Antipsychotic response to clozapine varies markedly among patients with schizophrenia. The disposition of clozapine is dependent, in part, on the cytochrome P-450 (CYP) 1A2 enzyme in vivo. In theory, a very high CYP1A2 activity may lead to subtherapeutic concentrations and treatment resistance to clozapine. This prospective case study evaluates the clinical significance of ultrarapid CYP1A2 activity and a recently discovered single nucleotide (C --> A) polymorphism in intron 1 of the CYP1A2 gene (CYP1A2*F) for treatment resistance to clozapine. In addition, we describe the effect of grapefruit juice or low-dose fluvoxamine (25-50 mg/d) coadministration on clozapine and active metabolite norclozapine steady-state plasma concentration and antipsychotic response.

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

Positive and negative symptoms are measurable characteristics that may represent core features of schizophrenia and offer a quantitative approach for studying the genetics of schizophrenia and related disorders. The Positive and Negative Syndrome Scale (PANSS) was used to assess 72 members of five families segregating schizophrenia. The study confirmed high internal reliability of PANSS scales in this sample with diverse lifetime diagnoses. Gender but not alcoholism affected scores. Schizophrenia/schizoaffective and schizophrenia spectrum disorder groups had higher mean scores for the positive and negative scales than other lifetime diagnostic groups, consistent with genetic transmission of these symptoms. Positive and negative symptom patterns did not subtype families. The results support the validity of positive and negative symptom measures as independent dimensions in familial schizophrenia.

Case management has been an integral part of psychiatric practice in the United States for over a decade and has generated a large body of literature. The application of case management principles to the care of people suffering from psychiatric disorders is becoming increasingly popular in the United Kingdom and Europe and literature is now beginning to be published. However, no definitive statements about the efficacy of case management have been made due to a range of conceptual and methodological problems. The present paper is a critical review of the case management outcome literature. Reported outcomes are reviewed in the context of study design and service characteristics. The authors conclude that case management practice can have at least some impact on patients' use of services (including marked decrease in in-patient bed days); satisfaction with services; engagement with services; and social networks and relationships when it is delivered as a direct, clinical service with high staff: patient ratios. A set of recommendations are suggested for the future practice and presentation of research into case management.

Although responsive to the total symptom profile, psychosocial measures typically utilized for evaluating quality of life and mental health status in HIV disease lacked sensitivity and specificity for measuring the consequences of lipodystrophy-associated fat distribution changes alone. Lipodystrophy severity did impact negatively on body image.