Akathisia Among Patients Undergoing Antipsychotic Therapy: Prevalence, Associated Factors, and Psychiatric Impact.

OBJECTIVES: The prevalence of akathisia is variably reported in the literature and its psychiatric impact is little studied. The aim of this study was to establish the prevalence, the associated factors, and the psychiatric impact of akathisia among patients undergoing antipsychotic treatment. METHODS: A cross-sectional descriptive study was carried out at the Department of Psychiatry A, at Razi Hospital, in Tunis. It included patients with psychosis, undergoing antipsychotic treatment, from June 2016 to February 2017. Akathisia was diagnosed according to the Barnes Akathisia Scale. RESULTS: The prevalence of akathisia was 19.5% (n = 24, schizophrenia/schizoaffective disorder, n = 20; bipolar disorder, n = 4). The delay between the diagnosis of the disease and the onset of akathisia was 7.1 ± 8.8 years. Among the sample of patients with akathisia, 20/24 were on monotherapy of which 14 on conventional antipsychotics and six on atypical antipsychotics. Patients with akathisia were on atypical (8/24), low-potency conventional (4/24), or high-potency conventional (17/24) antipsychotics. The average dose of antipsychotics in chlorpromazine equivalent was 2294.5 ± 3037.7 mg. After adjusting for confounders, the only factor significantly positively associated with the diagnosis of akathisia was the dose of antipsychotics prescribed ( P = 0.01). The following psychiatric manifestations were reported by patients with akathisia: dysphoria/irritability (16/23), anxiety (18/24), sadness (15/24), suicidal thoughts (11/24), heteroaggressivity (8/23), sleep disturbances (16/24), and suicidal attempts (9/24). CONCLUSIONS: Despite the high psychiatric and social burden of akathisia, it remains largely underdiagnosed and undertreated, because in part of its subjective component.

Psychotropic medications induced parkinsonism and akathisia in people attending follow-up treatment at Jimma Medical Center, Psychiatry Clinic.

OBJECTIVE: To determine the magnitude and factors associated with psychotropic drug-induced parkinsonism and akathisia among mentally ill patients. METHODS: A hospital-based cross-sectional study was conducted with a total of 410 participants attending a follow-up treatment service at Jimma Medical Center, a psychiatry clinic from April to June 2019. Participants were recruited using a systematic random sampling method. Drug-induced parkinsonism and akathisia were assessed using the Extra-pyramidal Symptom Rating Scale. Substance use was assessed using the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test. Data entry was done using EpiData version 3.1, and analysis done by the Statistical Package for Social Sciences version 22. Statistically, the significant association was declared by adjusted odds ratio, 95% confidence interval, and p-value less than or equal to 0.05. RESULTS: The mean age of the respondents was 33.3 years (SD ± 8.55). Most of the participants 223 (54.4%) had a diagnosis of schizophrenia. The prevalence of drug-induced parkinsonism was 14.4% (95% CI: 11.0 to 18.0) and it was 12.4% (95% CI: 9.3 to 15.4) for drug-induced akathisia. The result of the final model found out drug-induced parkinsonism was significantly associated with female sex, age, type of antipsychotics, physical illness, and anti-cholinergic medication use. Similarly, female sex, chlorpromazine equivalent doses of 200 to 600 mg, combined treatment of sodium valproate with antipsychotic, and severe khat/Catha edulis use risk level was significantly associated with akathisia. CONCLUSION: One of seven patients developed drug-induced parkinsonism and akathisia. Careful patient assessment for drug-induced movement disorders, selection of drugs with minimal side effects, screening patients for physical illness, and psycho-education on substance use should be given top priority.

Medication-Induced Akathisia with Newly Approved Antipsychotics in Patients with a Severe Mental Illness: A Systematic Review and Meta-Analysis.

