Hospitalization risks in the treatment of schizophrenia: comparison of antipsychotic medications

This study used administrative claims data to compare the relative risks for hospitalization among commercially insured patients with schizophrenia receiving atypical and typical antipsychotic drugs. Cox proportional hazard regression estimates, adjusted for differences in patient characteristics, suggested that among patients treated with the 4 atypical antipsychotic drugs, only olanzapine had a significantly higher risk for hospitalization than the typical antipsychotic drugs (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.20-2.75). In addition, risk for hospitalization with olanzapine was significantly higher than that for risperidone (HR, 1.34; 95% CI, 1.03-1.74) and numerically higher than that for quetiapine (HR, 1.40; 95% CI, 0.94-2.07). Overall, olanzapine was associated with a higher risk for hospitalization than the typical antipsychotic drugs and among the atypical antipsychotic drugs, risperidone and, potentially, quetiapine.     

Effects of antipsychotic medications on sleep in schizophrenia

Schizophrenia is often accompanied by sleep problems. Evidence exists that these sleep difficulties have significant effects on individuals with this disorder. The mainstay of treatment for this condition is the administration of medications that have effects on neurotransmitter systems, which play an important role in sleep-wake function, including histamine, acetylcholine, serotonin, norepinephrine and dopamine. Little systematic attention, however, has been paid to how the sleep effects of these agents might play a role in the course of treatment, function and quality of life of schizophrenia patients. Schizophrenia medications can improve sleep problems and reverse the sleep architectural derangements that are common among patients with schizophrenia and, therefore, have the potential to improve the quality of life and functional capacity of the patient. Conversely, some sleep-wake effects of these medications can impair patient function and quality of life. In this study, we review the effects of schizophrenia medications and discuss their relevance to optimizing the clinical treatment of people with schizophrenia with regard to sleep-wake function.     

Source monitoring improvement in patients with schizophrenia receiving antipsychotic medications

Rationale The absence of a relationship between cognitive deficit treatment response and positive symptom treatment response is often assumed, and few data have shed light on this issue. Most of these data have been collected using standard neuropsychological measures, which are ill-designed to assess the types of neurocognitive disturbances associated with psychotic symptoms. This study investigates the effect of treatment on source monitoring performance and its relation to the reduction of certain psychotic symptoms associated with the inability to identify self-generated mental events, known as "autonoetic agnosia". Objectives To determine whether risperidone, olanzapine, and haloperidol were differentially effective in reducing autonoetic agnosia and whether changes in this aspect of cognition were related to reduction of specific symptoms of psychosis. Methods From a cohort of 49 patients diagnosed with schizophrenia by DSM-IV criteria and randomly assigned to double-blind treatment with risperidone, olanzapine, or haloperidol, 16 patients were identified with symptoms believed to reflect autonoetic agnosia ("target symptoms") as assessed with the Schneiderian Symptom Rating Scale, and then evaluated during a baseline period, and then at 1, 2, and 3 weeks. Autonoetic agnosia was assessed as the ability of a patient to distinguish self-generated words from both experimenter-generated words and pictorially presented words. Results Analysis of patients from all treatment groups found a significant reduction in the number of "target" Schneiderian symptoms. Discrimination for items from the self-generated and heard sources significantly improved with treatment, as did the number of self-generated items that patients remembered as coming from the heard source ("self-hear errors"). The correlation between improvement in recognition of self-generated items and reduction in target Schneiderian symptoms after 2 weeks of treatment suggested a modest relationship between symptom improvement and changes in autonoetic agnosia. Conclusions While the differences between medications were not statistically significant, antipsychotic medication in general was associated with improvements in symptoms and cognitive deficits that may underlie autonoetic agnosia. Improvement of autonoetic agnosia was a weak predictor of positive symptom improvement in a limited sample.     

Cerebro- and cardiovascular conditions in adults with schizophrenia treated with antipsychotic medications

