Neuroleptics in progressive structural brain abnormalities in psychiatric illness

Abstract

Progressive abnormalities have been reported in schizophrenic patients. We did a prospective, longitudinal study of brain structure. 31 drug-naive psychotic patients underwent computed tomography (CT) at first admission to hospital and after 5 years of illness. We obtained written informed consent from all patients. A radiologist masked to the patients’ identities and diagnoses, date of scans, and the nature of the study compared the first and second CT scans. Brain atrophy was assessed on a visual scale, on which 0–1 meant no changes or dubious atrophy and 2–3 meant moderate or severe atrophic changes. After 5 years of illness, we found significant progression of frontal atrophy in 21 schizophrenic patients, compared with nine consecutively included healthy volunteers. We saw progressive frontal atrophy in ten non-schizophrenic patients, but to a lesser degree. During follow-up, schizophrenic patients recieved a median of 172 040 mg (range 19 540-928 450) neuroleptic medication (chlorpromazine equivalents). Seven nonschizophrenic patients received a median of 20 780 mg (range 678-141 596). The only atypical neuroleptic used was clozapine, administered to three patients, always in high doses and in combination with traditional neuroleptics. Patients were thought to have a chronic, non-remittent course of illness if all psychiatric records described a state of permanent psychosis, and if they were psychotic at the time of the reinvestigation. Some patients were described as remitted, but if in long interviews they showed firm delusive systems that seemed to be integrated but not necessarily overt parts of their lives, and if they were judged to be permanently deluded, despite their records, they were classified as non-remittent. This classification was made without knowledge of the results of the CT scans. Nine schizophrenic patients (eight men and one woman) had been continuously psychotic during follow-up. At reinvestigation, non-remittent patients had significantly higher ratings for psychopathology (SANS and SAPS) than remittent patients. Because of the small sample, we did exact tests in a logistic regression analysis with LogXact, adjusted for sex, course of illness, (remission/non-remission), diagnosis, and neuroleptic load. Course of illness and diagnosis had no significant impact on the development of frontal atrophy. Sex was significant (p=0·035) if course of illness was not included into the model, but sex became non-significant (p=0·138) if course of illness was included. Neuroleptic load was significant whether sex was included or not (p=0·013 and 0·0003, respectively). The estimated risk of atrophy increases by 6·4% for each additional 10 g neuroleptic drug. Non-remittent patients received a higher neuroleptic dose than remittent patients, but the model was corrected for this interaction. Association has been shown between frontal atrophy or aplasia and non-respondence to antipsychotic drugs, and neuroleptic side-effects as tardive dyskinesia and akathisia have been associated with wider sulci. These studies do not include neuroleptic load as a possible explanatory factor for the anormalities found. Traditional neuroleptics have been shown to affect brain structure because they enhance the volume of basal ganglia, but the potential impact of neuroleptics, on frontal cortex, for example, is not known. Factors causing progression of brain atrophy have not yet been identified. Our study showed an unexpected effect of