Brain distribution of selected antipsychotics in schizophrenia

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Abstract

The brain distribution of phenothiazine antipsychotics in 22 confirmed schizophrenic and 11 control subjects were collected at autopsy. Specimens were homogenized, extracted with n-butyl chloride, and analyzed via liquid chromatography–mass spectrometry, using atmospheric pressure electrospray ionization operating in the positive mode. Drug concentrations normalized for those observed in cerebellum showed three distinct patterns of distribution corresponding to different structural features of each type of phenothiazine. Those drugs with high affinity for dopamine receptors were detected in the highest concentrations in regions with high concentrations of such receptors. However, those associated with relatively lower dopaminergic activity were found in the highest concentration in the occipital cortex, a region with a relatively low concentration of dopamine receptors. The regional brain distribution of thioridazine and its metabolites was concentration dependent. These results have implications for determining the role of these drugs in the sudden and unexpected deaths of schizophrenics.

Introduction

There is a lack of studies examining how different antipsychotic drugs distribute in the brain at death. Due to differences in drug measurement between studies, comparison of results within and between drugs is difficult. One study of plasma concentrations of thioridazine and metabolites in humans found that although drug concentrations varied widely between patients, in all patients the relative concentration of thioridazine to mesoridazine was about one half and thioridazine to sulforidazine was two-fold [1]. In a study of antipsychotic drug distribution between blood and brain in rats [2], the observed ratio of brain-to-serum concentration varied widely, but the high potency drugs fluphenazine and haloperidol had more favorable brain-to-blood distribution than the low potency drug thioridazine.

Svendsen et al published the only study that reports postmortem concentrations of thioridazine and its metabolites and chlorpromazine in schizophrenic brains [3]. A review of the clinical histories revealed that five subjects had received thioridazine within 8 h of death. In only one subject who had been withdrawn from medication 4 days before death after chronic treatment, thioridazine and its metabolites selectively accumulated in particular regions of the brain. The most remarkable difference was between cortical and sub-cortical structures, in which the former had high thioridazine levels and lower mesoridazine levels, whereas the latter had high mesoridazine and lower thioridazine concentrations. Although these data are limited, there is evidence to suggest that most anti-psychotics distribute preferentially into the frontal cortex, midbrain, and caudate-putamen [3], [4], [5], [6], and a degree of differential distribution between the left and right brain hemispheres may occur [5], [7].

How a drug distributes in brain would not only seem to be important for post-mortem studies but could provide insight as to how different drugs may distribute in the living brain. Differential distribution may account for why drugs such as clozapine and olanzapine, that have similar receptor pharmacology [8], can have differing therapeutic outcomes [9]. The purpose of this study was to examine whether selected antipsychotic drugs distribute preferentially to particular brain regions in schizophrenic subjects, and to investigate the extent of correlation of blood concentrations with those concentrations in different brain regions. This will allow a better understanding of the interpretation and causes of sudden and expected death in this population.

Section snippets

Materials

Mesoridazine was obtained from the Division of Analytical Laboratories of the New South Wales Health Department (Lidcombe, New South Wales). Sulforidazine and fluphenazine sulfoxide were obtained from the Australian Government Analytical Laboratory (South Melbourne, Victoria). Thioridazine, haloperidol, chlorpromazine, and trazodone, (internal standard), were purchased from Sigma Aldrich Pty Ltd. (Castle Hill, New South Wales). All other reagents were HPLC grade and were obtained from Sigma

Subject demographics

Of the 22 schizophrenic subjects included in this study, there were approximately twice as many males as females. The average age was 45 ± 4.0 years. Table 1 lists demographic and toxicologic data in blood of all subjects. Data includes the last recorded antipsychotic drug(s) and, where available, amount of time between the last dose and death. Unfortunately, the estimated time between dose and death was unavailable in 17 of the 22 cases. In 3 of the 17 cases, no information on drug histories was

Regional brain distribution

The regional brain distribution for each compound using mean absolute concentrations is shown in Fig. 1. Fig. 2 shows this distribution with concentrations normalized for those in cerebellum. As shown in these figures, three distinct patterns of distribution were observed in this set of experiments (see also Table 4). Chlorpromazine, a low-potency phenothiazine with an aliphatic side chain, was found at highest concentrations in caudate-putamen and lowest in cerebellum (group 1). Thioridazine

Acknowledgments

This work was supported in part by the NH&MRC Schizophrenia Unit, the State Government of Victoria, the United States Air Force, The Brockhoff Foundation and the Rebecca L. Cooper Medical Research Foundation. Brian Dean is the recipient of a NARSAD Young Investigator award. The authors wish to thank Professor Nicholas Keks and Ms. Christine Hill for carrying out case-history reviews and diagnostic confirmation, and the Victorian Institute of Forensic Medicine for access to tissue and to staff

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Present address: County of San Diego Medical Examiner's Office, 5555 Overland Ave., Bldg. 14, San Diego, CA 92123, USA.

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