Neurobiological correlates of violent behavior among persons with schizophrenia

Men and women who develop schizophrenia are at increased risk, compared with the general population, to engage in violence toward others. The reasons for this robust finding remain obscure. We undertook a review of studies comparing neuropsychological test performance, neurological soft signs, and structural brain images of persons with schizophrenia with and without a history of violence. Our search identified 17 studies. The results are inconsistent and contradictory, mainly due to varying definitions of violence, differences in sample characteristics, and the use of diverse measures to tap the neurobiological correlates of violent behavior. The results suggest, however, that among men with schizophrenia, those who have displayed a stable pattern of antisocial and aggressive behavior since childhood, as compared with those with no such history, perform better on neuropsychological tests tapping specific executive functions and more poorly on assessments of orbitofrontal functions, show fewer neurological soft signs, and display larger reductions in volume of the amygdalae, more structural abnormalities of the orbitofrontal system, more abnormalities of white matter in the amygdala-orbitofrontal system, and smaller reductions in volumes of the hippocampus.     

Awareness of illness and nonadherence to antipsychotic medications among persons with schizophrenia

OBJECTIVE: The purpose of this study was to assess the effects of patients' awareness of their illness on the clinical presentation, management, and course of nonadherence to antipsychotic medications among patients with schizophrenia. METHODS: A national survey was conducted of psychiatrists who were treating patients with schizophrenia. The survey was sent to 771 psychiatrists, of whom 534 responded, for a response rate of 69 percent. The psychiatrists were asked to report on presentation, management, and course for one adult patient with schizophrenia who had been under their care for at least one year and who had been nonadherent to oral antipsychotics at some point in the past year. Patients who were aware that they had a mental illness were compared with those who were not aware. RESULTS: Of the 534 respondent psychiatrists, 310 reported on an eligible patient, and 300 of these patients were classified by illness awareness. Ninety-seven patients, or 32 percent, were not aware that they had a mental illness. These patients who lacked awareness had significantly longer episodes of antipsychotic nonadherence, were more likely to completely cease taking the antipsychotic medication, were more likely to have severe positive symptoms, and were more likely to be psychiatrically hospitalized after nonadherence than those who were aware of their illness. Psychological interventions and several types of family interventions were significantly less effective among patients who lacked awareness. CONCLUSIONS: A lack of awareness of mental illness is common among patients with schizophrenia who are nonadherent to antipsychotics. Such nonadherence tends to be especially disruptive and unresponsive to simple commonly used psychological interventions.     

Use of antipsychotic medications among HIV-infected individuals with schizophrenia

Persons with schizophrenia face elevated risk of infection with HIV. While HIV therapy is demanding, patients diagnosed with both conditions also require appropriate and consistent management of their psychiatric illness, for the same reasons that generally apply to persons with schizophrenia and because untreated psychiatric illness can interfere with full participation in HIV care. This study examines the correlates of use of and persistence on antipsychotic medications among HIV-infected individuals with schizophrenia, using merged New Jersey HIV/AIDS surveillance data and paid Medicaid claims. Persistence was defined as at least 2 months of medication use in a quarter. We identified 350 individuals who were dually diagnosed with HIV and schizophrenia. Overall, 81% of these beneficiaries had at least one claim for an antipsychotic medication at some point between 1992 and 1998. Multivariate techniques were used, including simple logistic regressions on use and robust longitudinal regressions that controlled for repeated observations on the same individual and treatment gaps. Among users of antipsychotic medications, persistence was very low at 37%. Racial/ethnic minorities were less likely to receive atypical antipsychotic medications. Use of atypical antipsychotics was associated with higher persistence. Our study confirmed past findings of racial disparities in the receipt of atypical antipsychotic medications. Findings suggest that use of atypical medications may benefit individuals dually diagnosed with HIV and serious mental illness.     

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.     

