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

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 47 Table 2. Selected Tests of the Dopamine Hypothesis of Schizophrenia Test Prediction of DHS Main Subform Result of DHS Tested CSF levels of HVA Increased* Reg, IT -- Basal levels of growth hormone Increased Reg, IT, or IRF -- Growth hormone stimulation to DA agonists Increased Reg, IRF - Basal levels of prolactin Decreased Reg, IT, or IRF -- Prolactin suppression by DA agonists Increased Reg, IRF -- Levels of DA or HVA in post-mortem brain Increased* Glob or Reg, IT - Psychotic symptoms in response to Increased Glob, IRF + amphetamine administration Increase in vivo levels of brain DA receptors Increased Glob or Reg, IRF -+ Association studies of DA-related genes D1 Altered Glob - D2 Altered Glob -- D4 Altered Glob -+ D5 Altered Glob ? COMT Altered Glob - DA transporter Altered Glob -- DA decarboxylase Altered Glob - Abbreviations: --, results strongly against prediction of DHS; - results moderately against prediction of DHS, +- results equivocal regarding DHS; +, genetic changes in DA receptors would most likely produce IRF but other changes could produce IT; ++ results strongly support prediction of DHS; Glob, global, reflecting DA function in general in the brain (or in unknown more specific areas); IRF, increased receptor function (due to increased number or sensitivity of DA receptors); IT, increased turnover; Reg, regional, reflecting DA function in specific brain areas. *Note that CSF levels of HVA and brain levels of DA or HVA primarily test for the IT version of the DHS. However, if the IRF version of the DHS were true, then you might expect the reverse result. That is, due to increased feedback due to increased receptor function, the levels of HVA or DA could be reduced.
48 ■ PPP / Vol. 18, No. 1 / March 2011 or IRF in this system should produce reduced prolactin levels in schizophrenic subjects. Marx and Lieberman (1998) conclude that the available literature suggests no systematic differences between medication-free schizophrenic subjects and control subjects in their basal level of prolactin. Several studies have also looked at the suppression of prolactin by DA agonist drugs—which would test the IRF version of the DHS—and found no systematic differences between schizophrenic patients and controls. The neuroendocrine hypotheses derived from DHS have not been empirically validated. How strong were these tests? Although we could find no published discussion of the broad relevance of these findings for the DHS (as there were for the CSF results), the conclusions seem similar. These results would argue against a global DHS but not more restricted hypotheses that postulated that IT or IRF versions of the DHS were still, true but resided elsewhere in the brain. Psychotic Symptoms in Response to Psychostimulant Administration As noted, an early key finding that helped lead to the original formulation of the DHS was the clinical observation of schizophrenia-like states resulting from administration of amphetaminelike drugs. A derivative empirical test for the DHS was developed that involved the administration, under controlled conditions, of modest doses of amphetamine to individuals with schizophrenia and matched controls. The prediction of the DHS was that schizophrenic individuals but not controls would develop psychotic symptoms upon amphetamine administration. This test would apply specifically to the IRF form of the DHS, which hypothesizes excess or supersensitive DA receptors. In a detailed review published in 1987, Lieberman et al. identified eleven controlled studies that compared the clinical response to psychostimulants in schizophrenic and nonschizophrenic comparison subjects. We were unable to locate any more recent controlled trials. Of these eleven studies (which administered amphetamine, methylphenidate or ephedrine), seven found the schizophrenics subjects to “worsen in substantially greater proportion” than non-schizophrenic controls, whereas four did not. This review paper also pooled the results across all studies and reports a highly significant difference in the rate of clinical worsening after psychostimulants in schizophrenic versus non-schizophrenic subjects (Lieberman et al. 1987). These results seem broadly consistent with the IRF subform of the DHS. However, the quality of this test of the DHS is a function of the degree to which the effects of these psychostimulants are specific to the DA system. To take one wellcharacterized psychostimulant as an example, amphetamine is a “dirty drug” and has greater potency at causing release of norepinephrine than of DA and is about equipotent in blocking the reuptake of the two neurotransmitters (Koob and Le Moal 2006). If stimulation of DA receptors were the sole means by which amphetamine increased psychotic symptoms, then the purer DA agonist drugs ought to have greater psychogenic potential. This has not generally been observed (Depatie and Lal 2001). In summary, evidence from psychostimulant challenge studies provides some support for the DHS. Brain DA Metabolites Although beset with a range of methodological difficulties, a direct test of the IT subform of the DHS would be to compare levels of DA or HVA in the brains of individuals with schizophrenia and controls. In their 1991 review, Davis et al. summarized five such studies in postmortem samples. In total, these studies examined four subcortical regions (amygdala, putamen, caudate, and accumbens) and the temporal, cingulate, and frontal cortex. Because several studies examined multiple brain regions, thirteen comparisons were summarized. Focusing where possible on schizophrenics who were neuroleptic-free at the time of death, no differences were found in ten comparisons and in three results were as predicted by the DHS. The positive findings were from three different regions: amygdala, accumbens, and caudate. We are aware of an additional study not included in this review (Farley et al. 1977), which found no significant elevation in levels of DA or HVA in the brains of schizophrenic individuals.
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