Neuroleptics and Brain Damage: An Annotated Bibliography

King of kings’ Bible – Galatians 5:19 Now the works of the flesh are manifest, which are [these]; Adultery, fornication, uncleanness, lasciviousness, 5:20 Idolatry, PHARMACY, hatred, variance, emulations, wrath, strife, seditions, heresies, 5:21 Envyings, murders, drunkenness, revellings, and such like: of the which I tell you before, as I have also told [you] in time past, that they which do such things shall NOT inherit the Kingdom of God. via the Preventive Psychiatry E-Newsletter # 218

Recent evidence of brain changes in humans associated with the So-Called "Antipsychotic Drugs" (including Risperdal, Abilify, Clozaril, Zyprexa, Seroquel, Geodon, Thorazine, Haldon, Prolixin, etc)

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., 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 neuroleptics.

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.

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.

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.”

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.
Chakos, M.H., Shirakawa, O., Lieberman, J., Lee, H., Bilder, R., & Tamminga, C.A. (1998). Striatal enlargement in rats chronically treated with neuroleptic. Biological Psychiatry, 44 (8), 675-684. The authors sought to find out whether the striatal enlargement found in humans treated with neuroleptics also occurred in rats. This was seen as important, since there remained the possibility that the changes in striatal volume seen to occur with neuroleptic treatment might be part of some disease process in human subjects with schizophrenia. Also, there had been some speculation that the apparent growth in the striatum of humans seen with MRI scans really were just changes in blood flow or metabolism. This study found, however, that rats experienced a similar growth in their striatum, as measured at autopsy. It also found that rats with movement disorders experienced greater growth in their striatum than did rats without such disorders. The authors, in their conclusion, state that “It is possible that neuroleptic-induced striatal volume changes play a role in the development of subtle cognitive impairment as well as the development of a movement disorder in vulnerable patients. An association between striatal enlargement and cognitive impairment has, in fact, been reported by Hokama et al (1995).”

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