The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys

Abstract

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of B20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

“…34 The expression patterns of GAD 67 , SST and GABA A a1 mRNAs, as revealed by in situ hybridization, did not differ across the groups of monkeys ( Figure 6). One-way ANOVA confirmed the absence of an effect of drug exposure on the expression levels of GAD 67 Because substances such as alcohol, benzodiazepines or valproic acid affect GABA neurotransmission, we assessed whether the usage of these substances by subjects with schizophrenia at the time of death had any effect on the expression changes of the 10 GABA-related transcripts revealed by microarray.…”

“…Antipsychotic-exposed monkeys As described previously, 34 experimentally naive, male macaque monkeys (Macaca fasicularis) (LABS of Virginia, Yemassee, SC, USA), 4.5-5.3 years of age, were chronically exposed to twice daily oral doses of haloperidol, olanzapine or placebo (n = 6 monkeys per group) for 17-27 months. The doses of haloperidol and olanzapine were gradually increased until the monkeys were receiving 24-28 mg of haloperidol or 11.0-13.2 mg of olanzapine per day.…”

“…The final trough drug plasma levels were within the range associated with clinical efficacy in humans (B1.5 ng/ml for haloperidol and B15 ng/ml for olanzapine). 34 Matched by terminal body weight, monkeys were euthanized in triads (one animal from each group) on the same day. Brains were rapidly removed, and the right frontal lobe was cut into coronal blocks, frozen in isopentane on dry ice and stored at -801C.…”

Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade

“…14 Since most antipsychotic compounds affect the levels of these and other neurotransmitters, the effect of specific transmitter systems on white matter integrity is challenging to disentangle. Preclinical 15 and clinical studies 16 have reported subtle white matter reductions after antipsychotic exposure. Haloperidol may downregulate genes associated with myelin and oligodendrocyte function.…”

Neocortical Gray Matter Volume in First-Episode Schizophrenia and First-Episode Affective Psychosis: A Cross-Sectional and Longitudinal MRI Study

“…Antipsychotic administration has been reported to be associated with changes in GM volumes in humans (24,25) and GM and WM reductions in nonhuman primates (29). Moreover, mood stabilizers such as lithium and valproate may increase GM volume (30,31).…”