Extrapyramidal Symptom Rating Research Articles

No Evidence Support Quetiapine in Treatment of Adolescent Bipolar Depression

Quetiapine, an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder. Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium, is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of Extrapyramidal Symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania. But for children and adolescent, quetiapine show no difference to placebo. The both RCT and evidence-based medicine study indicate that quetiapine have no efficacy for children and adolescent bipolar depression.

Safety profile of pimavanserin therapy in elderly patients with neurodegenerative disease‐related neuropsychiatric symptoms: a Phase 3b study

AbstractBackgroundPatients with neurodegenerative diseases including Parkinson’s disease often experience neuropsychiatric symptoms, including hallucinations and delusions, apathy, and agitation.1,2 These symptoms can greatly impair daily function and lead to reduced quality of life and significant caregiver burden. These patients are generally elderly and often frail. Treatment options are limited, representing a substantial unmet need. Pimavanserin, a 5‐HT2A receptor inverse agonist/antagonist, is FDA‐approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis.3 MethodThis Phase 3b, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study evaluated the safety of pimavanserin (34 mg) versus placebo in frail adults and elderly patients with neuropsychiatric symptoms related to neurodegenerative disease. The primary endpoint was safety and tolerability as measured by treatment‐emergent adverse events. Secondary safety endpoints included change from baseline in motor (Extrapyramidal Symptom Rating Scale‐Abbreviated [ESRS‐A]) and cognitive function (Mini‐Mental State Examination [MMSE]) at Week 8. Suicidality was assessed using the Columbia‐Suicide Severity Rating Scale (C‐SSRS) or Global Clinician Assessment of Suicidality (GCAS). Exploratory efficacy endpoints included Clinical Global Impression‐Severity (CGI‐S) and ‐Improvement (CGI‐I), 5‐level version of EQ‐5D (EQ‐5D‐5L), and Sleep Disorders Inventory (SDI).ResultOverall, incidence of TEAEs were similar between pimavanserin (n = 392) and placebo (n = 392); 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%) and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%) (Table 1). TEAEs leading to discontinuation or study termination were reported in 2.6% and 2.3% of patients on pimavanserin and placebo, respectively. The most frequently reported TEAEs included urinary tract infection (pimavanserin: 6.4%; placebo: 4.1%) and headache (pimavanserin: 2.0%; placebo: 3.8%). Mortality due to TEAEs was similar between groups (0.5% each). Pimavanserin did not impact motor‐ or cognition‐related function (ESRS‐A and MMSE, respectively); an improvement was seen in CGI‐I (MMRM LSM [SE]: ‐0.2 [0.07], p = 0.0140] and sleep function (SDI) at Week 8 (MMRM LSM [SE]: ‐0.3 [0.06], p<0.0001] compared to placebo (Figures 1, 2); no differences were observed across other measures.ConclusionPimavanserin was well tolerated in patients with neuropsychiatric symptoms related to neurodegenerative disease, consistent with the known safety profile of pimavanserin, informing its use in Parkinson’s disease psychosis. Pimavanserin was not associated with cognitive decline or motor dysfunction.

Risk of Poor Neonatal Adaptation Syndrome Among Infants Exposed to Second-Generation Atypical Antipsychotics Compared to Antidepressants: Results From the National Pregnancy Registry for Psychiatric Medications.

