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

OBJECTIVE: Clozapine remains the only medication indicated for refractory schizophrenia. As new antipsychotic drugs become available, their efficacy compared to clozapine, particularly in moderately ill patients, is of great clinical interest. We compared risperidone, the first of these, to clozapine in partially responsive patients. Further, since participation of patients usually excluded from clinical trials is increasingly important, we broadened inclusion to a wider patient population. METHODS: We compared clozapine (n = 53) to risperidone (n = 54) in a randomized, double-blind, 29-week trial in schizophrenia patients (diagnosed using DSM-IV) at 3 research outpatient clinics. Randomization was stratified by "narrow" or "broad" inclusion criteria. The study was conducted between December 1995 and October 1999. Time to treatment discontinuation for lack of efficacy and time to 20% improvement in the Brief Psychiatric Rating Scale psychotic symptom cluster were the primary outcome measures. RESULTS: There were no differences in all-cause discontinuation; clozapine-treated participants were significantly less likely to discontinue for lack of efficacy (15%) than risperidone-treated participants (38%) (Wilcoxon χ(2)1 = 6.10, P = .01). Clozapine resulted in significantly more global improvement (F2,839 = 6.07, P < .01) and asociality improvement (F2,315 = 6.64, P < .01) than risperidone. There was no difference in proportions meeting an a priori criterion of psychosis improvement (risperidone: 57%; clozapine: 71%). Significant adverse effect differences in salivation (F1 = 4.05, P < .05) (F1 = 12.13, P < .001), sweating (F1 = 5.07, P < .05), and tachycardia (F1 = 6.51, P < .05) favored risperidone. CONCLUSIONS: Clozapine-treated partially responsive patients were less likely to discontinue treatment for lack of efficacy and improved more globally than those treated with risperidone, although psychotic symptoms did not differ. These findings suggest that clozapine should not be restricted to the most severely ill, treatment-refractory patients; it should be considered as an alternative for patients who have some response to other antipsychotics, but still experience troubling symptoms.

The impact of olanzapine on tardive dyskinetic symptoms in a state hospital population.

BACKGROUND: Tardive dyskinesia is a serious adverse event, which is associated mainly with the use of the first-generation antipsychotic agents. Convergent data from clinical trials suggest that second-generation antipsychotic agents are less likely to cause tardive dyskinesia. However, the data with regard to the effect of switching from first- to second-generation antipsychotic agents on pre-existing dyskinetic symptoms during routine clinical care is sparse. METHODS: Sixty-three patients with DSM-IV schizophrenia or schizoaffective disorder (n = 61) or bipolar I disorder (n = 2) consecutively admitted to a state hospital, who were treated either with olanzapine (n = 35) or conventional antipsychotic agents (n = 28) by physician choice, were enrolled in the study. The severity and frequency of tardive dyskinetic symptoms using the Abnormal Involuntary Movement Scale were assessed in the two medication groups at baseline, 8 weeks, and 6 months. RESULTS: There were statistically significant reductions in the prevalence and severity of dyskinetic symptoms at 8 weeks and 6 months for the group treated with olanzapine but not for those treated with conventional agents. CONCLUSIONS: These preliminary data suggest that olanzapine may be a treatment option for subjects with tardive dyskinesia. However, the question whether olanzapine treats, ameliorates, or masks preexisting tardive dyskinesia was difficult to answer, as no dosage reduction or withdrawal was undertaken.

A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type.

OBJECTIVES: This pilot study evaluated the efficacy and safety of adjunctive topiramate compared with placebo in the treatment of patients with a diagnosis of schizoaffective disorder, bipolar type (SAD-BT). METHODS: A sample of 48 adult patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of SAD-BT (supported by the Structured Clinical Interview for DSM-IV Axis I Disorder, Patient Edition) were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100-400 mg/day) or placebo. Patients who had achieved a > or =20% decrease from baseline in their Positive and Negative Syndrome Scale (PANSS) total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. The dosage of the study medicine was continued unchanged from the earlier 8-week study period. At the end of the study period, the study medicine was tapered and discontinued over a 2-week period. Primary efficacy was assessed at 8 weeks using the mean change between treatment groups of the PANSS total scores in the intent-to-treat population of randomized patients. Several secondary measures were also assessed. Safety analyses included monitoring of adverse events, vital signs, electrocardiogram (ECG) and laboratory values. RESULTS: Even though both treatments reduced scores on various psychopathology rating scales, adjunctive topiramate treatment (nearly 275 mg/day) did not show increased efficacy relative to placebo on the primary outcome measure (PANSS scale) or any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than placebo-treated patients, which led to a significant reduction in body mass index (BMI). Relative to adjunctive placebo, topiramate-treated patients experienced higher rates of paresthesia, sedation, word-finding difficulty, sleepiness, and forgetfulness, but these differences were not statistically significant. There were no clinically significant abnormalities in either the ECG or laboratory results. There were no serious adverse events in the study. Further, there was no worsening of the PANSS total scores (to > or =10% from baseline), and no significant differences between the treatments on worsening of total Montgomery-Asberg Depression Rating Scale (MADRS) scores [1/13 (7.7%) for placebo; 1/25 (4.0%) for topiramate]. CONCLUSIONS: This pilot study did not support clinical efficacy for adjunctive topiramate treatment in patients with SAD-BT. There were no major safety or tolerability issues in this study. Confirming the results of other studies, topiramate-treated patients did experience greater body weight loss and reduction in BMI.

