Faculty Bibliography

BACKGROUND: A substantial number of patients with psychosis receive quetiapine in amounts that are greater than what is recommended in the product labeling approved by drug regulatory agencies. The purpose of this article is to review the past and present dosing patterns of quetiapine for the treatment of schizophrenia. METHOD: A PubMed search for the period January 1, 1990, to July 1, 2005, was conducted to identify English-language articles related to quetiapine dose in schizophrenia using the search terms quetiapine, dose, and schizophrenia. Trends in dosing of quetiapine in a large, state-operated psychiatric hospital system and the anecdotal evidence describing the use of quetiapine in excess of 800 mg/day were also reviewed. RESULTS: The registration studies of quetiapine suggest a target dose range of 300 to 500 mg/day for schizophrenia. In contrast, among inpatients hospitalized in New York State in the period of April 1, 2004, to June 30, 2004, the mean dose of quetiapine prescribed was 620 mg/day, with 33.6% receiving doses in excess of 750 mg/day. Patients with nonwhite ethnicity, length of stay of at least 1 year, or history of prior state hospital admission were more likely to receive doses greater than 750 mg/day. Patients receiving quetiapine as antipsychotic monotherapy or in combination with other antipsychotics were equally likely to receive doses greater than 750 mg/day. Published anecdotal reports describe the use of quetiapine in excess of 800 mg/day and up to 2400 mg/day among patients not responding to lower doses, but currently there are no published reports from double-blind randomized clinical trials establishing the utility of this high-dose treatment strategy. CONCLUSIONS: Dosing of quetiapine in clinical practice is higher than what has been established in the registration program for schizophrenia. Although there is anecdotal evidence describing the use of quetiapine in excess of 800 mg/day, double-blind randomized clinical trials are needed

OBJECTIVE: Patients exhibiting aggressive or criminal behavior present a challenge to treaters and caregivers. After discharge from an inpatient facility, such patients are at high risk of rehospitalization and rearrest. A long-term behaviorally based cognitive skills program was developed and administered to a group of such high-risk inpatients. The authors report the results of a postdischarge follow-up of this group. METHODS: After patients entered the inpatient treatment program, their psychiatric and criminal histories were recorded, and a battery of psychological measures were administered, including IQ tests and the Hare Psychopathy Checklist. After discharge, multiple sources were used to obtain information about patients' outcomes. RESULTS: Eighty-five patients were followed for between six months and two years after discharge. Thirty-three of these patients (39 percent) remained stable in the community, 35 (42 percent) were rehospitalized, and 17 (20 percent) were arrested. Several variables that were ascertained before discharge predicted rehospitalization or arrest rates: comorbid antisocial personality disorder, higher score on the Psychopathy Checklist, history of arrests for violent crimes, and history of a learning disability. In addition, patients who developed substance use problems or did not adhere to medication treatment after discharge were more likely to be rehospitalized or arrested. CONCLUSIONS: Arrest rates were low compared with those observed in studies with similar populations. Although this outcome may be attributable to the treatment program, this naturalistic study could not prove that. The predictors of poor outcome may be used to develop a follow-up treatment program that focuses more resources on patients who are at the highest risk

The main study was designed primarily to compare the clinical effects of four antipsychotics in 157 patients with schizophrenia or schizoaffective disorder. The secondary genetic study, reported here, is based on a subset of 60 patients who consented to genotyping assays. Based on previous work with the catechol-O-methyltransferase (COMT) 158 polymorphism, we hypothesized that the Met-Met homozygotes would be more hostile than the heterozygotes and the Val-Val homozygotes. Hostility ratings at baseline were used to test this hypothesis. The Met-Met homozygotes (N = 7) were found to have significantly higher levels of hostility than the other patients (N = 53). The hypothesis was thus supported. The finding should be replicated in a larger sample

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

BACKGROUND: We sought to develop and validate an excitement subscale from the Positive and Negative Syndrome Scale (PANSS) to allow the investigation of mania-like excitement symptoms in clinical trials of patients with schizophrenia using the PANSS and to provide clinicians with a short assessment tool for these states. METHODS: Baseline PANSS data from six double-blind, randomized registration trials of olanzapine, three in schizophrenia and three in acute bipolar mania, were used in these post-hoc analyses. Schizophrenia study data were pooled and randomly split in half. Exploratory principal component factor analysis was performed on half of the data. Factors were extracted based on minimum eigenvalue criteria (eigenvalue> or =1); loadings were determined using an equamax rotation. Confirmatory principal component factor analysis was performed on the other half of the data, retaining the original number of factors. Principal component factor analysis was also done for the pooled bipolar studies. Change in the new mania-like factor scores was then correlated with Young Mania Rating Scale (Y-MRS) scores in each bipolar study. RESULTS: Exploratory principal components analysis on the pooled schizophrenia data extracted five factors: negative, positive, excitement, cognitive, and depressive factors. The mania-like excitement factor was represented by four items (uncooperativeness, poor impulse control, excitement, and hostility), with only moderate loadings by tension and suspiciousness/persecution. Results were similar in the confirmatory analysis and the pooled bipolar studies. Change from baseline to endpoint for the mania-like factor correlated reasonably well (0.64-0.78) with change in Y-MRS scores in the bipolar studies. At baseline, bipolar patients scored higher than patients with schizophrenia on three of four PANSS mania-like factor items: poor impulse control, excitement, and hostility; the converse was true for most other PANSS items. CONCLUSION: Factor analyses of the PANSS consistently uncovered an excitement factor including uncooperativeness, poor impulse control, excitement, and hostility items. This factor may be useful in examining manic symptoms in studies where the addition of a scale specific to mania would be burdensome and where symptoms of excitement are part of the clinical presentation

BACKGROUND: The safety and efficacy of the first long-acting injectable atypical antipsychotic, risperidone, were assessed in stable patients with schizophrenia switched from oral antipsychotic medications. METHOD: Data were collected between July 1, 2001, and October 25, 2002. The study population included patients from clinics, hospitals, and physicians' offices. After a 4-week run-in period, symptomatically stable patients with schizophrenia (DSM-IV) who had been taking haloperidol (N = 46), quetiapine (N = 45), or olanzapine (N = 50) received 25 mg of long-acting risperidone. The oral antipsychotics were continued for 3 weeks after the first injection of long-acting risperidone. Injections were administered every 2 weeks at 25 mg up to a maximum dose of 50 mg for 12 weeks in this multicenter, open-label study. RESULTS: Long-acting risperidone was well tolerated. Of the 141 patients who participated in the study, the most frequently reported adverse events were insomnia (16%), headache (15%), psychosis (11%), and agitation (11%). The mean increase in body weight was 0.4 kg. No other clinically relevant laboratory abnormalities or significant electrocardiogram changes were observed during the 12-week treatment. Extrapyramidal Symptom Rating Scale total scores were reduced during treatment with long-acting risperidone. Improvements in symptoms of schizophrenia were observed with long-acting risperidone at week 4 and continued through the 12-week treatment with significant reductions in total Positive and Negative Syndrome Scale (PANSS) scores at week 8 (-2.5, p <.01) and week 12 (-3.9, p <.001). At endpoint, 37% (50/135) of these stable patients were rated as clinically improved (> or = 20% decrease in PANSS total scores). CONCLUSIONS: Switching treatment from oral antipsychotics to long-acting risperidone without an intervening period of oral risperidone was safe and well tolerated. Long-acting risperidone also significantly reduced the severity of symptoms in these stable patients with schizophrenia

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