Faculty Bibliography

BACKGROUND: There has been considerable support for the observation that atypical antipsychotics have a broader range of therapeutic effects than traditional antipsychotics. We are exploring whether this expanded clinical efficacy can also be seen in patients with treatment-resistant schizophrenia. METHOD: The subjects were 157 treatment-resistant inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week double-blind trial and rated with a standard measure of clinical antipsychotic efficacy (Positive and Negative Syndrome Scale [PANSS]). Factor analysis at baseline and endpoint together with changes in 5 PANSS-derived factors were examined. Data were gathered from June 1996 to December 1999. RESULTS: The underlying PANSS factor structure, as indicated by the factor loadings, was essentially identical at baseline and endpoint. At baseline, the excitement factor was followed by the positive, negative, cognitive, and depression/anxiety factors, explaining 49.4% of the total variance. At endpoint, the positive factor was followed by the negative, excitement, cognitive, and depression/anxiety factors, explaining 55.5% of the total variance. The endpoint data indicated statistically significant (p <.05) improvements over time on the positive factor for all 3 atypicals, but not for haloperidol. The negative factor showed significant improvement for clozapine and olanzapine, with significant worsening for haloperidol. Clozapine, olanzapine, and risperidone were superior to haloperidol on the negative factor, while clozapine was also superior to risperidone. The cognitive factor showed significant improvement for all atypicals, as did the depression/anxiety factor. Only clozapine showed improvement on the excitement factor and was superior to both haloperidol and risperidone. CONCLUSIONS: Treatment with atypical antipsychotics did not substantially change the underlying PANSS 5-factor structure. However, antipsychotic treatment with all 3 atypical medications was associated with significant improvements on 3 of 5 syndromal domains (positive, cognitive, and depression/anxiety) of schizophrenia. Clozapine and olanzapine also showed improvement on the negative factor. Only clozapine was associated with improvement on the excitement domain. This finding confirms that atypicals are associated with improvement of an expanded spectrum of symptoms in treatment-resistant patients

The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen

BACKGROUND: Prolactin levels are elevated to varying degrees by antipsychotics. Prolactin elevations may result in sexual and other adverse effects, and they may be related to antipsychotic effects. We used the data collected in a trial of antipsychotics to study the differential effect of these drugs on prolactin level, to explore the relation between clinical effects and prolactin level, and to determine the relationship between plasma levels of antipsychotics and prolactin level. METHOD: Treatment-resistant patients (133 men, 24 women) diagnosed with DSM-IV schizophrenia or schizoaffective disorder participated in a double-blind, randomized, 14-week trial comparing clozapine (N = 40), olanzapine (N = 39), risperidone (N = 41), and haloperidol (N = 37). Plasma levels of prolactin and antipsychotics were determined at baseline and at weeks 5, 8, 10, 12, and 14 during the trial. Clinical effects were measured with the Positive and Negative Syndrome Scale and the Extrapyramidal Symptom Rating Scale. Statistical analyses were limited to the 75 men for whom repeated prolactin levels were available. Data were gathered from June 1996 to December 1999. RESULTS: Risperidone caused significant elevation of prolactin levels (p <.05) that appeared to be dose-dependent. Clozapine and olanzapine were associated with decreases of prolactin, whereas haloperidol led to a minor, nonsignificant increase. Plasma olanzapine and prolactin levels were correlated. Prolactin levels were not related to clinical improvement or extrapyramidal side effects. CONCLUSION: Antipsychotics show major differences in their effects on prolactin, and risperidone has clearly the most robust effect