BACKGROUND: Akathisia is a common and distressing movement disorder that can be associated with the use of antipsychotics. It is characterized by a subjective (inner restlessness) and an objective (excessive movements) component. Akathisia can have a negative impact on clinical outcome and even lead to treatment discontinuation. Although medication-induced akathisia is more commonly associated with the use of first-generation antipsychotics (FGAs), it also occurs with second-generation antipsychotics (SGAs), including the newly approved antipsychotics (NAPs) asenapine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Until now, no meta-analysis has been published on the risk of akathisia for all NAPs, as monotherapy or adjunctive treatment, in patients with a severe mental illness. OBJECTIVE: The primary objectives of this systematic review and meta-analysis were to (i) compare akathisia incidence rates of the NAPs, as monotherapy or adjunctive treatment, in adult patients with a severe mental illness (i.e., schizophrenia, bipolar disorder, or major depressive disorder), using data from published and unpublished randomized controlled trials; and (ii) examine the role of several study characteristics explaining differences in akathisia incidence rates between studies. METHODS: A systematic literature search, using the PubMed, EMBASE, and Cochrane Library databases (until October 2018), was conducted for English-language placebo- as well as active-controlled clinical trials, including subjective (percentage of patients reporting akathisia) and/or scale-defined medication-induced akathisia incidence rates with NAPs (as monotherapy or as adjunctive treatment) in adult patients with schizophrenia, bipolar disorder, or major depressive disorder. Additional unpublished clinical trials were identified through the ClinicalTrials.gov electronic database. Two meta-analyses (incidence rates and odds ratio [OR] [placebo vs. active] of medication-induced akathisia with NAPs) were performed to obtain an optimal estimation of akathisia risks of adult patients with a severe mental illness under these treatment conditions and to assess the role of study characteristics. RESULTS: Two hundred and thirteen reports were selected as potentially eligible for our meta-analysis. Of these, 48 met the inclusion criteria. Eight records, identified through the ClinicalTrials.gov database and cross-referencing, and which fulfilled the inclusion criteria, were added, resulting in a total of 56 records (iloperidone = 5, asenapine = 11, lurasidone = 15, brexpiprazole = 13, cariprazine = 12). The estimated weighted mean incidence rate of akathisia was 7.7% (95% confidence interval [CI] 6.5-9.1), with estimates being 3.9% (95% CI 2.4-6.3) for iloperidone, 6.8% (95% CI 5.1-9.0) for asenapine, 10.0% (95% CI 7.4-13.5) for brexpiprazole, 12.7% (95% CI 10.1-16.1) for lurasidone, and 17.2% (95% CI 13.4-22.1) for cariprazine. After Tukey-adjustment for multiple testing, the incidence rate of akathisia was significantly (p < 0.05) lower for iloperidone than for brexpiprazole, lurasidone, and cariprazine. In addition, the incidence rate of akathisia was significantly (p < 0.05) lower for asenapine than for lurasidone and cariprazine. Finally, the incidence rate of akathisia was significantly (p < 0.05) lower for brexpiprazole than for cariprazine. Type of medication (p < 0.0001), diagnosis (p = 0.02), and race (p = 0.0003) significantly explained part of the heterogeneity of the incidence estimates of akathisia between studies. The estimated weighted OR of akathisia under medication, compared with placebo, was 2.43 (95% CI 1.91-3.10). The OR was smallest for iloperidone (OR 1.20; 95% CI 0.42-3.45) and increased for brexpiprazole (OR 2.04; 95% CI 1.09-3.83), asenapine (OR 2.37; 95% CI 1.32-4.27), lurasidone (OR 3.74; 95% CI 2.32-6.02), and cariprazine (OR 4.35; 95% CI 2.80-6.75). Only type of medication (p = 0.03) explained systematic differences in the OR for akathisia between placebo versus active treatment across studies. After Tukey-adjustment for multiple testing, no significant differences between these ORs were found. The severity of akathisia with NAPs generally is mild to moderate, only leading to treatment discontinuation in a minority of cases (< 5%). CONCLUSIONS: The use of a NAP raises the akathisia risk more than two-fold when compared with patients receiving placebo. Although distinctions between the different NAPs were not clear in placebo-controlled trials, the results of our meta-analyses and systematic review generally indicate that these differences more than likely reflect real differences, with iloperidone showing the most and cariprazine showing the least benign akathisia profile. Moreover, due to patient characteristics and methodological issues, incidence rates of akathisia with NAPs found in this meta-analysis may even be an underestimation of true incidence rates.

Switching to paliperidone extended release in patients with schizophrenia dissatisfied with previous olanzapine treatment: Post hoc analysis of an open-label, prospective study.