Leukopenia in clozapine treated patients may be induced by other drugs: a case series.

The combination of clozapine and other potentially leukopenic drugs may pose a greater risk for neutropenia. However, neutropenia may not always be due to clozapine. When adding potentially leukopenic drugs, clinicians should look for possible alternatives especially as clozapine is often a drug used as the last resort in treatment refractory schizophrenia.

Cognitive enhancement therapy for schizophrenia: effects of a 2-year randomized trial on cognition and behavior.

BACKGROUND: Deficits in social cognition and neurocognition are believed to underlie schizophrenia disability. Attempts at rehabilitation have had circumscribed effects on cognition, without concurrent improvement in broad aspects of behavior and adjustment. OBJECTIVE: To determine the differential effects of cognitive enhancement therapy (a recovery-phase intervention) on cognition and behavior compared with state-of-the-art enriched supportive therapy. DESIGN: A 2-year, randomized controlled trial with neuropsychological and behavioral assessments completed at baseline and at 12 and 24 months. SETTING: An outpatient research clinic housed in a medical center's comprehensive care service for patients with severe mental illness. PATIENTS: A total of 121 symptomatically stable, non-substance-abusing but cognitively disabled and chronically ill patients with schizophrenia or schizoaffective disorder. INTERVENTIONS: Cognitive enhancement therapy is a multidimensional, developmental approach that integrates computer-assisted training in neurocognition with social cognitive group exercises. Enriched supportive therapy fosters illness management through applied coping strategies and education. MAIN OUTCOME MEASURES: Six highly reliable summary measures--Processing Speed, Neurocognition, Cognitive Style, Social Cognition, Social Adjustment and Symptoms--were tested using analysis of covariance and linear trend analysis. RESULTS: At 12 months, robust cognitive enhancement therapy effects were observed on the Neurocognition and Processing Speed composites (P<.003), with marginal effects observed on the behavioral composites. By 24 months, differential cognitive enhancement therapy effects were again observed for the 2 neuropsychological composites and for Cognitive Style (P=.001), Social Cognition (P=.001), and Social Adjustment (P=.01). As expected, no differences were observed on the residual Symptoms composite. Effects were unrelated to the type of antipsychotic medication received. Enriched supportive therapy also demonstrated statistically significant within-group effect sizes, suggesting that supportive psychotherapy can also have positive, although more modest, effects on cognitive deficits. CONCLUSION: Many cognitive deficits and related behaviors of patients with stable schizophrenia are improved when sufficient exposure to relevant rehabilitation is provided.

The prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar subtype.

OBJECTIVES: To evaluate the point prevalence of the metabolic syndrome in patients with schizoaffective disorder--bipolar type. METHODS: Consenting patients who were participants in an ongoing clinical trial of adjunctive topiramate treatment for schizoaffective disorder, bipolar type were evaluated at baseline for the point prevalence of the metabolic syndrome. The criteria for the metabolic syndrome included: (a) waist circumference > 102 cm (40 inches) in males, or > 88 cm (35 inches) in females; (b) fasting serum triglyceride levels > or = 150 mg/dL; (c) fasting high density lipoproteins (HDL) cholesterol <40 mg/dL in men or <50 mg/dL in women; (d) blood pressure > or = 130/85 mmHg; and (e) fasting glucose > or = 110 mg/dL. Subjects who had at least three of these five criteria were defined as meeting criteria for the metabolic syndrome. RESULTS: Thirty-six subjects (males = 15, females = 21) were evaluated, and three were excluded for missing data. Among those 33 subjects with complete data, 14 subjects (42.4%, males = 7, females = 7, African Americans = 6, Caucasians = 8) met criteria for the metabolic syndrome. Not unexpectedly, those with the metabolic syndrome were significantly more likely to be obese, and have significantly higher mean systolic and diastolic blood pressure, mean fasting triglyceride levels and larger mean waist circumferences, and significantly lower HDL cholesterol levels; and a trend toward higher fasting blood glucose levels. Furthermore, the fasting mean total cholesterol in those with the metabolic syndrome was 217 mg/dL (+/-46). CONCLUSIONS: This preliminary report suggests that the point prevalence of the metabolic syndrome in patients with schizoaffective disorder appears to be higher than that reported in the general population of the USA. Targeted weight reduction and life style change strategies (increased exercise, smoking cessation, stress reduction) may provide useful interventions to decrease the morbidity and mortality that accompanies the presence of the metabolic syndrome in patients with psychiatric illnesses.

