Atypical Antipsychotic Risperidone Research Articles

The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials

Posttraumatic stress disorder (PTSD) is a prevalent and disabling mental illness. Small studies found atypical antipsychotics (AAs) to be beneficial in the treatment of patients with PTSD regardless of psychotic symptoms who are unresponsive to conventional pharmacological treatments such as serotonin selective reuptake inhibitors. This study reports the results of a meta-analysis of existing randomized, double-blind, placebo-controlled clinical trials (RCTs) of AAs as a monotherapy or augmentation therapy for the treatment of patients with PTSD. Seven RCTs were identified through extensive scans of databases, which included PubMed, MedLine, the National PTSD Center Pilots database, PsycINFO, Cochrane Central Register of Controlled Trials, and the Abstracts Library of the American Psychiatric Association with predefined inclusion criteria. Dichotomous and continuous measures were performed using a fixed effects model, heterogeneity was assessed, and subgroup analyses were done. Data from seven RCTs involving a total of 192 PTSD patients (102 randomized to AAs and 90 randomized to placebo) were analyzed. The results show that AAs may have a beneficial effect in the treatment of PTSD, as indicated by the changes from baseline in Clinician Administered PTSD Scale total scores [standardized mean difference (SMD)=-0.45, 95% confidence interval (CI) (-0.75, -0.14), P=0.004]. In addition, the overall SMD of the mean changes in the three Clinician Administered PTSD Scale subscores was statistically significant (P=0.007) between AAs and placebo groups, favoring AAs over placebo (SMD=-0.27, 95% CI=-0.47, -0.07). In particular, the symptom of 'intrusion' was mainly responsible for this significance. Clinical significance of the results, however, should be carefully interpreted and translated into clinical practice, given that the quality and availability of currently existing RCTs included in the analysis.

Relationship between prolactin secretion, and plasma risperidone and 9-hydroxyrisperidone concentrations in adolescents with schizophreniform disorder

Treatment with the atypical antipsychotic risperidone can result in elevated prolactin levels. To date, the relationships between plasma concentrations of prolactin, risperidone and its active 9-hydroxy-metabolite have been little investigated in adolescents with psychosis. Prolactin levels were determined at baseline in 16 hospitalized drug-naïve adolescents meeting DSM-IV criteria for schizophreniform disorder. Prolactin, risperidone, 9-hydroxyrisperidone levels were subsequently determined after 3 weeks of oral risperidone treatment. Compared with pretreatment values, prolactin levels at endpoint were significantly increased (p<0.00001) and correlated with risperidone doses (r=0.58, N=16, p<0.02), and plasma levels of risperidone (r=0.60, N=16, p<0.02) and 9-hydroxyrisperidone (r=0.54, N=16, p=0.03). These data suggest that risperidone's effect on prolactin release is dose-dependent in adolescents and is linked to both plasma risperidone and 9-hydroxyrisperidone concentrations.

Clozapine and Olanzapine but not Risperidone Impair the Pre-Frontal Striatal System in relation to Egocentric Spatial Orientation in a Y-Maze

Many studies indicate a dissociation between two forms of orientation: allocentric orientation, in which an organism orients on the basis of cues external to the organism, and egocentric spatial orientation (ESO) by which an organism orients on the basis of proprioceptive information. While allocentric orientation is mediated primarily by the hippocampus and its afferent and efferent connections, ESO is mediated by the prefronto-striatal system. Striatal lesions as well as classical neuroleptics, which block dopamine receptors, act through the prefronto-striatal system and impair ESO. The purpose of the present study was to determine the effects of the atypical antipsychotics clozapine, olanzapine and risperidone which are believed to exert its antipsychotic effects mainly by dopaminergic, cholinergic and serotonergic mechanisms. A delayed-two-alternative-choice-task, under conditions that required ESO and at the same time excluded allocentric spatial orientation was used. Clozapine and olanzapine treated rats made more errors than risperidone treated rats in the delayed alternation in comparison with the controls. Motor abilities were not impaired by any of the drugs. Thus, with regard to the delayed alternation requiring ESO, clozapine and olanzapine but not risperidone affects the prefronto-striatal system in a similar way as classical neuroleptics does.

