Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy.

OBJECTIVE: Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based. DATA SOURCES: The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected. STUDY SELECTION: 16 studies that provided incidence rates or data from which these rates could be calculated were included. DATA EXTRACTION: We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate. RESULTS: The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect. CONCLUSIONS: In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Effect of cannabis use on the course of schizophrenia in male patients: a prospective cohort study.

BACKGROUND: Findings on the impact of cannabis use on the course of schizophrenia are inconsistent and not conclusive. AIMS: To study the effect of cannabis use on the course of schizophrenia taking into account the effects of the quantity of cannabis use and important confounders. METHODS: Prospective cohort study with assessments of symptoms, confounders and hospitalizations at baseline, 6 month and 12 month follow up. RESULTS: In a representative cohort of 145 male patients with schizophrenia, 68 (46.9%) used cannabis. Mean age at onset of schizophrenia in cannabis using patients was significantly lower than in non-cannabis using patients. No other cross-sectional demographic or clinical differences were observed between users and non-users. In a series of longitudinal analyses, cannabis use was not associated with differences in psychopathology, but relapse in terms of the number of hospitalizations was significantly higher in cannabis using patients compared to non-cannabis using patients. CONCLUSIONS: Patients with schizophrenia using cannabis are more frequently hospitalized than non-cannabis using patients but do not differ with respect to psychopathology. Possible explanations for these findings are discussed.

Compulsory treatment with clozapine: a retrospective long-term cohort study.

BACKGROUND: Clozapine is the gold standard in treatment of treatment-resistant psychotic patients. We know little about the effects of compulsory treatment in patients unwilling to accept the necessary treatment. AIMS: To assess the effectiveness, tolerability and safety of compulsory treatment with clozapine (CTC). METHOD: A cohort of 17 consecutive patients given compulsory treatment with clozapine were rated retrospectively by their treating psychiatrists on the basis of their case notes. RESULTS: CGI-S decreased significantly over time until last observation after a mean of more than 15 months. No patient deteriorated as measured by CGI-I. At last observation as many as ten of the 11 patients still on clozapine were classified as much to very much improved. The degree of custodial restriction at last observation showed improvement in 11 patients and no change in six. No serious adverse events were observed. CONCLUSION: A trial of compulsory treatment with clozapine showed this treatment to be feasible, effective, safe and well tolerated.