clozapine and Disorders-of-Excessive-Somnolence

Atypical antipsychotics are emerging as the first-line pharmacologic treatment for irritability (i.e., aggression, self-injurious behavior, and severe tantrums) in children and adolescents with autistic and other pervasive developmental disorders. Results from placebo-controlled and open-label studies of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole in this subject population are reviewed. Additional placebo-controlled trials and studies of longer-term safety and tolerability are needed.

Topics: Adolescent; Aggression; Antipsychotic Agents; Aripiprazole; Autistic Disorder; Benzodiazepines; Child; Child Development Disorders, Pervasive; Child, Preschool; Clozapine; Dibenzothiazepines; Disorders of Excessive Somnolence; Humans; Obesity; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D(2) receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and "high-dose" olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Disorders of Excessive Somnolence; Haloperidol; Humans; Olanzapine; Prolactin; Schizophrenia, Childhood; Treatment Outcome; Weight Gain

Sleep propensity at daytime has not been investigated in untreated patients with schizophrenia. Furthermore, while the antipsychotics clozapine and olanzapine are considered to frequently cause 'sleepiness' or 'sedation', this has not been objectified yet. Therefore, 30 patients with schizophrenia were included in this randomized, double-blind study. Sleep propensity was assessed before and after 2, 4 and 6 weeks of treatment with either clozapine or olanzapine using a Multiple Sleep Latency Test (MSLT); in the MSLT, sleep latencies of 5 nap opportunities of 20 min during daytime are averaged. In addition, the number of sleep onsets was recorded. Mean sleep latency in untreated schizophrenic patients was 16.2 ± 0.8 min at baseline. Both antipsychotics induced an increase of sleep propensity as indicated by a shortened sleep latency and more sleep onsets during the treatment period as compared to baseline. These effects were strongest in the morning. Four patients receiving clozapine and 3 patients receiving olanzapine reported subjective sleepiness, in all but one commencing in the first treatment week and persisting until study end. While the mean sleep latency during treatment was significantly shorter in these patients (12.3 ± 0.8 min) than in those without subjective sleepiness (14.9 ± 0.7 min), a short sleep latency was not necessarily associated with subjective sleepiness. In conclusion, mean sleep latency was >36% longer (i.e. sleep propensity was lower) in untreated patients with schizophrenia than in healthy subjects previously consistently reported. Furthermore, clozapine and olanzapine increased sleep propensity in schizophrenic patients. A minority of patients reported subjective sleepiness.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Clozapine; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Male; Middle Aged; Olanzapine; Polysomnography; Psychiatric Status Rating Scales; Reaction Time; Schizophrenia; Sleep Stages; Statistics as Topic; Time Factors; Young Adult

This study compared the bioequivalence of FazaClo (clozapine orally disintegrating tablets) 100 mg to Clozaril (clozapine standard oral tablets) 100 mg after multiple doses in patients with schizophrenia.. This was a randomized, open-label, multiple-dose study in which patients with schizophrenia received FazaClo or Clozaril 100 mg twice daily for 5 days before crossing over to the alternate therapy. Blood samples were obtained at regular intervals during and after the completion of treatment, and standard pharmacokinetic parameters were calculated. Safety and patient satisfaction with FazaClo were also assessed.. Thirty-six patients were enrolled, of whom 33 completed the study and 30 were included in the steady-state analyses. All pharmacokinetic parameters for clozapine and desmethylclozapine (the major metabolite of clozapine) were similar between FazaClo and Clozaril in both the completer and steady-state populations. Geometric mean values for steady-state maximum and minimum concentrations and area under the plasma concentration-time curve for FazaClo were all within 95-105% of those for Clozarilwell within the range considered by the US FDA as acceptable for bioequivalence (80-125%). Patients also expressed a high level of satisfaction with the FazaClo orally disintegrating tablet formulation.. FazaClo produced pharmacokinetic profiles almost identical to those of Clozaril. This should provide clinicians with reassurance that patients who receive FazaClo will achieve plasma drug concentrations similar to those produced by the same daily dose of Clozaril, and that no cross-titration is necessary when switching from one of these clozapine formulations to the other.

Topics: Administration, Oral; Adolescent; Adult; Antipsychotic Agents; Area Under Curve; Clozapine; Cross-Over Studies; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Generic; Female; Half-Life; Humans; Intestinal Obstruction; Intestine, Small; Male; Metabolic Clearance Rate; Middle Aged; Patient Dropouts; Patient Satisfaction; Schizophrenia; Sweating; Tablets; Therapeutic Equivalency

Topics: Adult; Antipsychotic Agents; Clozapine; Disorders of Excessive Somnolence; Humans; Hypnotics and Sedatives; Male

Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, chi=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Schizophrenia; Sexual Dysfunction, Physiological; Sialorrhea

Topics: Antipsychotic Agents; Aryl Hydrocarbon Hydroxylases; Benzhydryl Compounds; Clozapine; Cytochrome P-450 CYP2C19; Disorders of Excessive Somnolence; Drug Interactions; Humans; Mixed Function Oxygenases; Modafinil; Schizophrenia

Psychotic patients treated with clozapine often experience persistent daytime sleepiness. This is a frequent side effect of clozapine that may reduce patient compliance. We hypothesized that clozapine might interfere with the circadian rhythms regulated by the biological clock. In 171 patients with major psychosis, we investigated the association between hypersomnolence during clozapine therapy and a CLOCK gene polymorphism (3111 T/C substitution). Forty-six patients showed persistent daytime sleepiness and were classified as "sleepy". "Sleepy" patients were significantly more likely to have a mutated allele compared to both "non sleepy" patients and healthy subjects (chi2 = 20.36, d.f. = 1, P = 0.000007, and chi2 = 13.91, d.f. = 1, P = 0.0002, respectively). We conclude that an interaction between clozapine and the CLOCK gene polymorphism 3111 T/C substitution could explain persistent daytime sleepiness in a significant proportion of patients treated with clozapine.

Topics: Adult; Antipsychotic Agents; Chi-Square Distribution; Chromatography, High Pressure Liquid; CLOCK Proteins; Clozapine; Cysteine; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Multivariate Analysis; Polymerase Chain Reaction; Polymorphism, Genetic; RNA, Messenger; Threonine; Time Factors; Trans-Activators

Topics: Clozapine; Disorders of Excessive Somnolence; Drug Monitoring; Humans; Male; Methylphenidate; Middle Aged; Psychotic Disorders; Sleep Wake Disorders