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 degeneration (2). 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 cerebellum (3). 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 processes (5). 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 drugs (6) 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.
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