A national study of violent behavior in persons with schizophrenia

CONTEXT: Violent behavior is uncommon, yet problematic, among schizophrenia patients. The complex effects of clinical, interpersonal, and social-environmental risk factors for violence in this population are poorly understood. OBJECTIVE: To examine the prevalence and correlates of violence among schizophrenia patients living in the community by developing multivariable statistical models to assess the net effects of psychotic symptoms and other risk factors for minor and serious violence. DESIGN: A total of 1410 schizophrenia patients were clinically assessed and interviewed about violent behavior in the past 6 months. Data comprise baseline assessments of patients enrolled in the National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness. SETTING AND PATIENTS: Adult patients diagnosed as having schizophrenia were enrolled from 56 sites in the United States, including academic medical centers and community providers. MAIN OUTCOME MEASURES: Violence was classified at 2 severity levels: minor violence, corresponding to simple assault without injury or weapon use; and serious violence, corresponding to assault resulting in injury or involving use of a lethal weapon, threat with a lethal weapon in hand, or sexual assault. A composite measure of any violence was also analyzed. RESULTS: The 6-month prevalence of any violence was 19.1%, with 3.6% of participants reporting serious violent behavior. Distinct, but overlapping, sets of risk factors were associated with minor and serious violence. "Positive" psychotic symptoms, such as persecutory ideation, increased the risk of minor and serious violence, while "negative" psychotic symptoms, such as social withdrawal, lowered the risk of serious violence. Minor violence was associated with co-occurring substance abuse and interpersonal and social factors. Serious violence was associated with psychotic and depressive symptoms, childhood conduct problems, and victimization. CONCLUSIONS: Particular clusters of symptoms may increase or decrease violence risk in schizophrenia patients. Violence risk assessment and management in community-based treatment should focus on combinations of clinical and nonclinical risk factors.     

Factors associated with adherence to treatment with olanzapine and other atypical antipsychotic medications in patients with schizophrenia

ObjectivesPoor treatment response is an important factor contributing to lack of treatment adherence. The goals of this research were to determine whether improvements in Positive and Negative Syndrome Scale (PANSS) symptom domains predict the likelihood of staying on treatment and whether differential responses to treatment with various atypical antipsychotics in specific symptom domains account for differences in discontinuation rates or treatment adherence.MethodsWe conducted a post-hoc analysis of pooled data from 5 randomized, double-blind, 24- to 28-week clinical trials in 1103 olanzapine-treated and 1090 risperidone-, quetiapine-, ziprasidone-, or aripiprazole-treated adult patients with schizophrenia. The 5 PANSS factors were tested as potential predictors of treatment adherence for all treatment groups combined. Treatment differences in the 5 PANSS factors and individual items were assessed between olanzapine and the other atypical antipsychotics combined. Secondary analyses repeated for the 21 Heinrichs Quality of Life Scale (QLS) items.ResultsImprovement in PANSS positive factor was the strongest predictor of treatment adherence, irrespective of medication (based on standardized scores, hazard ratio [HR], 1.58; 95% confidence interval [CI], +1.40 to +1.79; P < .001). Improvement in PANSS hostility (HR, 1.23; 95% CI, +1.11 to +1.37; P < .001) and depressive (HR, 1.15; 95% CI, +1.05 to +1.27; P = .002) factors was also a significant predictor; negative and disorganized thoughts factors were not. All QLS items had significant predictive effects. Olanzapine-treated patients showed significantly greater improvements than all other groups at week 24 on all 5 PANSS factors (P = .028 for negative; P < .001 for all others) and on 3 QLS items.ConclusionSignificant improvement in positive symptoms, regardless of treatment, followed by significant improvement in hostility and depressive symptoms, may best predict treatment adherence. Olanzapine-treated patients experienced significantly greater improvements in these specific symptoms than patients treated with the other atypical antipsychotics examined. These findings may further explain why olanzapine-treated patients continue treatment more often.     

