Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing.

Human leukocyte antigen B (HLA-B) is a gene that encodes a cell surface protein involved in presenting antigens to the immune system. The variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in response to carbamazepine treatment. We summarize evidence from the published literature supporting this association and provide recommendations for the use of carbamazepine based on HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this article is to provide information to allow the interpretation of clinical HLA-B*15:02 genotype tests so that the results can be used to guide the use of carbamazepine. The guideline provides recommendations for the use of carbamazepine when HLA-B*15:02 genotype results are available. Detailed guidelines regarding the selection of alternative therapies, the use of phenotypic tests, when to conduct genotype testing, and cost-effectiveness analyses are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on the PharmGKB website at (http://www.pharmgkb.org).

Differential regional zif268 messenger RNA expression in an escalating dose/binge model of amphetamine-induced psychosis.

Amphetamine-induced psychosis is most often associated with a high-dose multiple binge pattern of stimulant abuse. To simulate these conditions in rats, we used an escalating dose/binge administration paradigm. Animals were pretreated with escalating doses of amphetamine (1.0-8.0mg/kg) over four days, then exposed to nine daily binges (8.0mg/kg every 2h; four injections/day). Other animals received either multiple injections of saline, saline followed by acute amphetamine (8.0mg/kg) or single daily injections of amphetamine (8.0mg/kg) in parallel with the escalating dose/binge treatment. One hour after the last injection, all animals were decapitated and regional brain activation patterns were assessed using in situ hybridization with antisense probes for zif268. Acute amphetamine resulted in a significant elevation of zif268 messenger RNA in both the nucleus accumbens and dorsal striatum. However, whereas after single daily amphetamine treatment this index was no longer elevated above control levels in the dorsal striatum, multiple binge exposures were required for the nucleus accumbens to return to baseline. Agranular insular cortex and medial olfactory tubercle zif268 messenger RNA expression was also markedly increased after acute amphetamine treatment but, unlike the nucleus accumbens and dorsal striatum, this increase was not significantly attenuated by either single daily injection or multiple binge treatment. Zif268 messenger RNA expression in the lateral nucleus of the amygdala also remained elevated above baseline after binge treatment. The possible relationships of these changes in zif268 messenger RNA regional expression patterns to the development of psychosis in high-dose stimulant abusers are discussed.

Quantification of dopamine D1 and D2 receptor mRNA levels associated with the development of behavioral sensitization in amphetamine treated rats.

We hypothesized that changes in expression of dopamine (DA) D1 and D2 receptor genes in caudate/putamen (CP) would correlate with the development of behavioral changes in amphetamine treated rats. In order to test this hypothesis, we measured DA D1 and D2 receptor mRNA in CP, as well as locomotor behavior, in individual rats following amphetamine treatment. D1 and D2 mRNA levels were similar in caudate/putamen of rats treated with acute amphetamine, chronic amphetamine or saline injection. We found no correlation between D1 or D2 mRNA levels in caudate/putamen and the behavioral response to either acute or chronic amphetamine. These results suggest that behavioral sensitization to amphetamine is not mediated through transcriptional regulation of D1 or D2 mRNA levels in caudate/putamen.

Gender differences in outpatient research subjects with affective disorders: a comparison of descriptive variables.

BACKGROUND: Gender may play an important role in the etiopathophysiology of psychiatric illness and has become a subject of increasing interest because of its possible effects on biological markers, treatment outcome, and prognosis. Intrigued by this issue and as part of our attempt to further characterize research subjects in San Diego, we evaluated male and female research subjects from our affective disorders clinical research center on a variety of measures. Based on epidemiologic data, we postulated that female and male subjects would be similar to epidemiologic samples and would differ in terms of comorbid diagnoses and that female subjects would be more likely to have had a history of previous treatment. METHOD: The demographic characteristics; coffee, tobacco, and alcohol consumption patterns; symptom patterns; and current and lifetime comorbid DSM-III-R Axis I diagnoses of 124 female and 69 male outpatient research subjects were contrasted. RESULTS: Female research subjects had more comorbid problems with anxiety disorders, were more likely to have been previously treated, and were more likely to have a family history of psychiatric illness. CONCLUSION: Male and female research subjects were remarkably similar with respect to most characteristics assessed but, as postulated, differed in terms of their comorbid diagnoses and prior treatment history.