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

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 49 The results from post-mortem studies of DA or HVA levels have not, in general, confirmed predictions of the DHS. The positive findings that have emerged are inconsistent with respect to anatomical location. These studies provide a more direct test of the IT subform of the DHS than was possible using CSF or neuroendocrine approaches. In particular, post-mortem studies can examine abnormalities in DA function that are anatomically restricted in their effect. A complexity in the interpretation of these findings is that some of the IRF forms of the DHS would predict decreased brain levels of DA or HVA, the opposite of that predicted by the IT version. Brain DA Receptors As pointed out in 1975 by Matthysse and Lipinski, perhaps the excess DA transmission is due to IRF in turn the result of greater numbers or increased sensitivity of brain DA receptors. When the original DHS was articulated, it could not have been foreseen that the DA receptor—which was then postulated but not yet isolated—would first become two and then five different receptor subtypes. The literature on post-mortem and in vivo measurement of DA receptors in schizophrenia is both large and technically complex. We rely here largely on results from the most recent metaanalysis of the literature published in 2001 (Kestler et al. 2001) and a 2005 review by Abi-Dargham (Gunderson et al. 1995). Sufficient studies were available only to examine D1 and D2 receptors. Examining both post-mortem and in vivo studies, a moderate to large effect was observed for schizophrenic versus control subjects for the D2 but not the D1 receptor. Interestingly, both receptor density and affinity were elevated in patients with schizophrenia. The effects on the D2 receptor were substantially greater in patients currently or recently on neuroleptic medication. Controlling for this effect diminished but did not eliminate the observed difference. The results differed neither in post-mortem versus in vivo studies or across brain regions. A number of studies examined multiple regions. Of the thirty-six studies, thirty-four examined all or parts of the striatum (the terminal of the Nigrostriatal pathway). Only four examined the nucleus accumbens (a terminal region for the mesolimbic DA pathways) and two the frontal cortex (the terminal region for the mesocortical DA pathway). Although it is clear that schizophrenic subjects have elevated D2 receptor density in their brains, the more crucial question of whether this is due to schizophrenia or neuroleptic exposure is less clear than this review (Kestler et al. 2001) indicates for at least four reasons (J. Kleinman MD, personal communication, October 2005). First, the number of drug-naïve schizophrenic subjects studied post-mortem was probably too small to provide definitive data. Second, despite evidence that the men and women might differ systematically in the number of D2 receptors, several studies included in this review were poorly matched for sex in a way that could produce artifactually positive findings. Third, two of the studies that present the strongest evidence for elevated D2 receptor numbers in drug-free subjects have a large overlap in their schizophrenic subjects (Tune et al. 1993; Wong et al. 1997). Fourth, one study showing no schizophrenia control difference in baseline D2 receptor binding potential was not included in the review (Abi-Dargham et al. 2000). Abi-Dargham concludes that the findings on D2 receptors in schizophrenia post-mortem brain tissue “are related to prior neuroleptic exposure rather than to the disease process per se” (Gunderson et al. 1995). Abi-Dargham reviews seventeen imaging studies of striatal D2 receptors in drug-naïve or drug-free schizophrenic patients versus controls (Gunderson et al. 1995) and finds across studies a significant but modest 12% increase. Of concern however, is a strong temporal trend in these results. These studies can be divided into those published before 1991 (n = 5), between 1991 and 1995 (n = 6), and after 1995 (n = 7). The mean effect size for schizophrenia–control differences declines substantially across time: before 1991, +0.91; 1991 to 1995, +0.53; and after 1995, +0.16. These results, along with concerns about this literature raised above, at least casts some uncertainty about the correct interpretation of the D2 in vivo studies in schizophrenia. Abi-Dargham goes on to conclude that in vivo imaging studies have consistently failed to
50 ■ PPP / Vol. 18, No. 1 / March 2011 find evidence of altered striatal D1 receptor availability in schizophrenic patients and notes that the modest number of studies of prefrontal D1 receptors in schizophrenia have produced no consistent evidence of alterations (Gunderson et al. 1995). Even after recognition of these problems, D2 receptor studies provide some of the strongest direct empirical verification of the DHS obtained to date, of particular relevance to the IRF subform of the general theory. However, contrary to prior suggestions that a regional DHS was most plausible, these results are supportive of a global DHS, because excess DA receptors have been seen across three of the major brain DA systems. In fact, most of the positive evidence coming from a DA system—the nigrostriatal—that earlier advocates of the theory had argued was not likely to be primarily involved in schizophrenia. As may be recalled, the nigrostriatal DA system contributes most strongly to CSF HVA concentration. The negative results from the CSF HVA studies were discounted largely because the nigrostriatal system was thought to have little to do with the etiology of schizophrenia. Genetics At the inception of the DHS, it would have been impossible to foresee that tools would develop to test whether variants in genes involved in the brain DA system influence susceptibility to schizophrenia. Given that genetic factors impact strongly on liability to schizophrenia (Sullivan et al. 2003), if the DHS were true, some of this genetic risk would likely be expressed in variants that directly or indirectly resulted in increased brain DA function. This approach might be considered a further subdivision of the DHS, with specific genetic variants contributing to either the IT or IRF mechanisms, in either a global or specific regional manner (Figure 1). We do not pursue these specific issues further here. Association studies are the method of choice to determine whether specific genes are etiologically involved in a disorder. Therefore, we review the large literature for those genes known to be directly involved in DA function: DA receptors, synthetic and degradative enzymes, and the DA transporter. (For a more detailed recent review of this literature, see Talkowski et al. 2007). We begin with genes for which meta-analyses are available. The D2 receptor gene has been widely studied with most interest focusing on the Cys311Ser polymorphism. A recent meta-analysis of 27 case-control studies reported a significant but modest association between the Cys allele and schizophrenia with estimated odds ratios (ORs) of 1.4 (Glatt and Jonsson 2006). A meta-analysis of 10 studies of a different variant in the same gene (-141C insertion/deletion) found no evidence for association with schizophrenia (Glatt et al. 2004). The literature on the Ser9Gly variant in the D3 receptor gene and schizophrenia is vast, with seven published meta-analyses. The most recent of these included more than 11,000 total subjects and showed a very small and nonsignificant association with schizophrenia (Jonsson et al. 2004). In the D4 receptor, most interest has focused on the 48-basepair repeat in exon 3. A recent meta-analysis of 19 studies showed no significant association with schizophrenia (Jonsson et al. 2003). Seven studies had examined a twelve base-pair repeat in exon 1 and no significant association was found (Jonsson et al. 2003). However, three studies examined a promoter variant (-521C/T) and a meta-analyses of these studied indicated a modest and significant association with schizophrenia (OR = 1.22). The literature on the association between variants in the catechol-O-methyl transferase (COMT) gene and schizophrenia is immense and inconsistent. Two recent meta-analyses have reached negative conclusions for the widely studied Val/ Met polymorphism (Fan et al. 2005; Munafo et al. 2005) although other variants in the gene have been studied and found to be associated (e.g., Shifman et al. 2002). A study with more than 2,800 individuals looking at both the Val/Met polymorphism and a previously identified highrisk haplotype be was negative (Williams et al. 2005). (A haplotype is a DNA segment so short that it tends to pass through populations intact). A recent meta-analysis of six case-control studies of the VNTR polymorphism in the 3´ untranslated region of the DA transporter showed no evidence for association with schizophrenia [Gamma et al. 2005]). The most studied variant in the DA transporter gene is a variable number tandem repeat in the 3´ untranslated region of the gene. Gamma et
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