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Neuroleptics and Brain Damage: An Annotated Bibliography

(last updated Sept. 28, 1999)

Recent evidence of brain changes in humans associated with neuroleptic drugs:

Gur, R.E., Maany, V., Mozley, P.D., Swanson, C., Bilker, W., & Gur, R.C. (1998). Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. American Journal of Psychiatry, 155 (12), 1711-1717. Using MRI imaging, this study monitored changes in the size of the basal ganglia and thalamic regions of the brain as patients were treated with neuroleptic drugs. Treatment by neuroleptics increased the area of both regions. For typical neuroleptics, a higher dose was associated with a size increase in multiple areas, while atypcal neuroleptics increased the volume only of the thalamic portion. Furthermore, these researchers reported that increased size of these portions of the brain is associated with greater severity of symptoms. In other words, the patient’s brains were being changed in ways that would likely make it more difficult for them to ever withdraw from neuroleptic

Chakos, M.H., Lieberman, J.A., Bilder, R.M., Borenstein, M., Lerner, G., Bogerts, B., Wu, H., Kinon, B., & Ashtari, M. (1994). Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry 151 (10) 1430- 1436. Based on MRI measurements of patients who initially had under 12 weeks of lifetime exposure to neuroleptics, and comparison with data after 18 months of treatment, the authors concluded that "caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients." It was known prior to this study that chronically treated patients had increased volumes in this portion of their brains, but it had been thought this was due to the disease and not the treatment...drugs.

1998. Neuroleptics in progressive structural brain abnormalities in psychiatric illness.(Research Letters). The Lancet, 352 (9130) 784. This was a longitudinal study of patients, some schizophrenic, some not, from the beginning of their treatment with neuroleptics until 5 years later. Before and after scans of the brain were done using computed tomography (CT). The finding was that diagnosis had no significant impact on the development of frontal atrophy, but that “the estimated risk of atrophy increases by 6.4% for each additional 10 g neuroleptic drug.”

Gur, R.E, Cowell, P., Turetsky, B.I., Gallacher, F., Cannon, ?, Bilker, W., & Gur, R.C. (1998) A follow-up magnetic resonance imaging study of schizophrenia. Archives of General Psychiatry, 55 145-152. This study looked at changes in the frontal and temporal lobes of the brains of schizophrenics over a period of about 31 months. They found that for first episode patients, “higher medication dose was associated with greater reduction in frontal and temporal volume r = -0.75 and -0.66 respectively; P<.001).” Volume reduction was associated with decline in some neurobehavioral functions.

Evidence that Tardive Dyskinesia [TD - a well-established form of neuroleptic-induced brain damage that can result in permanent twitching of face and limbs] involves brain changes that impact cognitive functioning:

Paulsen, J. S., Heaton, R.K., & Jeste, D.V. (1994). Neuropsychological impairment in tardive dyskinesia. Neuropsychology,8 (2), 227-241. The authors reviewed 31 published studies of neuropsychological testing comparing schizophrenics with and without TD. 24 of these studies, or 77%, found TD patients did worse on such tests. In an attempt to improve on past studies, the authors did their own study which matched patients with and without TD on a variety of measures, including duration and severity of illness. Those with TD demonstrated greater neuropsychological impairment, and those with more severe TD manifested greater neuropsychological impairment. The authors go on to discuss brain changes which may be associated with both TD and neuropsychological impairment, and concludes that “it is likely that TD involves an alteration of brain function that affects both motor and cognitive control.”

Waddington, J.L., & Youssef, H.A. (1996). Cognitive dysfunction in chronic schizophrenia followed prospectively over 10 years and its longitudinal relationship to the emergence of tardive dyskinesia. Psychological Medicine, 26 681-688. Often the relationship between cognitive dysfunction and TD has been explained by suggesting that those with underlying cognitive dysfunctions are more prone to TD. This study sharply contradicts that explanation. The authors followed the cognitive functioning of a group of chronic schizophrenic patients over 10 years. Most were stable in regards to cognitive functioning: the exceptions were the individuals who developed TD during the course of the study. The authors write that “Those patients demonstrating prospectively the emergence of orofacial dyskinesia showed a marked deterioration in their cognitive function over the same time-frame withing which their movement disorder emerged, but this decline did not progress thereafter.” The authors conclude that the cognitive changes are related to the patho-physiological process which also results in TD.

Sachdev, P., Hume, F., Toohey, P., & Doutney, C. (1996). Negative symptoms, cognitive dysfunction, tardive akathisia and tardive dyskinesia. Acta Psychiatrica Scandinavica, 93 (6), 451-459. The authors, in their literature review, point out that while there are some studies that do not find a relationship between TD and cognitive deficits, there are many that do show a positive relationship between TD and cognitive deficits and none that show the opposite relationship. In the current study, TD was shown to be related to cognitive deficits, while tardive akathisia was shown to be even more strongly related to cognitive deficits. While the authors do not see this as proving that neuroleptics cause cognitive deficits, they recommend considering the possibility, and they compare TD and TA with other movement disorders such as Parkinson’s disease and Huntington’s disease, in which neuropsychological deficits and even subcortical dementia are known to occur.

