PubMed · 2887036
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P Benoit, A Peutillot. 1987. [Fluanxol].. https://pubmed.ncbi.nlm.nih.gov/2887036/
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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.
Issues to consider when evaluating maintenance drug therapy for patients with schizophrenia are discussed; these include potential adverse effects of antipsychotic therapy, such as weight gain, diabetes mellitus, extrapyramidal symptoms, sexual dysfunction, cognitive dysfunction, and cardiac effects, as well as quality of life. Patients with schizophrenia are more likely to be overweight than the general population. Olanzapine and clozapine have been associated with the greatest weight gain of the newer antipsychotics. While patients with schizophrenia are at increased risk of developing diabetes mellitus independent of antipsychotic therapy, diabetes may be more prevalent in patients taking the newer agents. Acute extrapyramidal symptoms occur in 75-90% of patients receiving first-generation antipsychotics like thioridazine and haloperidol. The probability of tardive dyskinesia (TD) occurring with second- and third-generation agents is less than 1% per year, compared with about 5% per year for the traditional antipsychotics. When patients are switched from a traditional antipsychotic to clozapine or olanzapine, TDs usually abate somewhat. Thioridazine causes a pronounced prolongation of the QTc interval, which can lead to ventricular arrhythmias. The slight increase in QTc interval caused by ziprasidone most likely will not be a problem in healthy individuals. Newer antipsychotics are associated with improved neurocognitive functioning and most cause less prolactin elevation, compared with traditional agents. The newer antipsychotic agents are not devoid of adverse effects, but those that do occur can be managed. Once issues related to adherence are resolved, rehabilitation of patients with schizophrenia will be a high priority.