The neurotensin analog NT69L enhances medial prefrontal cortical dopamine and acetylcholine efflux: Potentiation of risperidone-, but not haloperidol-, induced dopamine efflux

NT69L is a novel neurotensin (8–13) analog that produces atypical antipsychotic-like effects in animal models. Because atypical antipsychotic drugs increase dopamine (DA) and acetylcholine (ACh) efflux in the medial prefrontal cortex and DA efflux in the nucleus accumbens, the present study sought to further evaluate the putative antipsychotic-like effects of NT69L by assessing DA and ACh efflux in these regions. Dual probe microdialysis was conducted in awake freely moving male rats, without using an acetylcholinesterase inhibitor in the perfusion medium. NT69L (1.0 and 3.0 mg/kg) produced significant increases in extracellular DA and ACh efflux in the medial prefrontal cortex. NT69L (1.0 mg/kg, but not 3.0 mg/kg) produced a significant increase of DA, but not ACh, efflux in the nucleus accumbens. Pretreatment with the serotonin (5-HT) 1A receptor antagonist WAY100635 (0.2 mg/kg) significantly attenuated the 3.0 mg/kg NT69L-induced increase in medial prefrontal cortical DA efflux. Pretreatment with NT69L (1.0 mg/kg) significantly potentiated the effects of the atypical antipsychotic drug risperidone (0.1 mg/kg) on DA, but not ACh, efflux in the medial prefrontal cortex, while pretreatment with NT69L 1.0 mg/kg failed to alter the effects of haloperidol (0.1 mg/kg) on DA or ACh efflux in either region. These findings further suggest that NT analogs may be useful alone or adjunctively for the treatment of schizophrenia.

Risperidone- and Quetiapine-Induced Cholestasis

To describe a case of a patient who developed drug-induced cholestasis after being on risperidone maintenance therapy for 8 years. A 30-year-old male with schizoaffective disorder, bipolar type, and insulin-dependent diabetes mellitus had been stable on risperidone 6 mg at night for 8 years. His other medications included lithium 900 mg twice daily and enalapril 5 mg daily, as well as regular insulin and NPH insulin as needed. The patient developed cholestasis that resolved once risperidone was discontinued. Over the next 11 months, he tolerated trials of ziprasidone and olanzapine. When quetiapine was initiated, the patient developed signs and symptoms of cholestasis within 3 weeks after starting this medication. The signs and symptoms of cholestasis resolved with removal of quetiapine. The Naranjo probability scale indicated that these atypical antipsychotics (risperidone and quetiapine) were the probable cause of cholestasis in this patient. It is well known that atypical antipsychotics can cause isolated asymptomatic increases in aminotransferase levels. Liver injury, both the hepatic and cholestatic type, has been described previously, although the incidence with atypical antipsychotics is rare. To our knowledge, this is the first case of cholestasis that developed after years of treatment and reappeared with another antipsychotic agent. Given that liver failure, of either the hepatic or cholestatic type, is a relatively rare phenomenon with atypical antipsychotics, it seems that the most reasonable approach to manage this risk is through education. By educating patients on early warning signs of hepatotoxicity, this rare but potentially fatal consequence could be detected early to allow appropriate intervention.

Therapeutic drug monitoring and objective symptom rating for optimization of antipsychotic drug therapy

Therapeutic drug monitoring (TDM) and objective symptom rating are considered to be useful to optimize antipsychotic drug therapy. The aim of this prospective study was to analyze if serum concentrations and/or improvement according to Clinical Global Impressions (CGI-I) or Brief Psychiatric Rating Scale (BPRS) on week two of treatment have predictive validity for clinical improvement on week 5. The study included 80 schizophrenic patients treated under naturalistic conditions with the atypical antipsychotic drugs amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone or ziprasidone. Of the 48 patients who exhibited at least moderate improvement on week 2, only 2 patients were impaired on week 5. Of the 42 patients with only slight improvement or less on week two, 51% changed to at least moderately improved on week 5. For these patients improvement was not significantly different between patients with serum concentrations within the therapeutic range and patients with too low or too high serum levels of the antipsychotic drug. The results indicate that improvement according to the CGI-I and even better to BPRS is predictive for later improvement. It is concluded that TDM guided antipsychotic treatment should be accompanied by regular objective symptom rating for optimization of clinical outcome.