OBJECTIVE: To report on the relative risk of cerebro- and cardiovascular disorders associated with antipsychotic treatment among adults with schizophrenia. METHOD: Medical and pharmacy claims data from the South Carolina Medicaid program were extracted to compare the prevalence rates for four coded cerebrovascular (cerebrovascular disease; cerebrovascular accident; cerebrovascular hemorrhage; and peripheral vascular disease) and four cardiovascular (myocardial infarction; ischemic heart disease; arrhythmias; and cardiomyopathy) conditions. The analysis employed a retrospective cohort design with a 3 years time period as the interval of interest. Schizophrenic adults (18-54) (n = 2251) prescribed one of six atypical or two conventional antipsychotic medications were identified and comprised the analysis set. RESULTS: Incidence rates for cerebrovascular disorders ranged from 0.5 to 3.6%. No significant association between antipsychotic usage and cerebrovascular disorders was noted largely due to the low base rate. Incidence rates for overall cardiovascular conditions ranged from 6 to 20%. The odds of developing cardiomyopathy were significantly lower for aripiprazole (OR = -3.45; p = 0.02), while the odds of developing hypertension were significantly lower for males (OR = -1.37; p = 0.009) but significantly higher for patients prescribed ziprasidone (OR = 1.91; p = 0.01) relative to conventional antipsychotics. CONCLUSION: No significant association between antipsychotic usage and cerebro- or cardiovascular disorders was noted.     

Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents.

Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies.     

Management of schizophrenia in late life with antipsychotic medications: a qualitative review

Although patients with schizophrenia are reported to have excess mortality compared with the general population, many affected patients will nonetheless survive and continue to have the disorder in later life. Consequently, geriatric schizophrenia will be a significant public health concern in the years to come, and evidence-based treatment of schizophrenia in older patients is becoming an urgent issue. However, there has been a paucity of comparative data to guide selection of antipsychotics for schizophrenia in late life. The primary aim of this review was to synthesize the available evidence on management of late-life schizophrenia with antipsychotic medications; a secondary aim was to evaluate treatment resistance in this population. Accordingly, PubMed and EMBASE were searched using the keywords 'antipsychotics', 'age' and 'schizophrenia' to identify psychopharmacological studies of antipsychotics in late-life schizophrenia (last search 30 April 2011). The literature search identified 23 prospective studies of use of antipsychotics for schizophrenia in older patients (generally age ≥65 years), including eight double-blind trials. The sample size was smaller than 40 patients for 52% of the studies. Two of the double-blind studies were post hoc analyses and one was a placebo-controlled trial. In the largest double-blind study, olanzapine (n = 88, median dose 10 mg/day) and risperidone (n = 87, median dose 2 mg/day) were compared in patients not resistant to these therapies, with similar effects. There have also been several open-label trials of these two agents that have shown efficacy and tolerability in non-resistant patients. Evidence on other antipsychotics has been scarce and less robust. The gold standard for treatment-resistant schizophrenia is clozapine. However, almost all of the studies of clozapine to date have effectively excluded older patients with schizophrenia. Only one small study has evaluated clozapine (n = 24, mean dose 300 mg/day) in comparison with chlorpromazine (n = 18, mean dose 600 mg/day) in a difficult-to-treat older population; the investigators reported that both treatments were similarly efficacious. Furthermore, there has been little compelling evidence in favour of or against augmentation of antipsychotics with other psychotropic medications in the older age group. Treatment of non-resistant, late-life schizophrenia with olanzapine and risperidone appears to be supported by the available evidence. However, data on geriatric patients with schizophrenia are generally scarce, particularly for treatment-resistant subpopulations, underscoring the need for more research in this important area.     

The effect of citalopram adjunctive treatment added to atypical antipsychotic medications for cognitive performance in patients with schizophrenia

Cognitive enhancement in patients with schizophrenia is a major treatment priority. Because serotonergic approaches have been suggested as a possible mechanism to enhance cognition and many patients with schizophrenia are treated with selective serotonin reuptake inhibitor antidepressants, we evaluated a serotonin reuptake inhibitor, citalopram, as adjunctive therapy to atypical antipsychotic treatment for its cognitive enhancing effects in schizophrenic patients. Nineteen schizophrenic patients were treated in a randomized, placebo-controlled, crossover-designed 24-week study. In phase 1, subjects were randomized equally to 40 mg of citalopram or placebo and were evaluated prior to initiation of pharmacotherapy and at the end of phase 1 (after 12 weeks of treatment with double-blind agent). At the beginning of phase 2, subjects were crossed over to the other treatment and subsequently assessed after 12 weeks of treatment for symptom severity and cognitive performance. There were no statistically significant differences between citalopram 40 mg/d and placebo treatment on any clinical or cognitive measures. These results indicate that citalopram adjunctive treatment to atypical antipsychotics produces no significant cognitive improvement in patients with schizophrenia. Because the subjects in this study were all treated with atypical antipsychotics, it is possible that the pharmacologic profiles of atypical antipsychotic medications at serotonin receptors may have complicated the effects of citalopram augmentation. Further research on alternative serotonergic approaches to cognitive enhancement in schizophrenia is warranted.     

