Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.

BACKGROUND: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. METHODS: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. RESULTS: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. CONCLUSIONS: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial.

CONTEXT: The serotonin reuptake inhibitors are the treatment of choice for patients with obsessive-compulsive disorder; however, empirical support for this assertion has been weaker for children and adolescents than for adults. OBJECTIVE: To evaluate the safety and efficacy of the selective serotonin reuptake inhibitor sertraline hydrochloride in children and adolescents with obsessive-compulsive disorder. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: One hundred eighty-seven patients: 107 children aged 6 to 12 years and 80 adolescents aged 13 to 17 years randomized to receive either sertraline (53 children, 39 adolescents) or placebo (54 children, 41 adolescents). SETTING: Twelve US academic and community clinics with experience conducting randomized controlled trials. INTERVENTION: Sertraline hydrochloride was titrated to a maximum of 200 mg/d during the first 4 weeks of double-blind therapy, after which patients continued to receive this dosage of medication for 8 more weeks. Control patients received placebo. MAIN OUTCOME MEASURES: The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH GOCS), and the NIMH Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) rating scales. RESULTS: In intent-to-treat analyses, patients treated with sertraline showed significantly greater improvement than did placebo-treated patients on the CY-BOCS (adjusted mean, -6.8vs -3.4, respectively; P=.005), the NIMH GOCS (-2.2 vs -1.3, respectively; P=.02), and the CGI-I (2.7 vs 3.3, respectively; P=.002) scales. Significant differences in efficacy between sertraline and placebo emerged at week 3 and persisted for the duration of the study. Based on CGI-I ratings at end point, 42% of patients receiving sertraline and 26% of patients receiving placebo were very much or much improved. Neither age nor sex predicted response to treatment. The incidence of insomnia, nausea, agitation, and tremor were significantly greater in patients receiving sertraline; 12 (13%) of 92 sertraline-treated patients and 3 (3.2%) of 95 placebo-treated patients discontinued prematurely because of adverse medical events (P=.02). No clinically meaningful abnormalities were apparent on vital sign determinations, laboratory findings, or electrocardiographic measurements. CONCLUSION: Sertraline appears to be a safe and effective short-term treatment for children and adolescents with obsessive-compulsive disorder.

Gender differences in neuroleptic nonresponsive clozapine-treated schizophrenics.

Gender differences in neuroleptic-refractory chronic schizophrenic disorder patients were examined to determine whether a superior or equivalent antipsychotic response in women vs. men existed similar to that of the general schizophrenic population. Sixty-nine DSM-III schizophrenic patients (47 males and 22 females) were treated with clozapine using a standardized medication regime. The gender differences in these neuroleptic-nonresponsive chronic schizophrenic disorder patients differed from those previously observed in the general schizophrenic population in that an equivalent antipsychotic treatment response in females versus males was not found. These treatment-refractory women appear to be a severely ill subgroup of female schizophrenics with distinct onset of illness, course and treatment response characteristics.

Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients.

OBJECTIVE: The purpose of this study was to determine if plasma clozapine levels were associated with treatment response. METHOD: To examine this question, neuroleptic nonresponsive patients with schizophrenia or schizoaffective disorder were given clozapine, which was titrated to 500 mg/day by day 14 of treatment, and the dose was held fixed at least through day 21. Subsequently, clozapine doses were adjusted as clinically indicated, up to a maximum of 900 mg/day. Plasma clozapine levels were obtained at weeks 3 and 6, and standard clinical ratings (Brief Psychiatric Rating Scale [BPRS] and Clinical Global Impression) were done at baseline and at weeks 3 and 6. RESULTS: Data from 45 subjects were analyzed. There were no correlations between plasma clozapine levels and change in BPRS scores at treatment weeks 3 and 6. However, when the subjects were classified as responders or nonresponders, therapeutic response was associated with clozapine blood levels above 350 ng/ml. CONCLUSIONS: This study suggest that clozapine blood levels are correlated with clinical response.

Do white-cell count spikes predict agranulocytosis in clozapine recipients?

