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

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 45 Figure 1. Schematic view of alternative versions of the dopamine hypothesis of schizophrenia (DHS) as articulated early in its history. This figure is meant to be illustrative rather than exhaustive. DHS-functional excess DA in brain Regional excess DA Global excess DA Mesolimbic DASystem Mesocortical DA System Due to increased postsynaptic receptor function Due to increased turnover Due to increased postsynaptic receptor function Due to increased turnover Due to increased postsynaptic receptor function Due to increased turnover
46 ■ PPP / Vol. 18, No. 1 / March 2011 perspective. The last two areas are, by contrast, quite active foci of on-going research and therefore cannot be definitively summarized at this time. CSF Studies The first empirical method widely used to test the DHS was an examination of the key DA metabolite in humans—homovanillic acid (HVA)—in the CSF of schizophrenic versus control patients. If, as predicted by the DHS, DA systems in the brains of schizophrenic individuals are overactive, this overactivity should be reflected in increased levels of HVA in CSF. This expectation of an effect on the CSF is a subsidiary hypothesis of this variant of the general DHS. By 1976, Meltzer and Stahl reviewed a number of studies inconsistent with this prediction. Indeed, they showed, if anything, a tendency toward reduced DA metabolites in the CSF of schizophrenic patients. A later meta-analysis reached the same conclusion as the earlier Meltzer and Stahl review (Tuckwell and Kosiol 1993). These negative results raise two important points about the DHS. First, it could be understood as predicting global changes in brain DA function or only changes in specific DA systems. In this article, we refer to these two subforms of the DHS as global and regional, respectively. Second, functional excess of DA function could arise in two broad ways: IT or increased post-synaptic receptor function (IRF for increased receptor function) that could in turn result from changes in the number or sensitivity of receptors. Only the IT subform of the DHS predicts that individuals with schizophrenia would have excess CSF levels of HVA. (Indeed, some version of the IRF form of the DHS would predict decreased levels of CSF HVA.) The non-confirmation of the predictions of the DHS by the CSF findings had little impact on enthusiasm for the DHS. As noted by Meltzer and Stahl: this result should not be used to reject the hypothesis of increased DA turnover in schizophrenia since the functional activity of DA relevant to schizophrenia may not be measured by the method. (1976, 52) In humans, much of the HVA in CSF comes from the caudate nucleus (Sourkes 1973), the endpoint of the nigrostriatal DA system. We interpret Meltzer and Stahl’s comment as suggesting that these results argue against a global DHS—in which excess DA activity is seen in all brain DA systems—but does not disprove a more restricted DHS in which excess DA activity is limited to certain regional DA systems not reflected in CSF, particularly those outside the striatum. This point was elaborated upon by Carlsson in a 1978 review, which enumerated a total of five possible subforms of the DHS including IT, IRF, and other possibilities we do not examine in detail in this review, including “deficient inactivation of DA” and alterations in presynaptic DA systems. Hormonal Systems Because two pituitary hormones—growth hormone (GH) and prolactin—are significantly influenced by brain DA systems, early attempts were made to validate the DHS by determining whether expected abnormalities in these hormonal systems were seen in patients with schizophrenia. GH is phasically stimulated by DA in the arcuate nucleus of the hypothalamus. If schizophrenia were due to widespread IT in DA neurons or to IRF of the relevant DA receptors, then excess GH stimulation should be seen in schizophrenia. As reviewed by Marx and Lieberman (1998), studies of basal GH secretion in schizophrenic and control subjects have been inconsistent with a few finding increased levels of GH in schizophrenic subjects, but with most finding no difference. The IRF form of the DHS could be specifically tested by examining whether schizophrenia is associated with greater GH stimulation in response to DA agonist drugs. A modest number of studies have examined this question and results were quite variable. In aggregate, Marx and Lieberman conclude that “schizophrenic and control subjects do not appear to differ significantly in GH response to dopamine agonists” (1998, 415). The sensitivity of the GH system can also be tested by the administration of GH-releasing hormone. In a review of three such studies, compared with controls, schizophrenic patients had a similar GH response to GH releasing hormone in two studies and a diminished response in a third (Skare et al. 1994). Prolactin is inhibited by DA secreted into the portal vein of the pituitary. Increased DA turnover
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