Increased cardiovascular risk with second-generation antipsychotic agent switches.

OBJECTIVE: To model the risk of long-term, adverse cardiovascular events after switching from one second-generation antipsychotic medication (SGA) to another in patients with schizophrenia or schizoaffective disorder. DATA SOURCES: PubMed from 1985 to 2004 using the search terms atypical antipsychotics, obesity, weight, diabetes mellitus, dyslipidemia, hypercholesterolemia, lipids, second generation antipsychotics, antipsychotic agents, schizophrenia, metabolic syndrome, cardiovascular disease, and cardiovascular risk factors. STUDY SELECTION: By the authors. DATA EXTRACTION: By the authors. DATA SYNTHESIS: The selection of an SGA for an individual patient should be primarily based upon its therapeutic effectiveness. However, when two medications are clinically equivalent with respect to treatment outcomes, other important consequences of the medication choice should be considered. Depending upon the type of SGA switch, the risk of an adverse cardiovascular event may be lower, as when olanzapine is switched to risperidone, or may increase by as much as 33%, as when risperidone is switched to olanzapine or clozapine. CONCLUSION: Cardiovascular risk likely differs depending upon SGA choice, but limited data make it difficult to predict the metabolic changes associated with switching. Prospective controlled studies are needed to describe the cardiovascular consequences of switching among the antipsychotic agents so that evidence-based strategies can be developed for selection of the optimal SGA.     

Plasma leptin and adiposity during antipsychotic treatment of schizophrenia.

Alterations in plasma leptin have been reported in schizophrenia patients treated with antipsychotics, suggesting the hypothesis that impairments in leptin secretion or signaling might play a role in antipsychotic-induced weight gain. Plasma leptin was measured in 72 schizophrenia patients chronically treated with olanzapine (n=27), risperidone (n=24) or typical antipsychotics (n=21) and 124 healthy adult control subjects. ANCOVA was used to test effects of adiposity (body mass index kg/m2; BMI), subject group (treated patients vs untreated controls), and treatment group (specific medication groups and untreated controls) on plasma leptin concentrations. Additional analyses were performed in a subset of patients and controls individually matched for BMI to further assess group differences in plasma leptin independent of adiposity. BMI strongly predicted plasma leptin concentrations in the overall sample. In addition, a significant three-way interaction between BMI, subject group, and gender was observed. In the individually BMI-matched sample, modestly reduced plasma leptin levels (effect size 0.4 SD) were observed in treated patients in comparison to the BMI-matched healthy controls, with both groups including males and females. However, no differences in plasma leptin levels were observed in the matched sample when separately comparing male patients vs untreated male controls and female patients vs untreated female controls. Plasma leptin in chronically treated patients with schizophrenia is strongly predicted by adiposity, similar to untreated healthy individuals despite adequate power to detect a difference. The results argue against a role for defective leptin secretion or sensitivity in the weight gain induced by antipsychotic medications.     

Determinants of first- and second-generation antipsychotic drug use in clinically unstable patients with schizophrenia treated in four European countries

The present study investigated the use of antipsychotics in a sample of clinically unstable patients with schizophrenia who were recruited in four European sites. The study aimed: (i) to test whether the length of previous antipsychotic exposure was associated with the choice of antipsychotic medication; (ii) to test whether the severity of illness was associated with the use of second-generation antipsychotic agents (SGAs) or with the concomitant use of both first-generation antipsychotics (FGAs) and SGAs; and (iii) to investigate differences between study sites. Participants were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (The Netherlands) and Leipzig (Germany). Clinically unstable patients with a clinical diagnosis of schizophrenia and a research diagnosis of schizophrenia, established using the Item Group Checklist of the Schedule for Clinical Assessment in Neuropsychiatry, were enrolled. Sociodemographic and clinical data, including current antipsychotic drug therapy, psychopathology, adherence, insight, side-effects, attitudes towards medication and quality of life, were gathered. Three hundred and ninety patients were analysed in total. Almost 60% received SGAs, less than one-third FGAs, and less than 15% received both drug classes. Those receiving SGAs were younger and with a shorter length of antipsychotic drug therapy, whereas those receiving both drug classes were more often separated or widowed, unemployed and with a long history of antipsychotic drug therapy. The distribution of patients receiving FGAs, SGAs and both drug classes by illness-related variables showed that patients receiving both drug classes were more severely ill and complained of more side-effects. Using patients receiving FGAs as the reference category, multinomial logistic regression analysis showed that the length of antipsychotic treatment was negatively correlated with receiving SGAs, and that the severity of illness and being separated/widowed were positively correlated with receiving both drug classes. Compared with patients in Leipzig, patients in Amsterdam, Croydon and Verona were less frequently treated with SGAs and with combinations of both drug classes. Consistent with current clinical uncertainty with respect to what pharmacological treatment should be provided, patients with a long history of antipsychotic exposure were receiving FGAs, SGAs and combinations of both drug classes. Physicians tended to reserve polypharmacy for difficult-to-treat patients (i.e. for managing situations where, despite the lack of an evidence base, there is a pressing need to provide clinical answers).     

Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia

Accumulating evidence suggest a life-long impact of disease related mechanisms on brain structure in schizophrenia which may be modified by antipsychotic treatment. The aim of the present study was to investigate in a large sample of patients with schizophrenia the effect of illness duration and antipsychotic treatment on brain structure. Seventy-one schizophrenic patients and 79 age and gender matched healthy participants underwent brain magnetic resonance imaging (MRI). All images were processed with voxel based morphometry, using SPM5. Compared to healthy participants, patients showed decrements in gray matter volume in the left medial and left inferior frontal gyrus. In addition, duration of illness was negatively associated with gray matter volume in prefrontal regions bilaterally, in the temporal pole on the left and the caudal superior temporal gyrus on the right. Cumulative exposure to antipsychotics correlated positively with gray matter volumes in the cingulate gyrus for typical agents and in the thalamus for atypical drugs. These findings (a) indicate that structural abnormalities in prefrontal and temporal cortices in schizophrenia are progressive and, (b) suggest that antipsychotic medication has a significant impact on brain morphology.     

Genetics of antipsychotic treatment emergent weight gain in schizophrenia

Classic and modern antipsychotics can induce substantial weight gain causing diabetes, lipid abnormalities and psychological distress. Treatment emergent weight gain varies within the broad class of antipsychotics; however, an individual's propensity to develop weight gain largely depends on genetic factors. The first part of this review highlights current ideas and concepts related to antipsychotic-induced weight gain, including principles on energy homeostasis. The second part summarizes genetic findings emphasizing studies published after 2003 as prior studies have been reviewed in detail elsewhere. Candidate gene studies have produced significant findings in the 5-hydroxytryptamin 2C (5HT2C) and adrenergic alpha2a (ADRalpha2a) receptor genes, as well as in the leptin, guanine nucleotide binding protein (GNB3) and synaptomal-associated protein 25kDa (SNAP25) genes. Results from genome-wide association and linkage studies point to several chromosomal regions (e.g., 12q24) and some specific genes (e.g., promelanin concentrating hormone [PMCH], polycyctic kidney and hepatic disease 1 [PKHD1], peptidylglycine alpha-amidating monooxygenase [PAM]). However, more efforts are needed before risk prediction and personalized medicine can be made available for antipsychotic-induced weight gain.     

Cortisol/dehydroepiandrosterone ratio and responses to antipsychotic treatment in schizophrenia.

Dehydroepiandrosterone (DHEA) or their sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) exert multiple effects in the central nervous system, and may be involved in the pathophysiological processes in schizophrenia. This prospective study aimed to investigate whether serum cortisol/DHEA(S) molar ratios are associated with response to antipsychotic treatment during the exacerbation of schizophrenia. Serum DHEA(S) and cortisol were determined at baseline, and 2 and 4 weeks later for 43 medicated schizophrenia inpatients with acute exacerbation. The patients were treated with stable doses of antipsychotic agents up to 2 weeks prior to entering the study and for the 4-week duration of the study after which they were classified as either responders or nonresponders to treatment. Findings suggest that responders had significantly higher serum cortisol levels and cortisol/DHEA(S) ratios compared with nonresponders. These differences remained significant at three time points controlling for gender, age, severity of symptoms and emotional distress, benzodiazepines, type or dosage of antipsychotic agents, and background variables. The logistic regression model shows advantages of both cortisol/DHEA(S) molar ratios vs serum cortisol and DHEA(S) concentrations for prediction of responsivity to antipsychotic treatment. No significant canonical correlations were observed between changes from baseline through end-of-study in hormonal values and severity of symptoms and emotional distress among responders and nonresponders. Thus, these data provide evidence that elevated serum cortisol and cortisol/DHEA(S) ratios may serve as markers of biological mechanisms that are involved in responsivity of schizophrenia patients to antipsychotic treatment.