OBJECTIVE: This post hoc analysis of an open-label, single-arm, multicenter study was designed to assess the efficacy, safety, and tolerability of paliperidone extended release (ER) in Chinese patients with non-acute schizophrenia, after switching from olanzapine. METHODS: Patients with schizophrenia who were dissatisfied with prior olanzapine treatment switched to flexible paliperidone ER (3-12 mg/day) based on clinical judgment. Change from baseline to week 12 in Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint), PANSS subscale scores, response rate, Clinical Global Impression-Severity (CGI-S) score, personal and social performance (PSP) scores, patient satisfaction with treatment score, change in sleep quality, level of daytime sleepiness and safety were evaluated. RESULTS: Out of 118 enrolled patients, 95 (81%) completed the study. Mean duration of study was 76.9 (23.85) days. The primary endpoint, mean (SD) PANSS total score changed significantly from baseline to endpoint (-19.6 [18.71], P <.0001). Secondary endpoints including PANSS subscale score, PSP, patient satisfaction and daytime drowsiness also significantly improved (P <.001). Most commonly reported (≥1%) treatment-emergent adverse events were akathisia (n = 14 [12%]) and insomnia (n = 9 [8%]). CONCLUSIONS: Switching to flexible-dosed paliperidone ER in patients dissatisfied with prior olanzapine treatment achieved good efficacy and tolerability consistently over 12 weeks.

Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study.

RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naïve cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear. OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES). METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia. RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027). CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole.

Novel Adverse Events of Iloperidone: A Disproportionality Analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

BACKGROUND: The signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously". OBJECTIVE: To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). METHODOLOGY: The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal. RESULTS: The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold. CONCLUSION: Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.

Current Evidence-Based Practice for Pediatric Emergence Agitation.

This article provides a systematic review of pediatric emergence agitation, also known as emergence delirium. Major topics of this review include the incidence, risk factors, and impact of the phenomenon, in addition to current evidence-based strategies for prevention of pediatric emergence agitation. Emergence agitation causes tremendous psychological distress for the patient, family, and healthcare providers, as well as concerns for physical safety. Risk factors for pediatric emergence agitation are the child's age, genetic profile, length and type of surgical procedure, and use of inhalational anesthesia. In an attempt to prevent this problem, anesthesia providers should consider these factors and possible interventions when implementing an anesthetic plan. Evidence-based interventions that may decrease the incidence of pediatric emergence agitation include technology, familial involvement, pharmacologic adjuncts, and alternative methods of general anesthesia.

Fluphenazine (oral) versus placebo for schizophrenia.

BACKGROUND: Fluphenazine is one of the first drugs to be classed as an 'antipsychotic' and has been widely available for five decades. OBJECTIVES: To compare the effects of oral fluphenazine with placebo for the treatment of schizophrenia. To evaluate any available economic studies and value outcome data. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (23 July 2013, 23 December 2014, 9 November 2016 and 28 December 2017 ) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There is no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We sought all randomised controlled trials comparing oral fluphenazine with placebo relevant to people with schizophrenia. Primary outcomes of interest were global state and adverse effects. DATA COLLECTION AND ANALYSIS: For the effects of interventions, a review team inspected citations and abstracts independently, ordered papers and re-inspected and quality assessed trials. We extracted data independently. Dichotomous data were analysed using fixed-effect risk ratio (RR) and the 95% confidence interval (CI). Continuous data were excluded if more than 50% of people were lost to follow-up, but, where possible, mean differences (MD) were calculated. Economic studies were searched and reliably selected by an economic review team to provide an economic summary of available data. Where no relevant economic studies were eligible for inclusion, the economic review team valued the already-included effectiveness outcome data to provide a rudimentary economic summary. MAIN RESULTS: From over 1200 electronic records of 415 studies identified by our initial search and this updated search, we excluded 48 potentially relevant studies and included seven trials published between 1964 and 1999 that randomised 439 (mostly adult participants). No new included trials were identified for this review update. Compared with placebo, global state outcomes of 'not improved or worsened' were not significantly different in the medium term in one small study (n = 50, 1 RCT, RR 1.12 CI 0.79 to 1.58, very low quality of evidence). The risk of relapse in the long term was greater in two small studies in people receiving placebo (n = 86, 2 RCTs, RR 0.39 CI 0.05 to 3.31, very low quality of evidence), however with high degree of heterogeneity in the results. Only one person allocated fluphenazine was reported in the same small study to have died on long-term follow-up (n = 50, 1 RCT, RR 2.38 CI 0.10 to 55.72, low quality of evidence). Short-term extrapyramidal adverse effects were significantly more frequent with fluphenazine compared to placebo in two other studies for the outcomes of akathisia (n = 227, 2 RCTs, RR 3.43 CI 1.23 to 9.56, moderate quality of evidence) and rigidity (n = 227, 2 RCTs, RR 3.54 CI 1.76 to 7.14, moderate quality of evidence). For economic outcomes, we valued outcomes for relapse and presented them in additional tables. AUTHORS' CONCLUSIONS: The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. Fluphenazine's global position as an effective treatment for psychoses is not threatened by the outcome of this review. However, fluphenazine is an imperfect treatment and if accessible, other inexpensive drugs less associated with adverse effects may be an equally effective choice for people with schizophrenia.

Incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery: A multicentre controlled randomised trial.

BACKGROUND: Akathisia, a distressing movement disorder induced by butyrophenones, has been described with low doses of droperidol used for postoperative nausea and vomiting (PONV) prophylaxis, but the incidence remains unclear. OBJECTIVES: To determine the incidence of akathisia after PONV prophylaxis with two doses of droperidol in comparison with ondansetron, in patients undergoing ambulatory surgery. We hypothesised that the incidence of akathisia is higher with droperidol than that with ondansetron. DESIGN: Randomised controlled double blind trial. SETTING: Two University Hospital Centres and two private Clinics from January to September 2014. PATIENTS: Patients (n=297) undergoing general anaesthesia for ambulatory surgery were randomly allocated to receive PONV prophylaxis with droperidol (0.625 or 1.25 mg) or ondansetron 4 mg; patients of the three groups also received 4 mg of dexamethasone. Exclusion criteria were contraindication to droperidol and ondansetron, use of psychotropic medications or benzodiazepines or history of psychotic illness. INTERVENTIONS: Participants received droperidol (0.625 or 1.25 mg) or ondansetron 4 mg during general anaesthesia. After discharge from the postanaesthesia care unit presence and severity of akathisia were assessed using the Barnes Akathisia Rating Scale at 4 h postoperatively. MAIN OUTCOME MEASURES: Score of the Global Clinical Assessment of Akathisia of Barnes Akathisia Rating Scale. RESULTS: The number of akathisia observed was 1/118 (0.8%) in the ondansetron group, 1/84 (1.2%) in droperidol 0.625 mg group, and 3/87 (3.4%) in droperidol 1.25 mg group. The akathisia rate difference among the three groups was not significant (P = 0.52). We could not demonstrate significant differences in the incidence of akathisia between the two doses of droperidol. The only case of marked akathisia treated with benzodiazepines was observed after droperidol 1.25 mg. CONCLUSION: The use of droperidol or ondansetron for PONV prophylaxis is associated to a low incidence of akathisia (0.8 to 3.4%) after general anaesthesia for ambulatory surgery. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01942343.

Incidence of antiemetic-induced akathisia in patients at a comprehensive cancer center.

INTRODUCTION: Akathisia is a common and severely disabling medication-induced movement disorder. The condition is often missed, and patients suffer for a long time until diagnosed and managed properly. It is important to bring awareness to the clinicians for early detection and management of akathisia. METHODS: We reviewed a 4-year record of patients seen at a comprehensive cancer center for anxiety and restlessness. Patients diagnosed with akathisia and the medications causing akathisia were identified. Management of akathisia is discussed. RESULTS: The results showed that 4.7% of patients developed akathisia while taking antiemetic agents to control chemotherapy-induced nausea/vomiting. Early detection and management of akathisia resulted in quick recovery and reduced patients' suffering. CONCLUSION: Akathisia is an unpleasant feeling of motor restlessness with anxiety. Clinicians need to have a full understanding to identify the subtle difference between functional anxiety and akathisia.