The use of clozapine is limited by the risk of agranulocytosis. The incidence of agranulocytosis after 1 year was .80 percent in 11,555 patients registered in the Clozaril Patient Management System (CPMS) who received clozapine from February 1990 to April 1991. We noticed a tendency for white-cell counts to spike upward before agranulocytosis occurred. We analyzed the CPMS data to test whether a white-cell count spike at least 15 percent above the previous measurement predicted agranulocytosis within 75 days, with a 21-day lag to allow white-cell counts to decline to levels indicative of agranulocytosis. The occurrence of a spike, entered as a time-dependent covariate in proportional hazards regression, significantly predicted development of agranulocytosis (risk ratio, 3.02; 95% confidence interval, 1.38 to 6.57). Spikes were sensitive though nonspecific predictors, occurring frequently in patients who did not develop agranulocytosis. These results, while exploratory, indicate the potential usefulness of these spikes as guidelines to govern the use of clozapine.

A comparison of European and American dosing regimens of schizophrenic patients on clozapine: efficacy and side effects.

We present a comparison of the results from two studies of patients on clozapine. The American study (n = 84; Hillside Hospital, Glen Oaks, NY) and the European study (n = 63; Innsbruck University Clinics, Innsbruck, Austria) both examine efficacy and side effects in schizophrenic patients on this atypical neuroleptic. There is a very substantial difference in the dosing regimen used on both continents and this is reflected in the studies reported. A question with major clinical implications is whether the higher doses commonly used in the United States lead to a better outcome or a different profile of side effects. Outcome as a function of serum concentration will be examined. Results confirm a lower dose, lower clozapine blood level, and a lesser degree of side effects in the Austrian cohort when compared to the American sample. Surprisingly, the clinical efficacy of the lower dosing regimen was superior to the higher dose. Reasons for this anomaly are explored.

Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome.

OBJECTIVE: This study addressed the unique clinical properties attributed to the atypical antipsychotic clozapine, including its efficacy in patients with treatment-refractory psychosis and against negative symptoms, its lack of acute extrapyramidal side effects, and the longer time course of its therapeutic effects. METHOD: The clinical responses of 84 schizophrenic inpatients (66 with treatment-refractory illness and 18 who were intolerant of antipsychotic treatment) were examined. After all previous antipsychotic medications had been withdrawn, the patients were treated with clozapine according to a standardized titration and dosage schedule. Patients who tolerated and responded to treatment were discharged and maintained on a regimen of clozapine for up to 52 weeks. Patients were evaluated for behavioral response and side effects after weeks 3, 6, 12, 26, 39, and 52 of treatment. RESULTS: Fifty percent of the patients with treatment-refractory illness and 76% of the treatment-intolerant patients responded to clozapine in up to 52 weeks. The optimal period for a trial of clozapine appeared to be 12-24 weeks. Clozapine exhibited therapeutic effects on negative symptoms, but these were not clearly independent of its effects on positive symptoms and extrapyramidal side effects. Several variables, including early age at onset of illness and female gender, were found to be predictors of poor response to treatment. Predictors of good response included the presence of extrapyramidal side effects during previous treatment with classic neuroleptics and a diagnosis of paranoid schizophrenia. CONCLUSIONS: These findings have important implications for the use of clozapine and our understanding of the pathophysiology of treatment-resistant schizophrenia.

Predictors of response to clozapine.

Clinical and biological measures were examined for their relationship to clinical response to clozapine. Associations were found between therapeutic response and the following variables: male gender, paranoid schizophrenia subtype diagnosis, older age at onset of illness, shorter duration of illness, higher levels of pretreatment acute EPS, low pretreatment CSF HVA/5-HIAA, greater decrease in prolactin (PRL) and increase in growth hormone (GH) response to apomorphine stimulation pretreatment and greater inhibition by clozapine treatment of PRL and GH response to apomorphine, and plasma clozapine levels above 350 ng/mL. These results are consistent with other investigators' findings and have practical and heuristic implications for the use of clozapine and understanding its mechanism of action.