Treatment of Dementia in Community‐Dwelling and Institutionalized Medicare Beneficiaries

To establish nationally representative estimates of the use of agents to treat Alzheimer's disease and related dementias (ADRDs) and related behavioral symptoms in Medicare beneficiaries and to describe medication use according to residential status and other patient characteristics. Cross-sectional prevalence study. Community and various long-term care (LTC) settings. Twelve thousand six hundred ninety-seven beneficiaries from the 2002 Medicare Current Beneficiary Survey (MCBS), of whom 11,593 were community dwelling and 1,104 resided in various LTC settings. ADRDs were identified according to International Classification of Diseases, Ninth Revision, codes in Medicare claims and self- and proxy reports. Medication use was derived from self-reports (community) and extracts of facility medication administration records (LTC). In 2002, an estimated 3.4 million Medicare beneficiaries were diagnosed with ADRDs (8.1%), of whom 58.9% resided in the community (prevalence rate=5.1%) and 41.1% resided in LTC facilities (prevalence rate=57.2%). Use of antidementia drugs was similar across settings, with 24.7% of subjects with dementia in the community and 26.3% of those in LTC receiving prescriptions for donepezil, galantamine, or rivastigmine. Use of haloperidol was comparable (and low) in both settings. Use of atypical antipsychotics, especially risperidone, olanzapine, and quetiapine, was much higher in LTC residents (21.0%, 11.9%, and 7.1%, respectively) than in the community (5.1%, 4.0%, and 2.3%). The prevalence of ADRDs in LTC settings is much larger than in the community, but there is little difference in the proportions receiving antidementia drugs, although LTC residents are more likely to be treated with atypical antipsychotics (risperidone, olanzapine, and quetiapine), presumably for behavioral symptoms.

The Association Between HTR2C Gene Polymorphisms and the Metabolic Syndrome in Patients With Schizophrenia

The use of antipsychotics is associated with metabolic side effects, which put patients with schizophrenia or related disorders at risk for cardiovascular morbidity. The high interindividual variability in antipsychotic-induced metabolic abnormalities suggests that genetic makeup is a possible determinant. In this cross-sectional study, we investigated whether genotypes of the HTR2C receptor are associated with the metabolic syndrome in patients using antipsychotics. Patients were identified from a schizophrenia disease management program. In this program, patients' blood pressure, triglycerides, high-density lipoprotein-cholesterol, and waist circumference are measured regularly during follow-up. The primary end point of our study was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the HTR2C receptor gene (HTR2C:c.1-142948[GT]n, rs3813928 [-997 G/A], rs3813929 [-759 C/T], rs518147 [-697 G/C], and rs1414334 [C > G]). The included patients (n = 112) mainly (>80%) used atypical antipsychotics (clozapine, olanzapine, and risperidone). Carriership of the variant alleles of the HTR2C polymorphisms rs518147, rs1414334, and HTR2C:c.1-142948(GT)n was associated with an increased risk of the metabolic syndrome (adjusted odds ratio [OR], 2.62 [95% confidence interval {CI}, 1.00-6.85]; OR, 4.09 [95% CI, 1.41-11.89]; and OR, 3.12 [95% CI, 1.13-8.16]), respectively. Our findings suggest that HTR2C genotypes are associated with antincreased risk of metabolic syndrome in patients taking antipsychotics.

Effects of risperidone and quetiapine on cognition in patients with schizophrenia and predominantly negative symptoms

Evidence suggests that neurocognitive impairment is a key factor in the pathology of schizophrenia and is linked with the negative symptoms of the disease. In this study the effects of the atypical antipsychotics quetiapine and risperidone on cognitive function in patients with schizophrenia and with predominantly negative symptoms were compared. Patients were randomly assigned to double-blind treatment with quetiapine or risperidone for 12 weeks. Cognitive function was assessed at baseline, Week 6 and Week 12. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) at baseline, Week 6 and Week 12. Extrapyramidal side-effects were assessed each week using the Simpson-Angus Scale (SAS), adverse events were recorded as additional indicators of tolerability throughout the trial. In total, 44 patients were enrolled in the study. Data from the 34 patients who completed cognitive assessments at two or more time points out of three (baseline, Week 6 and Week 12) are analysed here. Quetiapine improved significantly global cognitive index z-scores at both Week 6 (p<0.001 vs. baseline) and Week 12 (p<0.01 vs. baseline), whereas risperidone improved significantly global cognitive index z-scores at Week 12 (p<0.05). Between-group comparisons at Week 6 showed significantly greater improvements in working memory and verbal memory with quetiapine than risperidone (p<0.05) and a significantly greater improvement in reaction quality/attention with quetiapine than risperidone at Week 12 (p<0.05). Quetiapine and risperidone produced significant improvements from baseline in PANSS total (p<0.001) and subscale scores at Week 12. Significant improvements in SANS total score were also seen in both the quetiapine (p<0.001) and risperidone (p<0.01) groups at Week 12 compared with baseline. SAS scores, measuring the incidence of extrapyramidal side-effects, were higher in patients receiving risperidone compared with those receiving quetiapine, and significant differences were seen at Weeks 3, 4, 5 and 7. Both quetiapine and risperidone improved cognition according to changes in cognitive index scores from baseline to Week 12. These results suggest that quetiapine and risperidone provide valuable treatment options for patients with schizophrenia with predominantly negative symptoms. Also, the improvements in cognition following treatment with quetiapine and risperidone may enhance long-term outcomes for these patients.

