Dr. Weeks Comment: Anti-psychotic, neuroleptic and tranquilizer medications (all the same category of drug) work. No doubt. Like all medications, they would not be on the market if they didn’t work. But what does “work” mean? Yes – it means to achieve something of the desired effect but with side-effects – negative results which harm while attaining some benefit.
Here is some evidence that these drugs are not without their risks:
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.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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 approximately 20% 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.
Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Both in vivo and post-mortem investigations have demonstrated smaller volumes of the whole brain and of certain brain regions in individuals with schizophrenia. It is unclear to what degree such smaller volumes are due to the illness or to the effects of antipsychotic medication treatment. Indeed, we recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine, at doses producing plasma levels in the therapeutic range in schizophrenia subjects, was associated with significantly smaller total brain weight and volume, including an 11.8-15.2% smaller gray matter volume in the left parietal lobe. Consequently, in this study we sought to determine whether these smaller volumes were associated with lower numbers of the gray matter’s constituent cellular elements. The use of point counting and Cavalieri’s principle on Nissl-stained sections confirmed a 14.6% smaller gray matter volume in the left parietal lobe from antipsychotic-exposed monkeys. Use of the optical fractionator method to estimate the number of each cell type in the gray matter revealed a significant 14.2% lower glial cell number with a concomitant 10.2% higher neuron density. The numbers of neurons and endothelial cells did not differ between groups. Together, the findings of smaller gray matter volume, lower glial cell number, and higher neuron density without a difference in total neuron number in antipsychotic-exposed monkeys parallel the results of post-mortem schizophrenia studies, and raise the possibility that such observations in schizophrenia subjects might be due, at least in part, to antipsychotic medication effects.
Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
University Hospital Marqués de Valdecilla, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain. firstname.lastname@example.org
The effect of antipsychotic drugs on brain morphology is under debate. Here we investigate the effects of risperidone, olanzapine and low doses of haloperidol on cortical and subcortical morphometry in first episode drug naïve patients with non-affective psychosis.
Morphological variables were measured in three treatment groups (haloperidol=18; risperidone=16; olanzapine=18) and in healthy subjects (N=38) at baseline and after one year. The relationship between brain morphometric changes and changes in clinical scores was also assessed.
At one year, the three antipsychotics had had an equal effect on the gray matter cortical structure, overall and lobes (all p’s>0.121.). A significant time-by-group interaction was found in lateral ventricle volume (F2,47=5.65; p=0.006). Post-hoc comparisons revealed a significant increase in lateral ventricles in patients treated with risperidone (p=0.009). Patients exposed to atypicals (olanzapine and risperidone) exhibited a decrease in caudate nucleus volume (p=0.001). In general, brain changes did not account in any significant manner for clinical changes over time in any treatment group.
We conclude that low doses of haloperidol, risperidone and olanzapine seem to have an equal effect on the gray matter cortical structure after 1 year of treatment. In contrast to typical antipsychotics, atypicals have differential effects on lateral ventricle and caudate nucleus volumes.
Antipsychotic drug effects on brain morphology in first-episode psychosis.
Departments of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA. email@example.com
Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia.
To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition.
Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes.
Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1).
Patients with first-episode psychosis (DSM-IV) and healthy volunteers.
Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d).
MAIN OUTCOME MEASURES:
Brain volume changes assessed by MRI.
Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume.
Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.