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

Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 55
lacking—a viable alternative theory against which
the DHS has had to compete. Thus, one potential
lesson from Kuhn for the DHS is a negative one:
it persisted because no sufficiently prominent and
more successful alternative theory ever developed,
in tandem with which the burgeoning empirical
anomalies of the DHS could generate a true crisis
leading to a subsequent revolution. At present,
there is still no consensus on an alternative theory
to the DHS, although most speculation seems to
focus on multi-neurotransmitter neurocircuitry,
in which glutamate may play a prominent role
(Harrison and Weinberger 2005).
Imre Lakatos
In an attempt to synergize Popper’s falsifiability
approach with Kuhnian insights, Lakatos
(1970) developed what he termed “a methodology
of research programs.” Research programs,
he suggested, typically responded to problems of
falsifying experiments, not with wholesale rejection
of their theory, but rather with modifications
of its peripheral elements, leaving intact what he
called its “hard core.” Furthermore, in contrast
with Kuhn, Lakatos suggested that proponents of
different programs could communicate with each
other and assess the relative strengths of different
“programs.”
Lakatos was particularly interested in distinguishing
two kinds of programs. Progressive
research programs confronted difficult empirical
facts, explained them using their theories, and generated
novel predictions that were subsequently
empirically confirmed. Einstein’s theory of general
relativity is an exemplar of a progressive research
program. It predicted the unexpected “bending”
of light around the sun observed by Eddington in
1919 and continues to be verified by increasingly
accurate physical measures of our universe (Bennett
2005).
By contrast, degenerating research programs
confront empirical difficulties with ad hoc alterations
to their hypotheses that explain the individual
anomaly, but do not account for new facts.
A classical example of a degenerating research
program is the Ptolemaic astronomic system
that, when confronted with increasingly accurate
measures of planetary motion, simply added more
epicycles.
Which of these systems does the DHS most
closely resemble? The DHS did generate a few
novel findings such as the association between
schizophrenia and the Cys311Ser polymorphism
in the D2 gene. However, this result must be set
against the many failed predictions of the theory,
many of which were accompanied by post hoc
rationalizations about the source of the failure.
Although the picture is mixed, in general, the DHS
has more closely resembled a degenerating than a
progressive research program.
Bayesian Approaches
One difficulty with Lakatos’s vision of scientific
progress is the lack of both a general measure to
assess how well a program is faring and a system
by which to determine how experimental successes
or failures incrementally impact on the validity
of an underlying theory. Several philosophers
of science have developed an approach to these
problems utilizing a Bayesian model of scientific
reasoning (Dorling 1979; Howson and Urbach
2005; Schaffner 1993).
From a Bayesian perspective, the DHS began
as a theory with a reasonable prior probability of
being true. The relationship between DA blockade
and antipsychotic drug action had been well
supported and consistent evidence indicated that
DA agonist drugs could produce psychotic-like
pictures. A Bayesian model allows each new experiment
to impact on the posterior probability
that a theory is true. A verification of the predictions
of the theory makes it more likely to be true.
A failure of verification makes it less likely to be
true. The size of the change in this probability
relates to the quality of the test. The better the
test, the bigger is the change in either direction.
So, when Eddington showed that light from a
distant star was really bent when it passed by the
sun, this had a big impact on the probability that
Einstein’s theory of general relatively was true.
It was a powerful test and the prediction of the
theory was validated.
How has the DHS fared from a Bayesian viewpoint?
It has had many tests, most of them of only
modest quality. However, a high proportion of
them were disconfirming—the prediction of the
DHS was not verified. Therefore, in aggregate,
although the DHS started with a reasonable prior