Atypical antipsychotic metabolism and excretion.

BACKGROUND: The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored. OBJECTIVE: To analyze the excretion profile of atypical antipsychotic agents and compare the overall magnitude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agents' biotransformation. METHODS: Published literature and each manufacturer's radiolabeled drug absorption, distribution, metabolism and excretion data and U.S. prescribing information were reviewed. RESULTS: With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e.,

Paliperidone extended-release for schizophrenia: effects on symptoms and functioning in acutely ill patients with negative symptoms.

BACKGROUND: Most patients with schizophrenia exhibit negative symptoms, even during acute episodes. These difficult-to-treat symptoms are often associated with poor functioning and outcomes. METHODS: A post-hoc analysis of pooled data from three 6-week double-blind studies included patients in an acute episode of schizophrenia who received paliperidone extended-release (ER) (3, 6, 9, or 12 mg) or placebo. Based on criteria developed by the authors, patients were stratified by the presence or absence of predominant negative symptoms at baseline (>or=40% of the maximum negative factor score and <40% of the maximum positive factor score on the Positive and Negative Syndrome Scale [PANSS]). RESULTS: Although these studies were not designed to examine patients with predominant negative symptoms, the criteria identified 23% of acutely ill patients (270/1193). The mean (SD) baseline PANSS negative symptoms factor score, 27.4 (3.3), was 49% of the maximum; the positive symptoms factor score, 23.7 (2.8), was 33% of the maximum. Completion rates with paliperidone ER (n=195) and placebo (n=75) were 64.6% and 44.0%, respectively. Greater improvements occurred with paliperidone ER vs placebo on PANSS (total, negative and other factors), Clinical Global Impressions-Severity and Personal and Social Performance scores at endpoint (all P values <0.05). Adverse events reported in >or=10% of patients were (paliperidone ER vs placebo): headache (14.4% vs 6.7%), insomnia (13.8% vs 21.3%) and sinus tachycardia (10.3% vs 1.3%). Paliperidone ER treatment was associated with a similar response profile in patients without predominant negative symptoms (paliperidone ER, n=647; placebo, n=276). CONCLUSIONS: Schizophrenia patients with predominant negative symptoms were identified in a population of acutely ill patients. Findings of this post-hoc analysis suggest that acutely ill patients with or without predominant negative symptoms respond similarly to treatment with paliperidone ER. No unexpected tolerability findings were observed.

Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome.

Hyponatremia/hypoosmolemia causes marked morbidity and prolongs hospital stays in a significant subset of schizophrenic patients. Case reports with methodological limitations suggest clozapine ameliorates this water imbalance. To more conclusively assess this possibility, we completed a 24-week open-label study in 8 male polydipsic hypoosmolemic schizophrenic inpatients. Subjects were treated initially for 6 weeks with a conventional neuroleptic, which was replaced by 300, 600, and 900 (if tolerated) mg/day of clozapine for sequential 6-week periods. On clozapine, mean plasma osmolality rose an average of 15.2 mosm/kg (95% CI: 5.5-25.0). Dosage of 300 mg/day of clozapine was sufficient to normalize plasma osmolality and was generally well tolerated. Clozapine appears to be the first effective pharmacotherapy for severe water imbalance in schizophrenia.

The evaluation of women with schizophrenia.

Schizophrenia affects approximately 1 percent of the population worldwide. Its manifestation and response to treatment are often different in women and men and sex hormones, such as estrogen, may help to explain some of these phenomenological and clinical differences. This article reviews important sex differences in symptom expression and treatment response of schizophrenia and focuses on gender-specific factors, such as motherhood, that require specific methods of assessment in women with the disorder. The evaluation of suicide risk, substance abuse, and medical comorbidity in women with schizophrenia is also addressed. Particular attention is paid to the evaluation needs of women receiving antipsychotics, some of which elevate serum prolactin levels.

Does minimizing neuroleptic dosage influence hyponatremia?

Neuroleptic dosage was reduced by 10% every 2 weeks in five male hyponatremic polydipsic patients with schizophrenia. Mean dose fell from 1980 +/- 1289 to 631 +/- 135 chlorpromazine equivalents/day over a mean of 12.2 weeks until behavioral relapse occurred. During this time, serum sodium did not vary from baseline levels (132.9 +/- 4.9 mEq/1), suggesting that minimizing neuroleptic dose does not alter the severity of hyponatremia in these patients.