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

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