Suicidal behavior in patients with psychotic disorders represents a seriously undertreated life-threatening condition. The International Suicide Prevention Trial (InterSePT) is the first large-scale, prospective study designed to evaluate the potential of antipsychotic medications to reduce suicidal behaviors in patients with schizophrenia or schizoaffective disorder who are known to be at high risk for suicide. The unique challenges to study design and the solutions identified for the InterSePT study are described. These challenges included defining suicidal behavior in patients with psychosis, endpoint selection, determination of analytic strategy, and development of scales to assess suicidal behavior. Given the life-threatening nature of suicidal behavior, ethical considerations required that the design minimize suicide attempts and deaths. While the study focused primarily on treatment of suicide, opportunities were used to collect data in related areas of interest, including suicide risk factors, other efficacy measures (e.g., Positive and Negative Syndrome Scale, Covi Anxiety Scale, Calgary Depression Scale), adverse events, pharmacoeconomics, and pharmacogenetics. Because of the complexity of the design issues, a steering committee, suicide monitoring board, and publication committee were established to assist with their management.

BACKGROUND: The InterSePT Scale for Suicidal Thinking (ISST) is a 12-item instrument for the assessment of current suicidal ideation in patients with schizophrenia and schizoaffective disorders. We report the psychometric characteristics of this new scale based on two studies. METHOD: In Study 1, 22 inpatients with schizophrenia and schizoaffective disorders, who had recently attempted suicide or engaged in suicidal ideation, were rated by three trained independent raters to examine interrater reliability. In Study 2, a total of 980 patients with schizophrenia or schizoaffective disorder with a history of suicidal ideation in the past 36 months were enrolled in a 2-year industry-sponsored suicide prevention study. At baseline, these patients were administered the ISST and the Clinical Global Impression Scale for Severity of Suicidality (CGI-SS) by the Principal Investigator (PI) and by a blinded rater (BR), who also administered the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDS), and the Scale of Functioning (SOF). Indices of internal reliability, construct and discriminant validity were examined. RESULTS: The intraclass correlation coefficient (ICC) for the total ISST score for the 22 subjects in Study 1 was 0.90 and mean weighted item kappa coefficients ranged from 0.66 to 0.92. In Study 2, internal reliability (Cronbach alpha) was high, ranging from 0.86 to 0.89 for the individual items, and the overall Cronbach alpha coefficient for all items was 0.88. The ISST (PI) total score was highly correlated with the CGI-SS by the blind rater (r = 0.61, p < 0.0001). ISST total scores significantly differentiated the different levels of CGI-SS (F = 519.2; p < 0.0001). Results of construct and discriminant validity analyses are also presented. CONCLUSION: The ISST is a reliable and valid instrument for the assessment of current suicidal thinking in patients with schizophrenia and schizoaffective disorder by both clinicians and researchers

OBJECTIVE: The authors assessed the efficacy and safety of the first long-acting atypical antipsychotic (long-acting injectable risperidone) in patients with schizophrenia. METHOD: In a 12-week, multicenter, double-blind, randomized study, patients received intramuscular injections every 2 weeks of placebo or long-acting risperidone (25 mg, 50 mg, or 75 mg). The primary measure of efficacy was the change in total score on the Positive and Negative Syndrome Scale. RESULTS: Of the 554 patients who were enrolled, 400 entered the double-blind study, and 370 received at least one postbaseline assessment. Mean changes in score of -6.2, -8.5, and -7.4 on the Positive and Negative Syndrome Scale were seen at endpoint for the 25-, 50-, and 75-mg risperidone groups, respectively; all three change scores were significantly different from that seen with placebo (+2.6). Improvements in positive and negative symptoms were also significantly greater in patients receiving risperidone. Long-acting risperidone was well tolerated. Adverse events related to extrapyramidal symptoms were spontaneously reported by 13% of patients receiving placebo and 10% of patients in the 25-mg risperidone group, with higher rates in the 50-mg and 75-mg groups. Severity of extrapyramidal symptoms was mild at baseline and throughout the trial in each treatment group. Mean weight changes were small in the 25-, 50-, and 75-mg risperidone groups (0.5 kg, 1.2 kg, and 1.9 kg, respectively). Injection site pain was rated as low by the patients, consistent with the investigators' pain ratings. CONCLUSIONS: Long-acting injectable risperidone was efficacious and well tolerated and provides both clinicians and patients with a new mode of treatment that can improve the outcome of long-term therapy.