Faculty Bibliography

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.

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

OBJECTIVE: Schizophrenia is characterized by high suicide risk and low awareness of disorder. Although awareness has benefits for medication compliance and clinical outcome, it is unclear how it may relate to suicide risk in this population. METHOD: This multicenter investigation assessed awareness and suicide-related behavior in 980 patients with schizophrenia or schizoaffective disorder. Patients were followed over 2 years and assessed by blinded raters for suicide-related events. RESULTS: Awareness of psychiatric condition at baseline was associated with increased risk of suicide events over the follow-up. This effect was mediated by depression and hopelessness levels. By contrast, changes in awareness associated with treatment decreased the risk of suicide. CONCLUSIONS: Although some patients may become depressed after acknowledging the clinical handicaps of their disorder, treatment-related changes in awareness are generally associated with a positive outcome relative to suicide risk. The complex interactions and mediation effects of these clinical variables require careful monitoring.

The pharmacological choices for the treatment of schizophrenia have been greatly expanded with the availability of the atypical compounds clozapine (Clozaril, Novartis), risperidone (Risperdal, Janssen-Cilag), olanzapine (Zyprexa, Eli Lilly & Co.), quetiapine (Seroquel, AstraZeneca), ziprasidone (Geodon, Pfizer Inc.) and aripiprazole (Abilify, Otsuka Pharmaceutical Co. Ltd). In this article, the effects of the newer antipsychotics and their side effects are reviewed. Key issues in acute and maintenance treatment, often lifelong, will be reviewed. Side-effect management to ensure adherence to an optimal treatment regimen will be discussed. Coexisting syndromes must be treated in concordance with the patient's clinical presentation. For treatment-resistant patients, atypical compounds are generally more effective than their typical counterparts but medication augmentation strategies are frequently recommended. Finally, the results of recent meta-analyses comparing the effects of atypical versus typical compounds will be critically reviewed and remaining gaps in the current pharmacotherapy of schizophrenia will be explored

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