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Briefing Paper
DO ANTIPSYCHOTIC DRUGS CHANGE BRAIN
STRUCTURE?
SUMMARY: Antipsychotic drugs, used to treat schizophrenia and
manic-depressive disorder (bipolar disorder), change some aspects of brain structure, as
do drugs used to treat Parkinson’s disease, epilepsy, and other brain diseases. Some
of the brain changes appear to be related to the efficacy of the antipsychotic drugs,
while other changes are probably related to the side effects of the drugs. Studying the
brain changes may eventually lead to a better understanding of how they work and the
prediction of which individuals are most likely to respond to which drugs and which
patients are most likely to develop side effects, include tardive dyskinesia.
* * *
Introduction
The publication of a paper by Dr. Paul Harrison, "Review: The Neuropathological
Effects of Antipsychotic Drugs"1 has focused attention on
this area of current research. Some opponents of the use of antipsychotic medication
have misunderstood such research and have argued that brain changes prove that
antipsychotic drugs are dangerous and should not be used. On the contrary, this research
is very important and may eventually lead to better and more effective medications.
The Stanley Foundation/NAMI Research Institute not only provides ongoing support for
Dr. Harrison (he is the Director of a Stanley International Research Center and
acknowledges the Stanley Foundation in the above-cited paper) but also supports many of
the researchers doing work in this field, including Dr. Natalya Uranova (supported by a
Stanley International Research Center) and Drs. Francine Benes and Rosalind Roberts (both
recipients of Stanley Research Awards).
The findings that antipsychotic drugs produce structural brain changes should not be a
surprise. Schizophrenia and manic-depressive disorder are known to produce structural
brain changes as part of the disease process, so it is reasonable to expect drugs that are
effective in treating these diseases to do likewise. Furthermore, many drugs known to be
effective in other brain disorders also produce structural brain changes. For example,
levodopa, a mainstay of treatment for Parkinson’s disease, has been shown to produce
some changes in the cellular mitochondria and neuronal degeneration2.
Phenobarbital, widely used for many years to treat some forms of epilepsy, has been shown
to produce "lasting effects on fine structure of cells" in the cerebellum3. And diphenylhydantoin, also commonly used to treat epilepsy,
has been shown to produce "marked dystrophic changes in the Purkinje cell axons"4 and to interfere with the formation of neuronal processes5. Drugs used to treat diseases of other organs of the body (e.g.,
heart, joints) also may cause structural changes of those organs.
Structural Brain Changes Caused by
Antipsychotic Drugs
The following are the structural brain changes that
appear to be caused by antipsychotic drugs. There is considerable ongoing work in this
research area. The majority of the work to date has been carried out in rats and needs to
be replicated in humans, since there are substantial species variation in brain structure
and function.
Increased size of the striatum: An increased size of the striatum
(the striatum is composed of the caudate and putamen and is part of the basal ganglia) has
been found in human MRI studies of individuals taking some antipsychotic drugs6 but not with clozapine. The increased size is thought to be due both
to increased blood flow and to structural changes of the neurons. It is not known whether
this increased blood flow has any relationship to either the efficacy of the drug or its
side effects.
- Increased density of glial cells in the prefrontal cortex: Glial
proliferation and hypertrophy of the prefrontal cortex is reported to be "a common
response to antipsychotic drugs" and may "play a regulatory role in adjusting
neurotransmitter levels or metabolic processes"7.
Increased number of synapses (connections between neurons) and changes in
the proportions and properties of the synapses: This includes changes in the
distribution and subtypes of synapses. The changes have been found primarily in the
caudate nucleus of the striatum, and there is some evidence that they may also occur in
layer 6 of the prefrontal cortex but not elsewhere. The changes may be secondary to the
effects of the antipsychotic drug on dopamine or glutamate neurotransmitters. It is not
yet clear what these changes mean; they may be related to the efficacy of the drug or may
possibly be a marker for side effects. If the latter, being able to identify such changes
in living individuals could potentially provide an early marker for tardive dyskinesia and
thus indicate which individuals should not take these drugs. Most of these studies have
been carried out in rats, so it is not yet known how applicable the findings are to
humans. Virtually all the studies have used haloperidol (Haldol), so it is not yet known
whether clozapine or other newer antipsychotics may also produce them.
Research on other kinds of structural brain changes caused by antipsychotic drugs
has been negative to date. There is no evidence, for example, that antipsychotic
drugs cause any loss of neurons or neurofibrillary tangles such as are found in
Alzheimer’s disease.
In summary, structural changes in the brain caused by antipsychotic drugs are of major
research interest since they may explain more precisely how these drugs work and/or
predict which individuals are more likely to experience side effects. The changes
caused by antipsychotic drugs used to treat schizophrenia and manic-depressive
disorder (bipolar disorder) are similar in kind to structural brain changes caused by
drugs used to treat Parkinson’s disease, epilepsy, and other brain diseases. It
is incorrect to characterize these brain changes as an indication that these drugs are
dangerous or should not be used.
References
1Harrison P. Review: the neuropathological effects of
antipsychotic drugs. Schizophrenia Research 40:87-99, 1999.
2Ogawa N, Edamatsu R, Mizukawa K, Asanuma M, Kohno M, Mori
A. Degeneration of dopaminergic neurons and free radicals. Advances in Neurology
60:242–250, 1993.
3Fishman RHB, Ornoy A, Yanai J. Correlated ultrastructural
damage between cerebellum cells after early anticonvulsant treatment in mice. International
Journal of Developmental Neuroscience 7:15–26, 1989.
4Volk B, Kirchg�ssner N. Damage of Purkinje cell axons
following chronic phenytoin administration: an animal model of distal axonopathy. Acta
Neuropathologica 67:67–74, 1985.
5Bahn S, Ganter U, Bauer J, Otten U, Volk B. Influence of
phenytoin on cytoskeletal organization and cell viability of immortalized mouse
hippocampal neurons. Brain Research 615:160–169, 1993.
6Chakos MH, Lieberman JA, Bilder RM, Borenstein M, Lerner G,
Bogerts B, Wu H, Kinon B, Ashtari M. Increase in caudate nuclei volumes of first-episode
schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry
151:1430–1436, 1994.
7Selemon LD, Lidow MS,
Goldman-Rakic PS. Increased volume and glial density in primate prefrontal cortex
associated with chronic antipsychotic drug exposure. Biological Psychiatry
46:161–172, 1999.
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