Objective: While poor neonatal adaptation syndrome (PNAS) has been particularly well described among infants exposed to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), this is not the case for second-generation antipsychotics (SGAs). In 2011, the US Food and Drug Administration (FDA) issued a drug safety warning regarding fetal antipsychotic exposure and risk for PNAS and extrapyramidal symptoms (EPS). The primary objective of this study was to examine the risk for PNAS among infants exposed to SGAs compared to SSRI/SNRI-exposed infants, leveraging the prospective, longitudinal design of the National Pregnancy Registry for Psychiatric Medications (NPRPM). Methods: The NPRPM is a prospective pharmacovigilance program in which pregnant women, aged 18–45 years, are enrolled and followed prospectively. Medical records were systematically reviewed and data abstracted using a checklist of PNAS and EPS symptoms specifically outlined in the FDA drug safety warning. The two study groups included infants exposed to an SGA during pregnancy and infants exposed to an SSRI/SNRI during pregnancy. The primary outcome was the presence of at least one or more PNAS symptoms during the first month of life. Other neonatal outcomes following exposure to the medication of interest, including preterm birth, neonatal intensive care unit (NICU) admission, rates of EPS, and whether infants were discharged home with their mothers, are also reported. Results: Of the 2,145 women enrolled in this study as of December 16, 2020, a total of 373 women and their infants (n = 384) were eligible for inclusion (n = 193 SGA-exposed infants and 191 SSRI/SNRI-exposed infants). Among SGA-exposed infants, 32.6% (63/193) experienced at least 1 PNAS sign compared to 34.6% of infants (66/191) in the SSRI/SNRI-exposed group. The majority of infants in each group showed no symptoms of PNAS. No differences were observed between the two groups with respect to rates of preterm birth, NICU admission, prevalence of EPS, and timing of infants being discharged home with their mothers. Conclusions: PNAS symptomatology was comparable among infants exposed prenatally to an SGA or to an SSRI/SNRI. These preliminary findings provide an estimated risk of PNAS among infants exposed to SGAs of roughly 30%. Interestingly, these findings are also consistent with estimates in the literature of PNAS in SSRI/SNRI-exposed infants, suggesting a possible common pathway underlying this phenomenon. Trial Registration: ClinicalTrials.gov identifier: NCT01246765

Efficacy and safety of pimavanserin in patients with Alzheimer’s dementia psychosis in the HARMONY phase 3, randomized discontinuation study: a post hoc subgroup analysis

AbstractBackgroundPimavanserin was investigated for the treatment of dementia‐related psychosis (DRP) in HARMONY (NCT03325556), a phase 3 randomized discontinuation study. As the study met the primary endpoint (one‐sided P = 0.0023), we evaluated the consistency of the efficacy for reducing the risk of relapse in the largest dementia patient subgroup (ie, Alzheimer’s dementia psychosis [ADP] patients) treated with pimavanserin 34mg.MethodEnrolled DRP patients (N = 392) entered the 12‐week open‐label (OL) period and received pimavanserin 34mg daily. During weeks 1‐4, dose could be adjusted to 20mg at investigator discretion. Patients meeting prespecified response criteria at weeks 8 and 12 were randomized to continue pimavanserin or receive placebo for up to 26 weeks in the double‐blind (DB) period. The primary endpoint was time from randomization to adjudicated relapse. Efficacy analyses included patients at the interim analysis (IA); safety analyses included all dosed patients.ResultOf 260 ADP patients, 243 stayed on pimavanserin 34mg throughout the OL period; 17 patients received pimavanserin 20mg beyond OL week 4. At baseline, mean age in the pimavanserin 34mg group was 75.7 years; mean MMSE score was 16.0. Twenty‐nine patients were terminated with sponsor termination of the study; of the remaining 214 patients, 130 (60.7%) met response criteria at weeks 8 and 12 and were randomized. At the IA, 116 ADP patients were randomized to pimavanserin 34mg (N = 57) or placebo (N = 59). Hazard ratio for psychosis relapse risk with pimavanserin 34mg versus placebo was 0.466 (95% CI: 0.179, 1.214); 6/57 (10.5%) pimavanserin‐treated and 14/59 (23.7%) placebo‐treated patients met relapse criteria. Treatment‐emergent adverse events incidence rates were: OL, 29.6% (72/243); DB‐pimavanserin 34mg, 39.7% (25/63); DB‐placebo, 34.3% (23/67). Pimavanserin did not have a negative effect on Mini‐Mental State Examination or Extrapyramidal Symptom Rating Scale‐Abbreviated score change from baseline versus placebo in the DB period.ConclusionIn a study that met its primary endpoint, a post‐hoc subgroup analysis in ADP, although not statistically significant, demonstrated a clinically meaningful reduction in the risk of relapse was observed in patients treated with pimavanserin 34mg versus placebo. Pimavanserin was not associated with an adverse impact on cognition or motor function.