Wade, J.B., Lehmann, L., Hart, R., Linden, D., Novak, T., & Hamer, R. (1989). Cognitive changes associated with tardive dyskinesia. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 1 (3), 217-227. “The results of multip regression analysis revealed a modest linear relationship between TD and cognition (p<.04) after controlling for the effects of years of illness, duration of hospitalization, motor speed, severity of illness, and medication.” The authors conclude that “our findings suggest that TD may represent both a motor and dementing disorder regardless of major psychiatric diagnosis.”

Famuyiwa, O.O., Eccleston, D., Donaldson, A.A., & Garside, R.F. (1979). Tardive dyskinesia and dementia. British Journal of Psychiatriy, 135 500-504. Schizophrenics both with and without tardive dyskinesia were compared with both EMI scans and psychological tests of intellectual function. Those with TD did worse on the tests, and it was suggested that the higher incidence of pathology in that group might be related to chronic neuroleptic toxicity.

Edwards, H. (1970). The significance of brain damage in persistant oral dyskinesia. British Journal of Psychiatry, 116, 271-275. The author sought to discover whether brain damage could be an important contributory cause of TD. To examine that possibility, he compared two samples matched for phenothiazine intake and age, one sample with TD, the other without. Both groups were checked for brain damage and dementia. 28 out of 34 in the group with TD, versus 14 out of 34 controls, showed at least some brain damage. Edwards mostly focused on brain damage putting patients at risk for TD, but he also raised the possibility that the drugs themselves cause permanent neurological damage.

Wade, J.B., Taylor, M.A., Kasprisin, A., Rosenberg, S., & Fiducia, D. (1987). Tardive dyskinesia and cognitive imparment. Biological Psychiatry, 22 393-395. Because not all studies have found a relationship between tardive dyskinesia and cognitive functioning, the authors conducted a study using tasks known to find cognitive impairment in Parkinson’s and Huntington’s diseases. These tasks were chosen because the authors believed these diseases might provide a neuropsychological, as well as a biochemical, model for TD. The authors found a modest but significant linear relationship between TD and reduced cognitive functioning, where those with the most severe forms of the disorder were most impaired cognitively.

Neuroleptics increase cognitive decline in elderly people with dementia:

McShane, R., Keene, J., Gedling, K., Fairburn, C., Jacoby, R., & Hope, T. (1997). Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up. British Medical Journal, 314 (7076), 266-271. This study looked at the impact of long term use of neuroleptics on the cognitive function of elderly people with dementia. It found that cognitive function declined twice as fast in those taking neuroleptics as in those not on neuroleptics. Brain differences were not found at autopsy, which means either that the cognitive decline was functional only, or that the brain differences escaped detection by the methods these researchers used.

A sampling of some of the animal studies showing brain changes afer neuroleptics:

Benes, F.M., Paskevich, P.A., Davidson, J., & Domesick, V.B. (1985) The effects of haloperidol on synaptic patterns in the rat striatum. Brain Research, 329, 265-274. This study finds changes in cell size and in number of vesicles in rats in a particular part of their brain. The authors cite other studies which have also found changes in rat brains caused by neuroleptics. In their conclusion the authors state that “The results of this study provide further evidence that haloperidol can induce synaptic alterations in the rat central nervous system, an effect which we first noted in the rat substantia nigra.”

Muller, P. & Seeman, P. (1977). Brain Neurotransmitter receptors after long-term haloperidol: dopamine, acetylcholine, serotonin, -Noradrenergic and naloxone receptors. Life Sciences 21, 1751-1758. This study looked at the effect of chronic haloperidol on a variety on neurotransmitters in rats. The authors concluded that “these results indicate that long-term haloperidol treatment produces rather selective increases in dopamine/neuroleptic receptors, without much change in 4 other types of receptors.” The dopamine receptor changes were very significant though, ranging from 34 to 45%.

Burt, D.R., Creese, I., & Snyder, S.H. (1977). Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain. Science, 196, 326-328. Another study looking at changes in dopamine receptors. “Chronic treatment of rats with the neuroleptic drugs haloperidol, fluphenazine , and reserpine elicits a 20 to 25 percent increase in striatal dopamine receptor binding assayed with Haloperidol.”

Jeste, D.V., Lohr, J.B., & Manley, M. (1992). Study of neuropathologic changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats. Psychopharmacology, 106, 154-160. In the literature review of research over 3 decades, most studies listed found brain changes. The current study also found brain changes: a lower density of large neurons in the striatum of middle aged rats. Older rats did not show significant differences, which the authors felt was because the neuroleptics were accelerating the loss of large neurons which naturally die later as a result of aging.

Nielsen, E.B., & Lyon, M. (1978). Evidence for cell loss in corpus striatum after long-term treatment with a neuroleptic drug (flupenthixol) in rats. Psychopharmacology, 59 85-89. The authors found a 10% cell loss in one region of the rat’s brains, which they concluded “further suggest that persistent irreversible anatomical changes can follow long-term neuroleptic treatment.”

Pakkenberg, H., Fog, R., & Nilakantan, B. (1973) The long term effect of perphenazine enanthate on the rat brain. Some metabolic and anatomical observations. This study found a significant decrease in the number of nerve cells in the basal ganglia of rats under long-term treatment.