Efficacy and safety of aripiprazole lauroxil once-monthly versus aripiprazole once-monthly long-acting injectable formulations in patients with acute symptoms of schizophrenia: an indirect comparison of two double-blind placebo-controlled studies.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for the treatment of schizophrenia. OBJECTIVE: To indirectly compare the safety and efficacy of AL and aripiprazole once-monthly (AOM). METHODS: A systematic search was performed to identify randomized, controlled trials of AOM and AL that met criteria for indirect comparison according to Bayesian network meta-analysis. The analysis indirectly compared AL and AOM treatment groups for efficacy by mean change in Positive and Negative Syndrome Scale (PANSS) total score and ≥30% reduction in PANSS total score, as well as tolerability including adverse events, akathisia, and weight gain. RESULTS: Two studies were selected, resulting in three active-treatment groups: AL 441 mg, AL 882 mg, and AOM 400 mg. All active treatments were efficacious compared with placebo. There were no differences in indirect comparisons of akathisia. All three groups showed some weight gain, but only the AOM 400 mg group was significantly greater than placebo. CONCLUSIONS: Results of this indirect comparison found that both doses of AL and the single AOM dose were therapeutic and efficacious for the treatment of schizophrenia with a similar safety profile.

Prevalence and pattern of antipsychotic induced movement disorders in a tertiary care teaching hospital in India - a cross-sectional study.

OBJECTIVES: To assess prevalence and pattern of movement disorders among patients taking antipsychotic medications. METHODS: This cross-sectional, intensive monitoring (patient interview, case record form review and clinical examination) study was conducted in patients taking antipsychotic drugs irrespective of duration for the development of movement disorders. The psychiatrist used Modified Simpson-Angus Scale score (10-item scale), Barnes' rating scale and Abnormal Involuntary Movement Scale to diagnose parkinsonism, akathisia and tardive dyskinesia, respectively. We assessed movement disorders for the preventability and seriousness. RESULTS: The overall prevalence of antipsychotic induced movement disorders was 5.67% (95% CI: 4.19-7.62). The prevalence of parkinsonism, akathisia and tardive dyskinesia was 5.10% (95% CI: 3.71-6.98), 0.85% (95% CI: 0.39-1.84) and 0.57% (95% CI: 0.22-1.45), respectively. There was a trend of high proportions of movement disorders in extreme of age group, female gender, patients treated with conventional antipsychotics, on poly therapy, patients of epilepsy with psychosis, schizophrenia and bipolar mood disorder. The movement disorder was lowest with quetiapine (2.02%). CONCLUSIONS: The higher use of atypical antipsychotics had reduced the occurrence of movement disorders in our setup.

[Drug-Induced Akathisia].

Akathisia consists of subjective inner restlessness, such as awareness of the inability to remain seated, restless legs, fidgetiness, and the desire to move constantly, and of objective increased motor phenomena, such as body rocking, shifting from foot to foot, stamping in place, crossing and uncrossing legs, pacing around. Although the broad definition of akathisia includes the inner and motor restlessness observed in patients with idiopathic Parkinson's disease, post-encephalitic parkinsonism, and restless legs syndrome, here we exclusively focus on the narrow definition of antipsychotic-induced akathisia. The most reliable treatment for acute akathisia is the reduction or the withdrawal of antipsychotic medication. However, this is often not possible because it may worsen the patients' mental condition. Various pharmacological agents have been used for the treatment of this condition. These include anticholinergic agents (e.g., biperiden and trihexyphenidyl), benzodiazepines, beta-adrenoceptor blockers (e.g., propranolol), and serotonin 2A receptor antagonists (e.g., mianserin, cyproheptadine, and mirtazapine).

Antidepressant-related jitteriness syndrome in anxiety and depressive disorders: Incidence and risk factors.

INTRODUCTION: Jitteriness syndrome (JS) is a poorly understood but important adverse effect of antidepressant drugs. This study examined the incidence and pattern of antidepressant-related JS and its predictors. METHODS: 209 patients diagnosed with any anxiety or depressive disorder and started on mirtazapine, sertraline, desvenlafaxine, escitalopram or fluoxetine were assessed at baseline, after 2 weeks, and after 6 weeks with psychopathology rating scales and for predefined categories of JS. RESULTS: The incidence of JS during the 6-week study was 27.7%, but only 6.7% in first 2 weeks. JS rates were similar in anxiety and depressive disorders. Mirtazapine was associated with the lowest rate of 14.3%, and other antidepressants with rates of 23-34%. High dose antidepressant treatment was significantly associated with JS (OR, 2.68; 95% CI, 1.37-5.25). No other variable predicted JS. JS was associated with significantly higher objective ratings of psychopathology. DISCUSSION: We conclude that up to a quarter of patients may suffer JS during the first 6 weeks of antidepressant initiation; higher antidepressant dose is a risk factor.