AC260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one), a selective muscarinic M1 receptor agonist, increases acetylcholine and dopamine release in rat medial prefrontal cortex and hippocampus

Both muscarinic and nicotinic receptors are implicated in cognition. We have previously suggested that stimulation of the muscarinic M1 receptor has a beneficial effect on cognition, based upon evidence that the muscarinic M1 receptor agonist of N-desmethylclozapine, the major metabolite of clozapine, may contribute to the ability of clozapine to improve some domains of cognition in schizophrenia. Present study examined the effectiveness of a new muscarinic M1 receptor agonist, 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584), to increase the release of acetylcholine and dopamine in the rat medial prefrontal cortex and hippocampus. Using microdialysis in awake, freely moving rats, AC260584, 3 and 10, but not 1 mg/kg (s.c.), significantly increased dopamine release in the medial prefrontal cortex and hippocampus. However, only the high dose of AC260584, 10 mg/kg (s.c.), significantly increased acetylcholine release in these regions. Moreover, the increases in acetylcholine release produced by AC260584, 10 mg/kg, were attenuated by the muscarinic M1 receptor antagonist telenzepine (3 mg/kg, s.c.) but not by the 5-HT1A receptor antagonist N-[2-(4-2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridyl) cyclohexanecarboxamide (WAY100635, 0.2 mg/kg, s.c.). However, the increase in dopamine release produced by 10 mg/kg AC260584 was blocked by both telenzepine and WAY100635. In addition, pretreatment with the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.) potentiated AC260584 (1.0 mg/kg, s.c.)-induced acetylcholine and dopamine release in the medial prefrontal cortex. These findings suggest that the muscarinic M1 receptor agonist property of AC260584 contributes to its enhancement of cortical acetylcholine and dopamine efflux. Therefore, AC260584, as well as other muscarinic M1 receptor agonists, may be a valuable target for the development of drugs which can improve the cognitive deficits in schizophrenia and perhaps other neuropsychiatric disorders, as well.

Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activation-dependent increase of dopamine D 1 receptor-mediated neurotransmission

The clinically achievable efficacy of the atypical antipsychotics on cognitive symptoms of schizophrenia is practically limited by their dose-dependent side effects. Thus, there is the need for adjuvant treatments or strategies for the cognitive impairments. Further, human autopsy and genetic data in schizophrenia have indicated the existence of the abnormality of nicotinic acetylcholine receptors (nAChR). In the present study, we aimed to investigate the synergistic effect and mechanisms of a combined treatment with an atypical antipsychotic risperidone and galantamine, which is a nAChR-allosteric modulator and a modest cholinesterase inhibitor, on the impairment of latent visuospatial learning and memory in mice resembling the cognitive impairment of schizophrenia. Repeated treatment with phencyclidine (PCP, 10 mg/kg, 14 days)-induced cognitive impairment in mice in a one trial water-finding test was used as a model of the cognitive impairment of schizophrenia. In vivo microdialysis was used to investigate the extracellular concentration of dopamine in the medial prefrontal cortex (mPFC). Combined treatment with galantamine and risperidone, at low, ineffective doses (both at 0.05 mg/kg) showed a synergistic effect to reverse cognitive impairment and increase extracellular concentration of dopamine in the mPFC. The synergistic behavioral effect was abolished by a dopamine-D 1 receptor antagonist, SCH 23390, and a nAChR antagonist, mecamylamine, but not a muscarinic AChR (mAChR) antagonist, scopolamine. Mecamylamine also blocked the synergistic effect on dopamine release in the mPFC of PCP-treated mice. The study indicates that galantamine and risperidone may have synergistic effect on the cognitive impairments in schizophrenia patients by synergistically promoting the nAChR activation-dependent increase of dopamine D 1 receptor-mediated neurotransmission.

Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons

Paliperidone (9-OH-risperidone) is the main metabolite of the atypical antipsychotic risperidone. While both drugs are potent dopamine (D)2 antagonists, they have quantitative differential affinities for serotonin (5-HT) and norepinephrine (NE) receptor binding sites. The present study aimed to determine if paliperidone exerts distinct effects on 5-HT and NE neuronal activity from those of risperidone. Risperidone and paliperidone were administered to Sprague-Dawley rats. Neuronal activity of 5-HT and NE neurons was assessed using in vivo electrophysiology. Acute administration of risperidone but not paliperidone inhibited the firing of 5-HT neurons, as previously reported. This inhibition was partially antagonized by the NE reuptake inhibitor desipramine, by the 5-HT(1A) receptor antagonist WAY 100635, and completely reversed when both drugs were given consecutively. Risperidone inhibited the firing of 5-HT neurons after 2 and 14 days of administration, with or without escitalopram. Paliperidone did not alter the firing rate of NE neurons by itself, but it reversed the suppression of NE neurons induced by escitalopram, as it was previously reported for risperidone. These results indicate that although risperidone and paliperidone share a qualitatively similar receptor binding profile in vitro, they differentially alter the firing of 5-HT and NE neurons in vivo. The capacity of paliperidone to reverse the selective serotonin reuptake inhibitor (SSRI)-induced inhibition of NE neuronal firing, without interfering with the effect of SSRIs of 5-HT neuronal activity, suggests that paliperidone may be a very effective adjunct in SSRI-resistant depression.

Decision analysis model evaluating the cost‐effectiveness of risperidone, olanzapine and haloperidol in the treatment of schizophrenia

To evaluate the cost-effectiveness of three antipsychotic medications (olanzapine, risperidone and haloperidol) in the treatment of schizophrenia using the Positive and Negative Symptom Scale. A decision analysis model was created to evaluate the cost-effectiveness of two atypical antipsychotics (risperidone and olanzapine) and haloperidol. Outcome probabilities were determined from published clinical trials. The main dependent variable of interest was to compare the incremental cost-effectiveness ratios (ICER) of the atypical antipsychotic with haloperidol, and also to compare the ICER of olanzapine and risperidone. Sensitivity analyses were conducted for olanzapine and risperidone to determine the effects of altering drug cost, efficacy and re-hospitalization rate on total costs. Risperidone and olanzapine were dominant strategies compared with haloperidol (less costly and more effective). Risperidone was also dominant when compared with olanzapine. A one-way sensitivity analysis for efficacy indicated that the efficacy of risperidone would need to decrease by approximately 3% from the base-case in order for olanzapine and risperidone to have equal total costs. In a two-way sensitivity analysis varying both the cost of olanzapine and risperidone, the difference in drug costs between them would have to increase from $2.12 per day to $4.12 per day in order to have equal total costs. In terms of varying re-hospitalization rates, the re-hospitalization rate for risperidone would have to increase from 3% to 33% greater than the re-hospitalization rate for olanzapine in order to have equal total direct costs. Based on this decision model, atypical antipsychotics were a dominant strategy over haloperidol primarily because of increased efficacy and lower re-hospitalizations. The ICER indicated that risperidone was dominant over olanzapine because of lower drug costs and increased number of responders, which leads to decreased total costs.

Quetiapine versus risperidone in elderly patients with behavioural and psychological symptoms of dementia: Efficacy, safety and cognitive function

