DO ANTIPSYCHOTIC DRUGS CHANGE BRAIN STRUCTURE?

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, Kirchgässner 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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