PMH5 EFFICACY AND SAFETY OF LURASIDONE AND OTHER ATYPICAL ANTIPSYCHOTIC AGENTS FOR BIPOLAR DEPRESSION: UPDATED SYSTEMATIC REVIEW AND META-ANALYSES

Since publication of a systematic literature review (SLR) and network meta-analysis (NMA) comparing the efficacy and safety of lurasidone with atypical antipsychotic monotherapies for the treatment of acute bipolar depression among adults, new clinical trial data have been released. The purpose of this study was to update an NMA comparing the efficacy and safety of lurasidone with all other atypical antipsychotic monotherapies in adult patients with bipolar depression. A SLR and NMA of randomized controlled trials (RCTs) was updated as of August 2018 using Embase, MEDLINE, PsycINFO, Cochrane library, clinicaltrials.gov, recent abstracts, and press releases. Outcomes included the Montgomery–Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions–Bipolar Disorder–Severity (CGI-BP-S) scale, weight gain, somnolence, akathisia, extrapyramidal symptoms (EPS), and all-cause discontinuation. Mean differences in change from baseline and mean odds ratios (OR) with 95% credible intervals were calculated. Seventeen RCTs of lurasidone, quetiapine (IR or XR), aripiprazole, olanzapine, ziprasidone and cariprazine for the treatment of bipolar depression were included. Lurasidone was significantly more efficacious than cariprazine (MADRS: -2.91 [-5.57, -0.20], CGI-BP-S: -0.44 [-0.74, -0.14]), aripiprazole (MADRS: -3.62 [-6.89, -0.36], CGI-BP-S: -0.42 [-0.77, -0.07]), and ziprasidone (MADRS: -3.37 [-6.49, -0.23], CGI-BP-S: -0.59 [-0.93, -0.24]). Lurasidone had similar efficacy vs olanzapine and quetiapine. Lurasidone had less weight gain than olanzapine (-2.54kg [-3.36, -1.72]), quetiapine (-0.83kg [-1.55, -0.12]), and cariprazine (-0.40kg [-1.30, 0.49]), and less somnolence than ziprasidone (OR: 0.28 [0.09, 0.66]) and quetiapine (OR: 0.32 [0.11, 0.68]). Rates of akathisia, EPS, and all-cause discontinuation were similar. Consistent with the previous NMA, lurasidone was efficacious and well-tolerated. The updated NMA showed lurasidone was more efficacious than cariprazine, aripiprazole, and ziprasidone among adults with acute bipolar depression. Lurasidone also had less weight gain than olanzapine and quetiapine, and less somnolence than quetiapine and ziprasidone.

Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis

This network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause discontinuation, extrapyramidal symptoms (EPS), and akathisia. Results were reported as median differences for continuous outcomes and odds ratios (ORs) for binary outcomes, along with 95% credible intervals (95% CrI). Lurasidone was significantly more efficacious than placebo on the PANSS (− 7.95, 95% CrI − 11.76 to − 4.16) and CGI-S (− 0.44, 95% CrI − 0.67 to − 0.22) scores. Lurasidone was associated with similar weight gain to placebo and statistically significantly less weight gain versus olanzapine (− 3.62 kg, 95% CrI − 4.84 kg to − 2.41 kg), quetiapine (− 2.13 kg, 95% CrI − 3.20 kg to − 1.08 kg), risperidone (− 1.16 kg, 95% CrI − 2.14 kg to − 0.17 kg), asenapine (− 0.98 kg, 95% CrI − 1.71 kg to − 0.24 kg), and paliperidone ER (− 0.85 kg, 95% CrI − 1.57 kg to − 0.14 kg). The odds of all-cause discontinuation were significantly lower for lurasidone than aripiprazole (OR = 0.28, 95% CrI 0.10–0.76) and paliperidone ER (OR = 0.25, 95% CrI 0.08–0.81) and comparable to other antipsychotics. Rates of EPS and akathisia were similar for lurasidone and other atypical antipsychotics. In this network meta-analysis of atypical antipsychotics in adolescent schizophrenia, lurasidone was associated with similar efficacy, less weight gain, and lower risk of all-cause discontinuation compared to other oral atypical antipsychotics.

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome.