Chlorpromazine versus penfluridol for schizophrenia.

BACKGROUND: The efficacy of chlorpromazine, a benchmark antipsychotic, has not been fully assessed in direct comparison with different individual antipsychotics. Penfluridol is another old antipsychotic with a long half-life so one oral dose may last up to one week. This could confer advantage. OBJECTIVES: To assess the clinical effects of chlorpromazine compared with penfluridol for adults with schizophrenia. SEARCH METHODS: On 31 March 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised clinical trials focusing on chlorpromazine versus penfluridol for adults with schizophrenia or related disorders. Outcomes of interest were death, service utilisation, global state, mental state, adverse effects and leaving the study early. We included trials meeting our selection criteria and reporting useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we planned to estimate the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The review includes three studies with a total of 130 participants. Short-term results for hospital admissions showed no clear difference between chlorpromazine and penfluridol (1 RCT, n = 29, RR 0.19, 95% CI 0.01 to 3.60, low-quality evidence). No clear difference in the incidence of akathisia was found at medium term (2 RCTs, n = 85, RR 0.19, 95% CI 0.04 to 1.06, low-quality evidence), and similar numbers of participants - nearly half - from each treatment group left the study early (3 RCTs, n = 130, RR 1.21, 95% CI 0.83 to 1.77, low-quality evidence). The risk of needing additional antiparkinsonian medication was less in the chlorpromazine group (2 RCTs, n = 74, RR 0.70, 95% CI 0.51 to 0.95). No useable data reported clinically important change in global or mental state. No data were reported for relapse. No deaths were reported by the trials. AUTHORS' CONCLUSIONS: Only three small studies provided data and the quality of reporting and evidence is low. Limited data indicate the efficacy and adverse effects profiles of chlorpromazine and penfluridol are generally similar. Penfluridol, however, may confer advantage by needing to be given only once per week. Firm conclusions are not possible without good-quality trials, and where these treatments are used, such trials are justified.

The Yusuf-Peto method was not a robust method for meta-analyses of rare events data from antidepressant trials.

OBJECTIVES: The aim of the study was to identify the validity of effect estimates for serious rare adverse events in clinical study reports of antidepressants trials, across different meta-analysis methods. STUDY DESIGN AND SETTING: Four serious rare adverse events (all-cause mortality, suicidality, aggressive behavior, and akathisia) were meta-analyzed using different methods. The Yusuf-Peto odds ratio ignores studies with no events and was compared with the alternative approaches of generalized linear mixed models (GLMMs), conditional logistic regression, a Bayesian approach using Markov Chain Monte Carlo (MCMC), and a beta-binomial regression model. RESULTS: The estimates for the four outcomes did not change substantially across the different methods; the Yusuf-Peto method underestimated the treatment harm and overestimated its precision, especially when the estimated odds ratio deviated greatly from 1. For example, the odds ratio for suicidality for children and adolescents was 2.39 (95% confidence interval = 1.32-4.33), using the Yusuf-Peto method but increased to 2.64 (1.33-5.26) using conditional logistic regression, to 2.69 (1.19-6.09) using beta-binomial, to 2.73 (1.37-5.42) using the GLMM, and finally to 2.87 (1.42-5.98) using the MCMC approach. CONCLUSION: The method used for meta-analysis of rare events data influences the estimates obtained, and the exclusion of double-zero event studies can give misleading results. To ensure reduction of bias and erroneous inferences, sensitivity analyses should be performed using different methods instead of the Yusuf-Peto approach, in particular the beta-binomial method, which was shown to be superior through a simulation study.

Efficacy and Tolerability of Asenapine Compared with Olanzapine in Borderline Personality Disorder: An Open-Label Randomized Controlled Trial.

