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

Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 59
physiological processes remote from those which
cause the disorder. For this reason, we suggest
that further evidence supporting the DHADA is
of minimal relevance to the validity of the DHS.
Although one can justly claim from the DHADA
that “dopamine must have something to do with
schizophrenia,” this is a weak argument because
the mode of action of drugs can be so far removed
from basic disease etiology as to be largely uninformative
about etiologic processes.
We suggest that, in their enthusiasm for this
theory, the biological psychiatry movement was,
initially and for many subsequent years, willing
to overlook the substantial limitations of the DHS
that we have reviewed above and conflate the DHS
and DHADA. Although a further explication of
this part of the story lies outside the bounds of this
review, a full historical understanding of the DHS
would require consideration both of scientific and
extra-scientific forces.
Concluding Thoughts
In conclusion, we want to be clear about what
we are and are not saying. We do not claim that
DA is unrelated to the etiology of schizophrenia
or that DA does not explain a lot about the action
of antipsychotic drugs. Furthermore, we
recognize that theories can be useful in guiding
treatment even if they are etiologically incomplete
or wrong (Schaffner 2002). Many hypotheses in
medicine that were not based on deep etiological
understanding have produced practical therapeutic
benefits. This is likely the case for the DHS.
By contrast, we do conclude that, as a scientific
theory, the DHS has to date performed relatively
poorly and has, from the perspective of leading
models of science, important deficiencies. Furthermore,
we suggest that the story of the DHS
has at least four important lessons for our field.
First, psychiatry needs theories with higher levels
of specificity and falsifiability. Global, nonspecific
theories like the DHS have heuristic value and can
play an important role in stimulating research
in the short run. However, such theories are less
effective at guiding research in the long run in
fruitful and progressive directions. Several of the
etiologic theories for schizophrenia that compete
with the DA hypothesis, including those focusing
on glutamate or NMDA receptors, probably also
suffer from lows levels of specificity and falsifiability.
Other leading “neurochemical” theories in
psychiatry, such as the serotonin hypothesis of depression,
may be similar (Lacasse and Leo 2005).
Second, science works best when diverse theories
with distinct predictions compete with one
another. This has been hard to implement in the
field of mental health research for many reasons.
Third, it has been common in the history of science
in general and the medical and social sciences in
particular for theories to be defended with a fervor
that cannot be justified by the available evidence.
More than we may wish to admit, this has been
the case with the DHS. As our science and field
matures beyond ideologically driven controversy,
it would be wise and mature for all of us, regardless
of whether we see ourselves as biological,
social or psychodynamic, to be more self-critical
about the theories we adopt and as more tolerant
of diversity in theory articulation. Finally, psychiatry
is probably not ready for “big” unitary
theories like the DHS. Although very tempting,
it will likely be more realistic and productive for
us to focus on smaller questions, and to settle for
“bit-by-bit” progress as we clarify, in a piecemeal
manner, the immensely complex web of causes that
contribute to disorders like schizophrenia (Kendler
2005; Schaffner 1994).
Acknowledgments
This work is supported in part by the Rachael
Banks Endowment Fund (KSK) and the National
Science Foundation under Grant Nos. 0324367
and 0628825 (KFS). Any opinions, findings,
conclusions, or recommendations expressed in
this material are those of the author(s) and do
not necessarily reflect the views of the National
Science Foundation. Helpful comments on earlier
versions of this essay were kindly provided by Joel
Kleinman, MD, Steven Matthysse, PhD, Solomon
Snyder, MD, Carl Craver, PhD, Robert Malenka,
MD, PhD, Karoly Mirnics, MD, John Bickle,
PhD, James Bogen, PhD, Peter Machamer, PhD,
Edouard Machery, PhD, Robert C. Olby, PhD,
and Carol Tamminga, MD.