To use multimodal neuroimaging to evaluate the influence of heterogeneous underlying pathology in corticobasal syndrome (CBS) on the neuroanatomical distribution of disease. We performed a retrospective evaluation of 35 patients with CBS with T1-weighted MRI, diffusion tensor imaging, and neuropathologic, genetic, or CSF evidence of underlying pathology. Patients were assigned to 2 groups: those with evidence of Alzheimer pathology (CBS-AD) and those without Alzheimer pathology (CBS-non-AD). Group comparisons of CBS-AD and CBS-non-AD assessed clinical features, gray matter (GM) cortical thickness, and white matter (WM) fractional anisotropy. CBS-AD was found in 34% (n = 12) and CBS-non-AD in 66% (n = 23) of CBS patients. Clinical evaluations revealed that CBS-non-AD had a higher frequency of asymmetric rigidity compared to CBS-AD, but groups otherwise did not differ in dementia severity, impairments in cognition, or rates of extrapyramidal symptoms. We found frontoparietal GM and WM disease in each group compared to healthy, demographically comparable controls, as well as multimodal neuroimaging evidence of a double dissociation: CBS-non-AD had WM disease in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus relative to CBS-AD, and CBS-AD had reduced temporoparietal GM relative to CBS-non-AD, including the precuneus and posterior cingulate. Patients with CBS have a pathology-mediated dissociation of GM and WM disease. Multimodality neuroimaging may be useful for improving in vivo pathologic diagnosis of CBS.

Med Check

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessMed CheckVabren WattsVabren WattsSearch for more papers by this authorPublished Online:6 Aug 2015https://doi.org/10.1176/appi.pn.2015.8a12Ketamine Effects Sustained Over Two MonthsAnother small-scale clinical trial for ketamine has catapulted the drug back into headlines of some major news outlets, suggesting that the effectiveness of the NMDA-receptor antagonist can be sustained with help from other pharmacoagents. Researchers from Columbia University administered various doses of lurasidone, olanzapine/fluoxetine, or quetiapine to eight patients with treatment-resistant bipolar depression for one month before infusing the patients with a one-time dose of ketamine (0.5 mg/kg) for 60 minutes, immediately followed by 300 to 1,000 mg daily doses of the tuberculosis drug D-cyclosporine, another NMDA antagonist, for eight weeks.The researchers observed a 50 percent reduction in depression and a 75 percent reduction in suicidality among participants over one to two weeks, which is not unusual when ketamine is administered alone or with FDA-approved antipsychotics for bipolar depression. What was unique, the researchers noted, was that these effects lasted up to two months in the presence of D-cyclosporine. While the authors of the study noted more studies are needed to assess D-cycloserine’s independent efficacy and safety in bipolar depression, the study received much praise from NeuroRX, a small biotech company that is developing a ketamine/lurasidone/D-cyclosporine combo treatment for bipolar depression. The company was not involved with this study.According to a statement released by NeuroRX, “This is the first clinical report showing that the ketamine effect can potentially be sustained for two months with additional agents.” Kantrowitz J, Halberstam B, Gangwisch J. Single-Dose Ketamine Followed by Daily D-Cycloserine in Treatment-Resistant Bipolar Depression. J Clin Psychiatry. 2015. 76(6):737-8.Pristiq Fails in Pediatric TrialsPfizer’s Pristiq ER was recently found to be no more effective in children than placebo, according to the company. This selective serotonin and norepinephrine reuptake inhibitor (SNRI) received approval by the FDA in 2008 for the treatment of major depressive disorder in adults.The phase 3 trial, which involved 340 youth aged 7 to 17 with major depressive disorder, was the first of four phase 3 pediatric trials being conducted as part of an FDA postmarketing commitment under the Pediatric Research Equity Act, which requires pharmaceutical companies to conduct pediatric studies with recently approved drugs for the same use for which those drugs were approved in adults.Lundbeck and Otsuku Set to Launch New AntipsychoticIn July, the FDA approved the Lundbeck and Otsuku co-developed drug Rexulti (brexpiprazole), which is intended to treat schizophrenia and major depressive disorder. The drug is a dopamine D2 and serotonin 5-HT1A partial agonist.The effectiveness of the new compound was shown in a multisite international study published April 17 in AJP in Advance. In the study, patients administered 2 mg and 4 mg of brexpiprazole for six weeks had significantly lower scores on the Positive and Negative Syndrome Scale than those who took placebo, with no clinically significant changes in baseline lipid and glucose levels and extrapyramidal symptom ratings (Psychiatric News, May 15, 2015).In a press statement, Lundbeck noted that in most trials concerning Rexulti, more than 90 percent of participants completed treatment protocols, making the drug one of the “best-in-class” for tolerability. The company expects that the drug could be on the market as soon as the end of this month.Adults Take More ADHD Meds Than Children Children are no longer the prime market for medicines used to treat attention-deficit/hyperactivity disorder (ADHD) in the United States, according to a recent report by Shire Pharmaceuticals. According to Shire, which manufactures the top-selling ADHD medication Vyvanse (lisdexamfetamine), compiled data from a national database on prescription drugs revealed that 53 percent of prescriptions for ADHD medications in 2014 (63 million prescriptions) were for adults, up from 39 percent in 2007. Children aged 6 to 17 accounted for 47 percent of such prescriptions in 2014, down from 61 percent in 2007.A report in Bloomberg suggests the market shift may be due to growing evidence that the disorder can persist into adulthood and findings that show that more parents of children with ADHD are being diagnosed with the condition amid the growing awareness that ADHD can be inherited.During a conference call with analysts, Shire’s CEO Flemming Ornskov said that the company “has shifted more efforts into the adult ADHD market” and will be directing sales representatives to spend more time telling physicians about studies concerning adult use of ADHD medications. ■ ISSUES NewArchived