Objective In this study we directly compared the efficacy and tolerability of the atypical antipsychotics quetiapine and risperidone in elderly patients with dementia and symptoms of disturbed perception, thought content, mood or behaviour (behavioural and psychological symptoms of dementia—BPSD). Methods We conducted an 8-week, rater-blinded, randomised study of 72 outpatients (55–85 years) with BPSD (assessed by NPI baseline score), who received flexibly-dosed quetiapine (50–400 mg/day) or risperidone (0.5–2 mg/day). Primary efficacy measure: Neuropsychiatric Inventory (NPI) Parts 1 and 2; secondary efficacy measures: Clinical Global Impression (CGI), Cohen-Mansfield Agitation Inventory (CMAI), Mini-Mental State Examination (MMSE), Age-adjusted concentration test (AKT). Safety evaluations included the incidence of extrapyramidal symptoms (EPS) and adverse events (AEs). Results Sixty-nine of 72 patients were evaluable for efficacy (72 were evaluated for safety), 4 patients discontinued (3 due to AEs: quetiapine 2, risperidone 1; 1 lost to follow-up). Sixty-five patients received quetiapine ( n = 34; mean dose 77 ± 40 mg/day) or risperidone ( n = 31; mean dose 0.9 ± 0.3 mg/day). There was no significant difference between treatments on NPI scores; within treatment groups, NPI scores decreased significantly from baseline to Week 8 ( P ≤ 0.05 vs. baseline). Most patients (quetiapine arm 67.6%, risperidone arm 71.0%) experienced clinical improvement (CGI-Improvement scores); both agents reduced agitation (CMAI scores); and there was no cognitive impairment (MMSE and AKT scores). There were no significant differences between treatments in any safety measures, including EPS. Four patients experienced serious AEs (quetiapine arm 3; risperidone arm 1); none were considered treatment-related by the study investigator. There were no cerebrovascular AEs or deaths. Conclusions Quetiapine or risperidone, at low doses, were equally effective and generally well tolerated (including no cognitive impairment) in the treatment of BPSD in elderly patients.

Neither Atypical Nor Conventional Antipsychotics Increase Mortality or Hospital Admissions Among Elderly Patients With Dementia: A Two-Year Prospective Study

Antipsychotics are widely used to manage behavioral disorders in patients with dementia. Recently, serious concerns have been raised about the stroke and mortality risk of atypical antipsychotics when administered to patients with dementia. The aim of this study was to examine the impact of atypical and conventional antipsychotics on mortality and hospital admissions among Finnish elderly institutionalized patients with dementia in a two-year follow up and to compare their prognosis with that of nonusers. The authors examined 254 very frail patients with dementia, mean age 86 years, from seven Finnish nursing homes and two hospitals in 1999-2000. Medical records provided information on the use of daily antipsychotic medication; central registers confirmed mortality for up to two years. Nearly one-half (48.4%) of the patients used antipsychotic medication: 37.4% received conventional neuroleptics (N = 95) and 11.0% received atypical antipsychotics (N = 28). The mean number of hospital admissions was higher among the nonusers than among the users of conventional or atypical antipsychotics. Of the users of atypical antipsychotics (risperidone, olanzapine), 32.1% died within 2 years. The respective figures for users of conventional neuroleptics were 45.3%, and for the nonusers, 49.6%. In the Cox proportional hazard model, a high number of medications and the use of physical restraint predicted higher mortality at two years. The use of atypical antipsychotics showed lower risk of mortality, if any. The respective test for conventional antipsychotics was nonsignificant. Among these frail and very old patients with dementia, neither the use of atypical antipsychotics nor the use of conventional neuroleptics increased mortality or hospital admissions. The use of restraints, however, doubled the risk of mortality.

Hospitalization risks in the treatment of bipolar disorder: comparison of antipsychotic medications

This study compared the relative risk for hospitalization of patients with bipolar and manic disorders receiving atypical and typical antipsychotics. This retrospective study was based on administrative claims data extracted from the PharMetrics database during 1999 through 2003. Comparisons were made among atypical antipsychotics (risperidone, olanzapine, quetiapine or ziprasidone), as well as between each of these versus a combined group of the leading typical antipsychotics. Relative risk for hospitalization was estimated with Cox proportional regression, which adjusted for differences in patient characteristics. Risperidone and olanzapine demonstrated higher risks for hospitalization than quetiapine [hazard ratio (HR) 1.19, p < 0.05 for both], translating into higher annual mental health inpatient charges of $260 per patient. Risperidone and olanzapine also showed higher estimated risks than ziprasidone, which approached the p < 0.05 threshold. Differences between each of the atypicals and the combined typicals were not significant. Patients with putative rapid cycling had a threefold greater risk for hospitalization than other patients with bipolar disorder. In these patients, comparisons among atypical antipsychotics showed that risperidone had a significantly higher hospitalization risk than olanzapine (HR 3.31, p < 0.05), resulting in higher annual mental health inpatient charges of $4,930 per patient. In the treatment of bipolar and manic disorders, risperidone and olanzapine were associated with a higher risk for hospitalization than quetiapine, and possibly ziprasidone. In the treatment of putative rapid cyclers, olanzapine was associated with a lower risk for hospitalization than risperidone.

Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats

Prepulse inhibition (PPI) of the startle reflex has been extensively studied because it is disrupted in several psychiatric diseases, most notably schizophrenia. In rats, and to a lesser extent, in humans, PPI can be diminished by dopamine (DA) D(2)/D(3) and serotonin 5-HT(1A) receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D(2) receptors and various levels of 5-HT(1A) activation. It thus appeared warranted to assess, in Sprague-Dawley rats, the effects of these antipsychotics on basal PPI. SSR181507, sarizotan, and bifeprunox decreased PPI, with a near-complete abolition at 2.5-10 mg/kg; SLV313 had a significant effect at 0.16 mg/kg only. Co-treatment with the 5-HT(1A) receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT(1A) agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT(1A) receptors, such as aripiprazole (another DA D(2)/D(3) and 5-HT(1A) ligand), and established typical and atypical antipsychotics (haloperidol, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) had no effect on basal PPI (0.01-2.5 to 2.5-40 mg/kg). The present data demonstrate that some putative antipsychotics with pronounced 5-HT(1A) agonist activity, coupled with partial agonist activity at DA D(2) receptors, markedly diminish PPI of the startle reflex in rats. These data raise the issue of the influence of such compounds on sensorimotor gating in humans.

Simultaneous analysis of classical neuroleptics, atypical antipsychotics and their metabolites in human plasma

A high-performance liquid chromatographic method has been developed for the simultaneous determination of classical neuroleptics (chlorpromazine, haloperidol, loxapine and clotiapine), atypical antipsychotics (clozapine, quetiapine and risperidone) and their active metabolites (N-desmethylclozapine, clozapine N-oxide and 9-hydroxyrisperidone) in human plasma. Separation was obtained by using a C8 reversed-phase column and a mobile phase composed of 70% aqueous phosphate buffer containing triethylamine at pH 3.0 and 30% acetonitrile. The UV detector was set at 238 nm and amitriptyline was used as the internal standard. A careful pre-treatment procedure of plasma samples was developed, using solid-phase extraction with cyanopropyl cartridges, which gives high extraction yields (>or=93%). The limits of quantitation (LOQ) were always lower than 2.6 ng mL-1 and the limits of detection (LOD) were always lower than 0.9 ng mL-1 for all analytes. The method was applied with success to plasma samples from schizophrenic patients undergoing polypharmacy with two or more different antipsychotics. Precision data and accuracy results were satisfactory and no interference from other central nervous system (CNS) drugs was found. Hence the method is suitable for the therapeutic drug monitoring (TDM) of the analytes in psychotic patients' plasma.

Alopecia associated with quetiapine

Alopecia has previously been reported with the atypical antipsychotic medicines olanzapine and risperidone, but has not been described with quetiapine. Case reports of alopecia associated with quetiapine reported to the New Zealand Intensive Medicines Monitoring Programme were reviewed. The World Health Organization international spontaneous reporting database was also searched for additional case reports. Literature searches were conducted for previous reports of alopecia associated with quetiapine. The Intensive Medicines Monitoring Programme database included two case reports of alopecia associated with quetiapine. Assessment of these cases suggested a causal relationship with the medicine. The World Health Organization international database included a further 15 case reports, providing evidence supporting this association. No previously published reports of alopecia associated with quetiapine were identified. In conclusion, these are the first published case reports of alopecia associated with quetiapine.

Insomnia and excessive daytime sleepiness in psychotic patients taking traditional or atypical antipsychotic medications

The aim of the study was to evaluate quantitative sleep disorders in forty patients with a psychotic disorder (F 20 or F25 at ICD X International Classification), who are taking antipsychotic medication.We studied 100 patients, affected by schizophrenic or schizoaffective disorder, aged from 20 to 65 years old. These patients were divided in four groups each containing 25 people who were taking neuroleptics or atypical antipsychotic (olanzapine, risperidone or aripiprazole).The variability of quantitative sleep disorder was measured using questions 4-5-6 of Hamilton Depression Scale to evaluate early, intermediate or late insomnia, and the Epworth Sleepiness Scale to assess EDS (excessive daytime sleepiness)We all know the sedative effects of neuroleptics, furtherless it is not unexpected that most of the atypical antipsychotics are sedating, and thus have the potential to impair judgement, thinking or motor skills giving the patients the sensation of being different from the other people. Many times we forget that the other side of insomnia is the excessive daytime sleepiness….In the future, we have to manage these disorders, if we want to avoid lack of compliance and further drop out of therapy.