A random-assignment, double-blind, clinical trial of once- vs twice-daily administration of quetiapine fumarate in patients with schizophrenia or schizoaffective disorder: a pilot study.

OBJECTIVE: To evaluate the efficacy and safety of administering quetiapine once vs twice daily. METHOD: Utilizing a double-blind design, 21 hospitalized adult men or women with DSM-IV schizophrenia or schizoaffective disorder, who had received unchanged doses (for 2 weeks) of either 400 or 600 mg daily of quetiapine administered in 2 doses, were randomly assigned to once- or twice-daily administration for 4 weeks and then crossed over to the opposite dosing regimen for an additional 4 weeks. Standard psychopathology and safety measures were used in the study. RESULTS: Nearly 70% (15/21) of the subjects met the a priori efficacy responder criteria with no statistical differences in response between those assigned to once- or twice-daily quetiapine administration. Statistical analyses confirmed that most subjects maintained efficacy during the switch to once- or twice-daily administration with quetiapine. A minority (15%) did experience worsening of symptoms or orthostatic hypotension during the crossover. Quetiapine was generally well tolerated at either twice- or once-daily administration. CONCLUSIONS: These pilot data suggest that it is clinically feasible to switch most quetiapine-treated subjects receiving a therapeutic twice-daily dosing schedule to a once-daily regimen. A minority may experience worsening of symptoms or orthostatic hypotension during the switch. This strategy of administering quetiapine entirely at bedtime may promote improved adherence to treatment.

Attitudes towards taking Medicine among those patients who either received Olanzapine or First Generation Antipsychotic Agents.

This project evaluated the attitudes of psychiatric patients towards receiving either olanzapine or the first-generation antipsychotic agents. Newly admitted patients to a state psychiatric hospital who were either prescribed olanzapine (n=35) or other first-generation antipsychotic agents (n=34) were compared on measure of their personal attitudes toward receiving medicines using the Drug Attitude Inventory (DAI). Subjects were evaluated prior to receiving olanzapine and 8 weeks later unless they were discharged or discontinued sooner. The olanzapine-treated group recorded significantly greater improvements on their positive attitude scores toward taking the medicine, and reduced negative attitude scores relative to the comparator group. These results remained statistically significant even after correction of baseline differences between the two groups for the positive attitudes and a statistical trend persisted for negative attitude scores too. During the subsequent 30 month follow-up, significantly fewer of the olanzapine treated subjects (5, 14.3%) were readmitted to the hospital compared with 13 (38.2%) of the comparator group. These data suggest switching patients to olanzapine may improve their attitudes towards taking medicines at least in the short-term. These preliminary data need affirmation or refutation in a controlled random-assignment longer-term clinical trial where specific measures of adherence are evaluated, and where the comparators are the other second generation antipsychotic agents.

The use of concomitant medications in psychiatric inpatients treated with either olanzapine or other antipsychotic agents: a naturalistic study at a state psychiatric hospital.

Concomitant medications are frequently used in the treatment of resistant psychiatric conditions to augment the primary psychotropic agent or to ameliorate side effects. The present study evaluated the prescription of concomitant psychiatric medications for psychiatric inpatients that were prescribed either olanzapine at its first commercial availability or another first-line antipsychotic agent. Sixty-nine newly admitted patients (mainly with schizophrenia) who were prescribed either olanzapine (n = 35) or another first-line antipsychotic agent (n = 34) were assessed (for the prescription of other concomitant psychotropic drugs) before (2-4 weeks prior to study) and following 8 weeks of treatment (unless discharged sooner). The results indicate that significantly fewer olanzapine-treated subjects were prescribed anticholinergic agents as compared to those prescribed other first-line antipsychotic agents, and a similar trend was noted in the prescription of mood stabilizers as well. Olanzapine-treated subjects used less as needed (PRN) antipsychotic medication compared to pre-olanzapine treatment period. Olanzapine-treated subjects used more anxiolytic agents compared to the control group in the early stages of treatment, probably due to the greater baseline severity of illness. These data suggest that olanzapine use is associated with less use of anticholinergic and mood-stabilizing agents as compared to older antipsychotic agents. These results also suggest that there is less need for PRN antipsychotic medication following olanzapine treatment. More severely ill subjects may require more anxiolytics during olanzapine initiation. The need for less anticholinergic and mood-stabilizing agent use with olanzapine could lead to greater adherence to long-term treatment and perhaps decreased cost (i.e. use of blood and organ system monitoring with mood stabilizers). At the end of treatment, olanzapine-treated subjects had statistically significantly lesser concomitant medicine usage compared to control subjects.