Aripiprazole induced severe parkinsonism: a case report

Aripiprazole, a D2 and 5-HT1A receptor partial agonist and 5-HT2A receptor, is an atypical antipsychotic. Previous studies indicated that the rate of extrapyramidal symptoms caused by aripiprazole is very close to that of placebo. However, there are studies and case reports in the literature describing aripiprazole-induced extrapyramidal symptoms. In this presented case, while using 10 mg/day of aripiprazole, severe parkinsonism appeared and theyd is appeared after discontinuation of the drug.

Atypicality of Atypical Antipsychotics Revisited

Background: All antipsychotic agents marketed since clozapine have been categorized as “atypical”, without regard for the true definition of “atypicality”. The standard practice of designating every new agent as “atypical” not only ignores the definition, but conveys a false sense of safety for the majority of these medications when considering the risks of movement disorders, both acute and latent. Though receptor profiles are unique to each medication, the antipsychotic effect of all agents is attributed to reducing dopamine activity in the mesolimbic area, usually through the blockade of dopamine type 2 (D2) receptors, whether the agent is “tightly” or “transiently bound”. Yet, antagonism of D2 receptors in the striatum is associated with the potential for extrapyramidal symptoms (EPS), as well as the development of tardive dyskinesia (TD). Clozapine is categorized as “atypical” because its use is not associated with EPS or TD at a rate greater than placebo, as it provides antipsychotic efficacy at a lower saturation of D2 receptors than traditional antipsychotics. As newer second-generation agents came to market, the definition of “atypical” has been modified to include a variety of characteristics unrelated to movement side effects. Nevertheless, many clinicians still assume that “atypicality” indicates a risk of EPS and TD at no-greater-than-placebo rates. Objective: This paper examines each of the 10 second-generation agents approved in the United States for treatment of schizophrenia (and cariprazine, for which approval is pending), and examines which ones meet the strict definition of “atypical” (ie, risk of EPS and TD no greater than placebo). Data source: A literature search using PubMed and Google Scholar, involving various combinations of the keywords “antipsychotic,” “atypical,” “typical,” “first generation,” “second generation,” “schizophrenia,” “tardive dyskinesia,” “movement disorders,” and “extrapyramidal symptoms,” in addition to the 11 agents by chemical name, yielded a vast set of clinical trials, systematic reviews, case reports, and receptor-profile studies. These articles and reports were narrowed to the appended reference list, based on the report’s/trial’s contribution to the discussion of “atypicality.” Results/Conclusions: Of the 10 second-generation agents currently in use, and the one awaiting approval, only clozapine, quetiapine, and iloperidone meet the criteria necessary for the designation of “atypical” (ie, rates of EPS and TD no greater than placebo).

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A 3‐week, randomized, placebo‐controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania. After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5-20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values. Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean +/- SE changes in YMRS scores were observed on day 2 with asenapine (-3.0 +/- 0.4) and olanzapine (-3.4 +/- 0.4) versus placebo (-1.5 +/- 0.5, both p < 0.01) and were maintained until day 21 (-10.8 +/- 0.8 with asenapine, -12.6 +/- 0.8 with olanzapine; both p < or = 0.0001 versus placebo, -5.5 +/- 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures. These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.