Augmenting atypical antipsychotic medications with clozapin

Typical antipsychotic medications have considerably improved clinical outcome of patients suffering from schizophrenic psychoses, but up to 40% of the cases show treatment resistant symptoms. Even therapy with atypical antipsychotic drugs such as risperidone, quetiapine, olanzapine, sulpiride, amisulpride, and ziprasidone often fails to reach complete remission due to resistant, positive or negative symptoms or dose-limiting side effects. As this also holds true in the case of monotherapy with clozapine, a substance known to be effective against treatment-resistant schizophrenia, increasing numbers of patients receive atypical antipsychotic drugs in addition to clozapine. This review systematically evaluates case reports and clinical investigations on the use of clozapine combined with risperidone, olanzapine, quetiapine, sulpiride, amisulpride, or ziprasidone. Details on indication, methodology, and effects of the investigations are summarized. Only one double blind, placebo-controlled trial on the combination with sulpiride exists within a number of altogether 31 publications about 1182 treatments. Favorable effects on positive and/or negative symptoms or improvements of clozapine-induced side effects were described for every combination approach. In some cases pharmacokinetic interactions or serious unfavorable effects occurred. In conclusion it might be accepted that most of the combination therapies follow a neurobiological rational. There a major differences in the level of evidence that they are safe, tolerable and effective. We discuss criteria for the indication for augmenting clozapine therapy and the differential indication for existing alternatives. Additional randomized prospective trials are needed in order to evaluate these strategies systematically.     

Prodromal schizophrenia and atypical antipsychotic treatment

Early recognition and intervention in psychosis is the focus of more intensive research. In this paper, we critically review the ideas that have emerged in this field. We also propose a model or hypothesis for testing in the prodromal phase of schizophrenia. Attention to practical and ethical issues, particularly with the use of atypical antipsychotics in one arm of the protocol, is addressed. Studies by Yung and Falloon describe prodromal intervention with psychosocial strategies and time-limited low potency neuroleptics, respectively, that suggest benefits of such a model. Although we have respect for the DSM system, this paper is written more from a Bleulerian than Kraepelinian perspective in that we emphasize affective, cognitive, and negative symptoms in addition to positive symptoms. The paper recognizes the strong conceptual disagreements implicit in this area stemming not only from Kraepelin and Bleuler but work from the 1930s by Cameron. The clinical research advocated is timely in that the atypicals are more congruent to the Bleulerian conception with a neurodevelopmental hypothesis of schizophrenia. We also have exciting new imaging and genetic technologies to refine our concepts of schizophrenia and its prodromal and premorbid phases.     

Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia

OBJECTIVE: Schizophrenic patients have high rates of cigarette smoking. The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications. METHOD: Forty-five subjects were randomly assigned to 1) the group therapy program of the American Lung Association (N=17) or 2) a specialized group therapy program for smokers with schizophrenia (N=28) that emphasized motivational enhancement, relapse prevention, social skills training, and psychoeducation. All subjects participated in 10 weeks of treatment with the nicotine transdermal patch (21 mg/day) and 10 weekly group therapy sessions and continued to receive their prestudy atypical (N=18) or typical (N=27) antipsychotic medications. Outcome variables included treatment retention, rate of smoking abstinence, and expired-breath carbon monoxide level. RESULTS: Smoking abstinence rates did not differ in the two group therapy programs. However, atypical antipsychotic agents, in combination with the nicotine transdermal patch, significantly enhanced the rate of smoking cessation (55.6% in the atypical agent group versus 22.2% in the typical group), which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels. Risperidone and olanzapine were associated with the highest quit rates. CONCLUSIONS: The results suggest that 1) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia, 2) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation, and 3) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia.     

Metabolic effects associated with atypical antipsychotic medications

Despite the plethora of evidence that demonstrates the efficacy of novel antipsychotic medications, there are mounting concerns about their side effects. Major concerns are data that link some agents with metabolic effects, such as obesity, type 2 diabetes, and CVD. For these reasons, patients receiving novel antipsychotic medications must be closely monitored for metabolic side effects and treated to reduce risk factors associated with CVD.     

Weight change and atypical antipsychotic treatment in patients with schizophrenia

Schizophrenic patients who have been prescribed atypical antipsychotics have a potential risk of gaining weight. The implications of weight gain for clinical care may differ depending on whether a patient is underweight or overweight at baseline. The exact mechanism for weight gain is not known, but several factors have been identified that can help predict which patients are at risk for gaining weight. These factors include better clinical outcome, increased appetite, and low baseline body mass index. In patients treated with olanzapine for up to 3 years, weight gain trended toward a plateau at approximately 36 weeks. Weight gain interventions, including behavioral modifications, show promise in controlling or reducing weight in patients treated with antipsychotics.     