BACKGROUND: Asenapine is a new second-generation antipsychotic that is understudied in borderline personality disorder (BPD). Only one study investigating the use of the drug in this indication (an open-label pilot study) has been conducted to date. OBJECTIVE: The present open-label, randomized, controlled trial aimed to evaluate the efficacy and tolerability of asenapine in comparison with olanzapine, the most broadly studied antipsychotic in BPD. METHODS: A total of 51 outpatients aged between 18 and 50 years with a diagnosis of BPD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were assigned for 12 weeks to asenapine (5-10 mg/day) or olanzapine (5-10 mg/day). Participants were assessed at baseline and after 12 weeks with the following instruments: the Clinical Global Impression Scale, Severity item (CGI-S), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Social Occupational Functioning Assessment Scale (SOFAS), Borderline Personality Disorder Severity Index (BPDSI), Barratt Impulsiveness Scale, version 11 (BIS-11), Modified Overt Aggression Scale (MOAS), Self-Harm Inventory (SHI), and Dosage Record and Treatment Emergent Symptom Scale (DOTES). Analysis of variance repeated measures was performed. Intention-to-treat analysis with last observation carried forward was conducted. RESULTS: There were 11 drop-outs (21.57%): six patients taking asenapine and five patients receiving olanzapine. Two patients who received asenapine stopped the drug, one due to oral hypoesthesia and the other due to moderate anxiety. Two patients receiving olanzapine discontinued the treatment because of significant weight gain (≥3 kg). The remaining seven drop-outs resulted from the lack of compliance with the trial prescription. Forty out of the 51 patients (78%) completed the trial: 19 patients received asenapine, while 21 patients received olanzapine. We found a significant within-subject effect (trial duration) for all rating scales, except from the HAM-D, the MOAS, and two items of the BPDSI, namely, "identity disturbance" and "parasuicidal behaviors." A significant effect between subjects was found for the two items of the BPDSI "affective instability" and "dissociation/paranoid ideation." Asenapine was found superior to olanzapine in reducing the affective instability score (P = 0.001), whereas olanzapine was found superior to asenapine in reducing dissociation/paranoid ideation (P = 0.012). However, the study was found to be underpowered to detect a difference between the drugs on the dissociation/paranoid ideation item of the BPDSI. Two patients receiving asenapine experienced akathisia and another two restlessness/anxiety, while three patients receiving olanzapine reported somnolence and two fatigue. CONCLUSIONS: Asenapine and olanzapine were demonstrated to have a similar efficacy. While asenapine was found to be more efficacious than olanzapine in treating affective instability, olanzapine was superior to asenapine in treating paranoid ideation and dissociation. However, the study was underpowered to detect a difference between groups on the dissociation/paranoid ideation item. Both medications were well tolerated, with asenapine being related to a higher frequency of oral hypoesthesia and akathisia, and olanzapine being prone to induce weight gain. The open-label study design, lack of a placebo group, and small sample size constitute major limitations of this trial. Our findings need to be replicated in further studies. Clinical Trials Registry code: ACTRN12614000551695.

Physical Health Outcomes in Preschoolers with Prior Authorization for Antipsychotics.

OBJECTIVE: To examine incidence of adverse health outcomes and associated factors among preschoolers (under age 6) who received antipsychotic treatment through the Florida Medicaid Prior Authorization (PA) program. METHODS: Using Florida's PA registry linked to the state's Medicaid claims data, we ascertained incident outcomes during PA-approved antipsychotic use between April 2008 and September 2015 (7.5 years). Six outcomes associated with use of antipsychotics included: diabetes, obesity, hyperlipidemia, hyperprolactinemia, cardiovascular disease (CVD) (including hypertension, ventricular arrhythmia, and other CVDs), and extrapyramidal symptoms (EPS) (including dystonia, akathisia, parkinsonism, and tardive dyskinesia). Outcome-specific incidences were stratified by short-term (≤1 year) and long-term (>1-7 years) antipsychotic use. We used multivariate modified Poisson regressions to determine factors associated with these outcomes among preschoolers. RESULTS: The overall crude incidence during PA-approved antipsychotic use was highest for EPS and obesity (57 and 19 cases/1000 children-years, respectively). The rate of these two outcomes differed by duration of antipsychotic use. We observed a higher obesity (23.8 vs. 9.6, p < 0.001) and dystonia incidence (7.2 vs. 2.5, p < 0.05), but lower akathisia incidence (44.4 vs. 60.6, p < 0.05) among long-term antipsychotic users compared with short-term users. Five outcomes-ventricular arrhythmia, other cardiovascular side effects, hyperprolactinemia, parkinsonism, and tardive dyskinesia-occurred rarely (<2.0/1000 children-years). Preschoolers who were younger at baseline (≤2 years old vs. 4-5 years old) and Black (vs. White) were at a higher risk of EPS. CONCLUSION: Risk for EPS and obesity deserves clinical attention during antipsychotic treatment among preschoolers. Controlled studies that allow interpretation of these incidence rates in the context of background risk and that formally quantify the incremental risk associated with antipsychotic initiation during early childhood are needed.