Incidence and persistence of tardive dyskinesia and extrapyramidal symptoms in schizophrenia

Although it has been suggested that second-generation antipsychotics (SGA) may reduce the rate of prevalent tardive dyskinesia (TD), little is known about the incidence and outcome of TD in those exposed exclusively to SGA. The incidence and subsequent persistence of TD and extrapyramidal symptoms (EPS) was calculated in a cohort of patients with schizophrenia treated predominantly with SGA. This cohort of more than 10,000 patients with schizophrenia was seen six times over a period of two years. Dichotomous measures of EPS and TD were used to calculate the yearly incidence rates of TD and EPS as well as their subsequent cumulative persistence rate in a subset of 9104 and 6285 patients at risk for TD and EPS, respectively. Of 9104 individuals who did not present with TD at baseline, 138 developed TD, yielding a TD incidence rate of 0.74% (95% CI: 0.62, 0.87) and a subsequent cumulative persistence rate of 80%. Of 6285 individuals without EPS at baseline, 464 developed EPS yielding an incidence rate of 3.7% (95% CI: 3.4, 4.0) and a subsequent cumulative persistence rate of 82%. Incidence rates of TD and EPS may be low in the SGA era. However, once emerged, these disorders prove persistent, suggesting strong moderators effects of underlying predisposing factors.

Olanzapine orally disintegrating tablet vs. risperidone oral solution in the treatment of acutely agitated psychotic patients

Objective Efficacy and tolerability of risperidone oral solution (RIS-OS) and olanzapine orally disintegrating tablet (OLZ-ODT) were compared for the treatment of acute psychotic agitation. Method During a 2-month period, patients scoring ≥15 on the Excited Component for Positive and Negative Syndrome Scale (PANSS-EC) were assigned to treatment with OLZ-ODT ( n=34) or RIS-OS ( n=53) on psychiatric emergency situations, and assessed every 15 min. Results Two (OLZ-ODT and RIS-OS) by five (0-, 15-, 30-, 45- and 60-min time points) repeated-measures analysis of variance revealed only a significant main effect of time course on PANSS-EC ( F=82.2, P<.0001). No differences in the number of patients receiving additional injection due to worsening were found (OLZ-ODT, 11.8%; RIS-OS, 9.4%). No differences in rate of extrapyramidal symptoms and patient satisfaction with assigned treatment were found. However, patients in the OLZ-ODT group recovered significantly more from tachycardia than those in the RIS-OS group ( t=2.17, P=.03). Conclusion OLZ-ODT and RIS-OS treatments yielded similar improvements in acutely agitated patients who accepted oral medication. However, on one physiological parameter (i.e., tachycardia) OLZ-ODT might be superior to RIS-OS. Physiological indicators may also be useful for measuring levels of agitation.

Risperidon vs haloperidol in treatment of schizophrenia

Previous studies suggest that the serotonin-3 (5-HT3) receptor antagonist ondansetron possesses the therapeutic potential for schizophrenia. This study was designed to determine whether ondansetron as an adjunct to haloperidol could enhance the clinical efficacy and reduce the adverse side effects in chronic treatment-resistant schizophrenia.Under double-blind, randomized conditions, 121 treatment-resistant inpatients with chronic DSM-IV-diagnosed schizophrenia received haloperidol (4–30 mg/day) combined with either placebo (N = 63) or a fixed dose of 8 mg/day of ondansetron (N = 58) for 12 weeks. Efficacy was defined as the change from baseline to endpoint in score on overall scale and subscales of the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Side effects were evaluated using the Treatment Emergent Symptom Scale and Extrapyramidal Symptom Rating Scale.Ondansetron combined with haloperidol produced a significantly greater improvement on PANSS overall scale and subscales for negative symptoms, general psychopathology, and cognition at endpoint compared to placebo with haloperidol, but no between-treatment group difference was observed on the subscale for positive symptoms and CGI-S. The ondansetron-treated group had a significantly higher proportion of patients with a 30% or greater baseline-to-endpoint reduction in PANSS total score than placebo. Patients in adjunctive ondansetron therapy also experienced significantly lower incidence and severity of parkinsonism and akathisia as well as fewer behavioral hyperactivity, cardiac, and gastrointestinal side effects.Ondansetron is an effective adjunctive agent in enhancing the effectiveness and reducing some adverse side effects of antipsychotic therapy for chronic, treatment-resistant schizophrenia, particularly for negative and cognitive symptoms.

Spotlight on Quetiapine in Acute Mania and Depression Associated with Bipolar Disorder1

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.