Effectiveness of switching antipsychotic medications

OBJECTIVE: Changing antipsychotics is common despite the dearth of information on risks and benefits associated with medication changes. The authors examined phase 1 findings from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study to explore whether it was more advantageous to continue taking the medication being received at baseline or to switch to a different antipsychotic. METHOD: First, for patients randomly assigned to treatment with olanzapine (N=314) or risperidone (N=321), the authors assessed the impact of being assigned to stay with the medication they were receiving at entry into the study versus being assigned to switch to these medications from a different antipsychotic. Second, for patients whose baseline antipsychotic was olanzapine (N=319), risperidone (N=271), or quetiapine (N=94), the authors examined the impact of being randomly assigned to stay with the same antipsychotic versus switch. Finally, the authors assessed the impact of removing the data of 209 patients whose random assignment was to stay with their baseline antipsychotic. The authors followed analysis strategies for CATIE; primary outcome was time until all-cause treatment discontinuation. RESULTS: Individuals randomly assigned to olanzapine and risperidone who were continuing with their baseline medication had significantly longer times until discontinuation than did those assigned to switch antipsychotics. When these "stayers" were removed, differences seen in the original CATIE phase 1 analyses were attenuated, although the original pattern of results remained. CONCLUSIONS: Comparisons of medication effectiveness should take into account whether medications being compared were each newly initiated. Further, unless the clinical situation requires a medication change, prescribers may want to take steps to optimize current medication regimens (e.g., dosage adjustments, behavioral or psychosocial interventions) before switching medications.     

Cognitive improvement in schizophrenia with novel antipsychotic medications

The syndrome of schizophrenia often includes negative symptoms and severe cognitive deficits that are resistant to change with conventional pharmacotherapy. The efficacy of clozapine in the reduction of the negative syndrome has prompted a series of studies implicating circumscribed cognitive improvements. Restrictions on the use of clozapine have encouraged the development and introduction of novel compounds with a clinical efficacy profile similar to clozapine that are hoped also to have beneficial cognitive effects. The present review summarizes studies of the cognitive efficacy of novel antipsychotic medications, particularly in regard to issues in experiment design and study implementation that might facilitate additional research. Although preliminary support exists for relatively circumscribed improvement of cognitive status with the use of clozapine and risperidone—and more general improvement with the use of olanzapine—specific inferences relating cognitive change to particular treatments will remain speculative until more sophisticated investigations are completed. The present review emphasises the most relevant design limitations in past studies to provide practical suggestions for the implementation of subsequent investigations. Previous results have established the possibility of a medication-based change in cognitive status in schizophrenia. Future research will determine the validity of these changes, the cerebral mechanism involved, and their significance to improved prognosis.     

New-onset type-2 diabetes associated with atypical antipsychotic medications

PURPOSE: This study compared the one-year incidence of new-onset type-2 diabetes mellitus (DM) and changes in weight in patients with a variety of psychiatric diagnoses prescribed olanzapine, risperidone, or quetiapine, compared to a reference group receiving haloperidol and no other antipsychotic medication. RESEARCH DESIGN AND METHODS: Data was abstracted from charts of subjects newly initiated and then maintained for one year on olanzapine (n=112), risperidone (n=100), quetiapine (n=100), and haloperidol (n=100). Baseline and one-year DM status, height, and weight were collected, as well as concurrent psychotropic medications, medical and psychiatric comorbidities. FINDINGS: Using a multivariate model, logistic regression identified a significant association between olanzapine (but not other atypical agents) and the development of diabetes compared to haloperidol over the one-year period (odds ratio 8.4, 95% CI 1.8-38.7). Baseline obesity was independently associated with new-onset DM, but only marginally greater weight gain was found among olanzapine users. CONCLUSIONS: The middle-aged American veterans in this study cohort were highly vulnerable to the diabetogenic effects of olanzapine, but a close correlation with weight change was not found. Patients administered olanzapine should receive careful laboratory monitoring for elevated plasma glucose in addition to weight measurement.     

Tardive dyskinesia in children treated with atypical antipsychotic medications.

Recent years have witnessed increased antipsychotic treatment of children despite limited long‐term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic‐naïve patients (n = 80) with similar age, sex ratio, and diagnoses. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fisher's exact test). Nine of 62 African–American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European–American children (P = 0.003, Fisher's exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side‐effect profile of the atypical antipsychotic drugs in children may be much different than that in adults. © 2007 Movement Disorder Society