First, this proposal increased the anatomic specificity of the original hypothesis proposing specific pathways or regions for the action of DA. Second, and more radically, it reversed the direction of the original hypothesis with respect to one of these major DA tracts. Figure 2 outlines the changes in the DHS as articulated by Davis et al. Note that the apex of the figure is yet more abstract and reads “DHS = dysregulation of DA in brain.” The boxes under the mesocortical DA system now read “decreased turnover” or “decreased post-synaptic receptor function.” Attempts at Empirical Evaluation of the DHS—Summary We could not summarize herein all studies relevant to the DHS, reviews of which continue to appear regularly in the psychiatric literature (e.g., Abi-Dargham 2004; Hietala and Syvalahti 1996; Willner 1997). For example, we have not examined studies of plasma levels of HVA, which may help to evaluate a “global” DHS. Surprisingly, no meta-analyses or detailed reviews of this literature were found. Several (Garcia et al. 1989; Maas et al. 1993; Zhang et al. 2001) but not all studies (Steinberg et al. 1993) report elevated levels of plasma HVA in schizophrenic versus control subjects. However, a minority of plasma HVA comes from central DA neurons (Amin et al. 1995). Furthermore, plasma HVA levels can be substantially influenced by state variables (Csernansky and Newcomer 1994), such as diet (Donnelly et al. 1996; Kendler et al. 1983), exercise (Kendler et al. 1983), and mental stress (Sumiyoshi et al. 1999). Studies of plasma HVA are unlikely to provide definitive evidence about the validity of the DHS. We also have not reviewed the empirical literature favoring the role of DA in neuroleptic action. We do not dispute the strength of this evidence, but argue (see below) that it is of limited relevance to an evaluation of the DHS. Table 2 summarizes the empirical tests of the DHS that we have evaluated. Two summary points are noteworthy. First, overall, the DHS has performed poorly. Few of its predictions have been empirically validated (although we do not claim that the quality of these tests has been uniformly high or that we have reviewed all the relevant information). Second, many of these tests were not evaluating the same scientific hypothesis. Some were testing the IT version of the DHS and others the IRF version. Some were testing regional versions of the DHS and other global versions. In seeking a perspective on the current status of the DHS, we could find no more appropriate view than this recent quote from in a text edited by Carlsson and Lecrubier (2004, 99) from original comments by Stahl: In spite of much research effort over more than 30 years, direct evidence for changes in brain dopamine concentrations or in dopamine receptor densities remained frustratingly intangible. However, in recent years a new lease of life has been given to this hypothesis. . . . Rather than seeing dopamine hyperactivity as a primary source of pathology in schizophrenia, we now see this rather as a vector of a more complex primary etiology, which allows the expression of psychotic symptomatology. In this model, the primary deficit would lie in inappropriate information processing in the prefrontal cortex, perhaps through structural anomalies in synaptic organization during development, perhaps due to plastic changes in connectivity involving anomalies in glutamatergic transmission. In addition, the abnormalities in dopaminergic neurotransmission may be better considered as dysregulation rather than hyperactivity, with certain symptoms, particularly cognitive ones being related to insufficient dopaminergic activity in the cortex. The simpler form(s) of the DHS—as originally postulated—are difficult to recognize in this formulation. Consistent with Davis’s modification, the emphasis is on DA “dysregulation” rather than hyperactivity. DA abnormalities are no longer given etiologic primacy, which in this account seems to have been shifted to glutamate. If this reflects a “new lease on life” for the DHS, it is in the form of a substantially altered theory, and even more likely, as a virtual replacement of the original DHS. This is an issue we return to toward the end of the next section. Philosophical Analysis How successful has the DHS been and, by what criteria should we evaluate its performance? Trying to answer this question leads us through several major theories of scientific progress and to two further questions: (i) Would a more produc-
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