Clinical improvement in 336 stable chronically psychotic patients changed from oral to long-acting risperidone: a 12-month open trial

Modern atypical antipsychotics have advantages over older neuroleptics. We hypothesize that their utility may be further enhanced by sustained drug delivery without daily oral self-dosing. This report examines the effects of a year of treatment with long-acting risperidone for chronically psychotic patients previously stabilized with oral risperidone. This open trial of long-acting risperidone involved 336 patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder judged clinically stable on a consistent daily oral dose of risperidone for > or =4 wk. Based on oral doses, subjects were assigned clinically to bi-weekly intramuscular injections of 25-75 mg of long-acting risperidone for up to 50 wk. Clinical assessments at regular intervals included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions (CGI) scale, adverse event reports, and the Extrapyramidal Symptom Rating Scale (ESRS). PANSS total scores improved overall from a moderate baseline score of 64.5+/-17.7 to 58.8+/-19.9 at end-point (p<0.001), by> or =20% in 50% of patients, with greatest improvement in negative symptoms. Prevalence of favourable CGI - Severity ratings increased by 2.4-fold (p<0.0001). Ratings of extrapyramidal symptoms also improved [e.g. physician-rated parkinsonism scores decreased by 20% (p<0.0001)]. Tissue reactions and other adverse effects of repeated intramuscular injections were rare and mild. Psychotic patients considered stable but symptomatic with oral risperidone treatment showed further improvements in symptom ratings and extrapyramidal dysfunction during a year of bi-weekly injections of long-acting risperidone.

Quetiapine

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.

Olanzapine vs. other antipsychotics in actual out‐patient settings: six months tolerability results from the European Schizophrenia Out‐patient Health Outcomes study

The European Schizophrenia Out-patient Health Outcomes study is an observational study investigating treatment in schizophrenia. We report treatment-emergent adverse events during the first 6 months of treatment. The rate of extrapyramidal symptoms (EPS), anticholinergic use, weight gain and sexual related dysfunctions were assessed in 8,400 out-patients. Patients typical antipsychotics and risperidone experienced significantly more EPS and anticholinergic use than patients in the clozapine, olanzapine, and quetiapine cohorts. Patients treated with amisulpride, typical antipsychotics and risperidone were significantly more likely to have sexual related dysfunctions and/or amenorrhea. Increases in weight and body mass index occurred in all cohorts, but were significantly greater in the olanzapine and clozapine cohorts. Patients treated with olanzapine, quetiapine and clozapine had better tolerability outcomes regarding EPS and sexual related dysfunctions compared with patients receiving risperidone, amisulpride and typicals. Patients treated with olanzapine and clozapine had higher weight increases than patients treated with risperidone, quetiapine and typicals.

Outcomes and Costs of Risperidone versus Olanzapine in Patients with Chronic Schizophrenia or Schizoaffective Disorders: A Markov Model

Objective To compare expected outcomes and costs of care in patients with chronic schizophrenia or schizoaffective disorders who are treated with risperidone versus olanzapine. Methods A Markov model was developed to examine outcomes and costs of care in patients with chronic schizophrenia or schizoaffective disorders receiving risperidone or olanzapine. The time frame of interest was 1 year. The model focused particular attention on the likelihood of therapy switching and discontinuation as a result of treatment-emergent side effects, as the efficacy of these two agents is similar. Measures of interest included the incidence of relapse and selected side effects including extrapyramidal symptoms (EPS), prolactin-related disorders and diabetes, expected change in body weight, and the percentage of patients remaining on initial therapy at the end of 1 year. Costs of antipsychotic therapy and psychiatric and nonpsychiatric services also were examined. Results At 1 year, the rate of EPS was estimated to be slightly higher for risperidone, as was the incidence of symptomatic prolactin-related disorders. The expected incidence of diabetes mellitus, while low, was slightly higher for olanzapine. Approximately 25% and 4% of olanzapine and risperidone patients, respectively, were projected to experience an increase in body weight ≥ 7%. The estimated percentage of patients remaining on initial therapy at the end of 1 year was higher for risperidone than olanzapine (76.9% vs. 45.6%, respectively). Expected mean total costs of care per month of therapy were $2163 for risperidone and $2316 for olanzapine. Results from sensitivity analyses suggest that the probability of therapy discontinuation following weight gain > 5 kg would have to be lower than 0.1 for the number of patients remaining on therapy at the end of 1 year to be the same for risperidone and olanzapine. Conclusions Compared with risperidone, treatment with olanzapine may result in greater increases in body weight, higher rates of therapy discontinuation, and higher costs of medical-care services.