PubMed · 6125291
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C E Speicher, M I Walters. 1981. Phenothiazines.. https://pubmed.ncbi.nlm.nih.gov/6125291/
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Clozapine is a potent antagonist of 5-HT3 receptors, which are ligand-gated ion channels that mediate rapid excitatory responses in the central nervous system. Two different isoforms of 5-HT3 receptor subunit genes (HTR3A and HTR3B) have been identified. They have been assigned to chromosome 11q23.1-q23.2, a region which in the past has been linked to schizophrenia and bipolar disorder. In this study, we performed a systematic mutation screening of the 5-HT3A and 5-HT3B receptor genes and tested the variants for association with clozapine response in a sample of 266 clozapine-treated patients. Two polymorphisms at the 5-HT3A gene and five new variants in the 5-HT3B gene were finally detected. Of these, only the more frequent mutations (178-C/T and 1596-A/G in 5-HT3A and a CA-repeat in 5-HT3B) were genotyped in our clozapine sample. Association analysis showed similar allele and genotype distributions among clozapine responders and nonresponders. These results make unlikely the possibility that 5-HT3A and 5-HT3B receptor genes underlie variation in clinical response to clozapine. However, the promoter regions of both genes have yet to be investigated.
There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. The rapidly evolving disciplines of pharmacogenetics and pharmacogenomics seek to uncover this genetic variation in order to predict treatment outcomes. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up-individualized therapy. Pharmacogenomic studies utilize genomic technologies to identify chromosomal areas of interest and novel putative drug targets, while pharmacogenetic strategies rely on studying sequence variations in candidate genes suspected of affecting drug response or toxicity. The candidate gene variants that affect function of the gene or its protein product have the highest priority for investigation. This review will provide demonstrative examples of functional candidate gene variants studied in a variety of antipsychotic response phenotypes in the treatment of schizophrenia. Serotonin and dopamine receptor gene variants in clozapine response will be examined, and in the process the need for sub-phenotypes will be pointed out. Our recent pharmacogenetic studies of the subphenotype of neurocognitive functioning following clozapine treatment and the dopamine D(1) receptor gene (DRD1) will be presented, highlighting our novel neuroimaging data via [(18)F]fluoro-2-deoxy-D-glucose (FDG) metabolism position emission tomography (PET) that demonstrates hypofunctioning of several brain regions in patients with specific dopamine D(1) genotype. Preliminary candidate gene studies investigating the side-effect of clozapine-induced weight gain are also presented. The antipsychotic adverse reaction of tardive dyskinesia and its association with the dopamine D(3) receptor will be critically examined, as well as the added influence of antipsychotic metabolism via the cytochrome P450 1A2 gene (CYP1A2 ). Results that delineate the putative gene-gene interaction between DRD3 and CYP1A2 are also presented. We have also utilized FDG-PET subphenotyping to demonstrate increased brain region activity in patients who have the dopamine D(3) genotype that confers increased risk for antipsychotic induced tardive dyskinesia. The merits and weaknesses of neuroimaging technologies as applied to pharmacogenetic analyses are discussed. To the extent that the above data become more widely verified and replicated, the field of psychiatry will move closer to clinically meaningful tests that will be useful in deciding the best drug for each individual patient.
The safety and efficacy of i.m. ziprasidone and olanzapine for treating acute agitation in patients with schizophrenia are described, along with factors to consider when evaluating the cost-effectiveness of these agents. Agitation is defined as excessive motor and verbal activity. Acute agitation has traditionally been treated with the combination of haloperidol 5 mg and lorazepam 2 mg i.m. Controlled trials have shown, however, that combination therapy of haloperidol or droperidol plus lorazepam i.m. is better than single-drug treatment at one hour but not earlier. Phase II and III clinical trials showed that both i.m. ziprasidone mesylate 10 mg and 20 mg and olanzapine 2.5 mg-10 mg controlled agitation faster in patients with schizophrenia than p.o. ziprasidone 2 mg and placebo. In addition, i.m. olanzapine 10 mg controlled agitation faster in patients with schizophrenia faster than haloperidol in 15 minutes. Olanzapine i.m. was also superior to placebo in patients with dementia and in patients with bipolar disorder with and without psychotic symptoms, suggesting that agitation may be a syndrome that is similar across a multitude of disease states. Dystonic reactions occurred in 2.6% of patients taking ziprasidone, compared with 9.2% of patients taking haloperidol. No patients receiving olanzapine experienced a dystonic reaction. Ziprasidone has been associated with prolonged QTc Intervals. Pharmaco-economic evaluations should include costs associated with repeat i.m. injections for agitated patients, increased time in the emergency room, case of switching from i.m. to oral therapy, adverse effects, and relapse, as well as medication costs. I.m. olanzapine and ziprasidone show promise for treating acute agitation in patients with schizophrenia, especially because of their safer adverse effect profile and faster onset of effectiveness compared with haloperidol.