Clozapine, negative symptoms, and extrapyramidal side effects.

The importance of persistent negative symptoms in schizophrenia as a limiting factor in psychosocial and vocational rehabilitation has been increasingly emphasized. As a result, treatment trials and new drug development programs are focusing more attention on negative symptoms. Unfortunately, there is enormous phenomenological overlap between negative symptoms and neuroleptic-induced parkinsonism. We report data from a cohort of 56 clozapine-treated patients demonstrating significant correlations between measures of akinesia and anergia. Despite an average drug washout of over 2 weeks, the persistence of drug-induced parkinsonism can confound the assessment of therapeutic drug effects on negative symptoms.

Clozapine dose in the United States and Europe: implications for therapeutic and adverse effects.

The report (1) provides an overview of clozapine doses used in trials conducted in Europe and the United States, (2) compares data on efficacy, and (3) compares side effects of clozapine from recent European and U.S. investigations. The reviewed European trials used a mean dose of 283.7 mg/day, while the mean dose in the U.S. studies was 444 mg/day. Even though the mean doses used in the United States are considerably higher than those used in Europe, the response rates for the two continents are strikingly similar. The main differences in a comparison of two samples evaluated in New York and Innsbruck were found in the prevalence of seizures (Innsbruck, 0%; United States, 7.1%) and confusion (Innsbruck, 0%; United States, 14%). Excitement was less prevalent in the U.S. study. The data presented appear to suggest that a lower dose of clozapine may be as effective as a higher dose in the management of treatment-resistant schizophrenic patients and may cause fewer side effects.

The use of clozapine in neurologic disorders.

The advent of clozapine has marked a major advance in the treatment of schizophrenia because of its low incidence of extrapyramidal side effects and superior efficacy. Because of a relatively high incidence of agranulocytosis, approved indications for use are limited to treatment-refractory or neuroleptic-intolerant patients with schizophrenia. However, an emerging body of literature suggests that clozapine may be preferable to typical neuroleptics for treating psychosis in certain neurologic disorders. In addition, clozapine may have a place in the treatment of movement disorders that are caused by or are a result of the pharmacologic treatment of some neurologic illnesses. In general, clozapine doses used in these settings are lower than that for treating psychosis in schizophrenia. This article reviews the experience with clozapine in selected neurologic disorders.

Flumazenil reversal of benzodiazepine-induced sedation for a patient with severe pre-ECT anxiety.

We describe various measures to reduce severe anxiety that interfered with much-needed maintenance electroconvulsive therapy in a 32-year-old man. Treatment with ketamine met with moderate success, and then large doses of lorazepam and midazalam were used. The potential anticonvulsant effect of these drugs was successfully reversed by the administration of intravenous flumazenil just prior to the treatments.

Does clozapine cause tardive dyskinesia?

BACKGROUND: The authors attempted to determine if chronic exposure to clozapine can cause tardive dyskinesia. METHOD: Twenty-eight schizophrenic or schizoaffective patients with no prior history of definite tardive dyskinesia were treated with clozapine for at least 1 year, and their ongoing modified Simpson Dyskinesia Scale ratings were analyzed. These data were then compared with those of another group of similarly diagnosed patients who were treated with a conventional neuroleptic for at least 1 year. RESULTS: Two patients in the clozapine-treated group (both of whom had ratings of questionable tardive dyskinesia at baseline) were later rated by the modified Simpson Dyskinesia Scale as having mild tardive dyskinesia on at least two consecutive ratings 3 months apart. Although there was uncertainty about whether clozapine definitely caused the tardive dyskinesia in those two patients, a survival analysis comparing the clozapine-treated group with the neuroleptic-treated group showed a lower risk of tardive dyskinesia developing in the clozapine-treated group. CONCLUSION: This study was unable to definitively conclude whether clozapine causes tardive dyskinesia. However, if cases do develop, the risk of tardive dyskinesia is likely to be less with clozapine than with typical neuroleptics.