Incidence and risk factors of acute akathisia in 493 individuals with first episode non-affective psychosis: a 6-week randomised study of antipsychotic treatment.

INTRODUCTION: Acute akathisia is a neuropsychiatric syndrome with a negative effect on illness outcome. Its incidence in patients treated with antipsychotics has shown to be highly variable across studies. OBJECTIVES: Our goals were to investigate prevalence, risk factors for the development of acute akathisia, and differences in incidence between antipsychotics in a sample of 493 first episode non-affective psychosis patients. METHODS: This is a pooled analysis of three prospective, randomized, flexible-dose, and open-label clinical trials. Patients were randomized assigned to different arms of treatment (haloperidol, quetiapine, olanzapine, ziprasidone, risperidone, or aripiprazole). Akathisia was determined using the Barnes Akathisia Scale at 6 weeks after antipsychotic initialization. Univariate analyses were performed to identify demographic, biochemical, substance use, clinical, and treatment-related predictors of acute akathisia. Considering these results, a predictive model based of a subsample of 132 patients was constructed with akathisia as the dependent variable. RESULTS: The overall incidence of akathisia was 19.5%. No differences in demographic, biochemical, substance use, and clinical variables were found. Significant incidence differences between antipsychotics were observed (Χ 2 = 68.21, p = 0.000): haloperidol (57%), risperidone (20%), aripiprazole (18.2%), ziprasidone (17.2%), olanzapine (3.6%), and quetiapine (3.5%). The predictive model showed that the type of antipsychotic (OR = 21.3, p = 0.000), need for hospitalization (OR = 2.6, p = 0.05), and BPRS total score at baseline (OR = 1.05, p = 0.03) may help to predict akathisia emergence. CONCLUSIONS: Among second generation antipsychotics, only olanzapine and quetiapine should be considered as akathisia-sparing drugs. The type of antipsychotic, having been hospitalized, and a more severe symptomatology at intake seem to predict the development of acute akathisia.

High Incidence and Prevalence of Drug-Related Movement Disorders in Young Patients With Psychotic Disorders.

BACKGROUND: Drug-related movement disorders (DRMDs) reduce quality of life and contribute to medication noncompliance of patients with psychotic disorders. Little is known about the epidemiology of DRMDs in relatively young patients a few years after onset of psychosis. This is an important period to study, as the impact of the antipsychotic treatment on the long-term potentiation of the neural pathways associated with psychotic disorders and DRMDs is still minimal. This study investigated the prevalence, incidence, persistence, and clinical correlates of DRMDs in patients during their first years after disease onset. METHODS: The Genetic Risk and Outcome of Psychosis study is a longitudinal study of 1120 relatively young patients with nonaffective psychosis and a mean age and illness duration of 27 and 4 years, respectively. The following drug-related movement disorders were assessed at baseline and at the 3-year follow-up: parkinsonism, akathisia, tardive dyskinesia, and tardive dystonia. We determined prevalence, incidence, and persistence and investigated clinical correlates at and over the baseline and follow-up assessment. RESULTS: Patients' mean age and illness duration at baseline were 27.1 and 4.3 years, respectively. In 4 patients, 1 developed a DRMD over the 3-year study period. Prevalence, incidence, and persistence rates were highest for parkinsonism (32%, 21%, and 53%) followed by akathisia (9%, 5%, and 17%) and tardive dyskinesia (4%, 3%, and 20%). Significant associations were found between DRMDs and the patients' age, IQ, and psychopathology. CONCLUSIONS: The prevalence, persistence, and incidence of DRMDs in this sample were high despite the relatively young age, recent onset of the disorder, and treatment primarily with second-generation antipsychotics. These findings emphasize that screening, diagnosis, and treatment of DRMDs are still important.