A descriptive analysis of spontaneous reports of antipsychotic-induced tardive dyskinesia and other extrapyramidal symptoms in the Japanese Adverse Drug Event Report database.

AimThe aim of this study is to summarize the spontaneous reports of tardive dyskinesia (TD) and extrapyramidal symptoms (EPSs) that occurred in Japan over the past decade. MethodsThe study analyzed TD and EPS cases reported in the Japanese Adverse Drug Event Report database between April 2011 and March 2021. The cases were stratified by the diagnoses of schizophrenia, bipolar disorders, and depressive disorders. ResultsIn total, 800 patients including a total of 171 TD cases and 682 EPS cases were reported in the JADER database across psychiatric diagnosis. The cases were caused by first-generation antipsychotics (FGA, TD: n = 105, EPS: n = 245) and second-generation antipsychotics (SGA, TD: n = 144, EPS: n = 598). The SGA were categorized based on Neuroscience-based Nomenclature (NbN) regarding pharmacological domain and mode of action, which were reported evenly as the offending agents. Among reported treatment and outcome in TD cases (n = 67, 37.6%) and EPS cases (n = 405, 59.3%), the relatively limited number of TD cases were reported as recovered/improved was also limited (n = 32, 47.8%) compared to those of EPS cases (n = 266, 65.7%). Some cases still had residual symptoms or did not recover fully (TD: n = 21, 31.3%, EPS: n = 77, 19.0%). CONCLUSION: Tardive dyskinesia and EPS have been widely reported in Japan over the past decade across psychiatric diagnoses and antipsychotic classes. LIMITATIONS: It is important to acknowledge the presence of reporting bias and the lack of comparators to accurately assess risks. Owing to the nature of spontaneous reporting, the estimation of prevalence is not feasible.

Clinical benefit of second-generation long-acting injectable antipsychotics in preventing re-hospitalization in patients with schizophrenia: A real-world study in Japan.

BACKGROUND: Real-world evidence on the benefits of long-acting injectable (LAI) antipsychotics (AP) in patients with schizophrenia is limited, especially in the employed population in Japan. This study evaluates the effectiveness of LAI AP in preventing re-hospitalization in patients with schizophrenia, including the employed population. METHODS: This retrospective, observational, population-based study used the Japan Medical Data Center (JMDC) health insurance claims database to identify patients having schizophrenia before or on the day of the first LAI AP prescription (index date), and receiving LAI AP between April 1, 2012 and December 31, 2019. The number of all-cause, psychiatric-, and schizophrenia-related hospitalizations at baseline (365 days before index date) and during the 1-year follow-up period were evaluated. RESULTS: Of the 1692 patients who received LAI AP during the study period, 146 were included (employed: 55 [37.7 %]; dependent: 91 [62.3 %]). The mean age was 37 years; 50.7 % (n = 74) were females. During baseline period, 61 (41.8 %) patients were not hospitalized. During the follow-up period, 67 (45.9 %) patients underwent hospitalization ≤ 7 days; all-cause: 100 (68.7 %); psychiatry-related: 104 (76.2 %); schizophrenia-related: 114 (78.1 %). A higher proportion of patients were hospitalization-free during the follow-up in the employed vs. dependent population: all cause: 69.1 % vs. 61.5 %; psychiatric-related 76.4 % vs. 67.0 %, schizophrenia-related: 87.3 % vs. 71.4 %. CONCLUSION: This study demonstrated the effectiveness of LAI AP in preventing hospitalization in Japan. During the follow-up period, patients with schizophrenia receiving LAI AP, including the employed population, had a significant decrease in hospitalization length and re-hospitalization rate compared to baseline.

Different symptomatic improvement pattern revealed by factor analysis between placebo response and response to Esketamine in treatment resistant depression.

AIMS: The aim of this study is to determine whether there is difference in the change in each symptom of depression and in symptomatic improvement pattern between placebo and antidepressant responses. METHODS: Using data from a randomized, double-blind (DB), placebo-controlled trial of esketamine (ESK) in patients with treatment-resistant depression (TRD), we conducted exploratory analyses. To determine differences in the change in each depressive symptom on the MADRS subscale between placebo and antidepressant responses, a two-way factorial analysis was conducted using the amount of change on Day 2 and 28 of treatment. In addition, exploratory and confirmatory factor analyses were conducted on the MADRS subtotal variables on Day 2 and 28 of treatment to determine symptomatic improvement pattern between placebo response and antidepressant responses. RESULTS: We found that as well as MADRS total score, each subscale of MADRS score did not significantly differ between esketamine and placebo at Day 2 and 28. On the other hand, factor analysis revealed that the factor structure of the response was different between esketamine and placebo at the 2nd day. There was no difference in the factor structure between esketamine and placebo in response on Day 28 of treatment. CONCLUSION: Factor analysis revealed different patterns of symptom improvement in the early phase of the intervention between esketamine and placebo. This finding suggests that a data driven approach may provide detailed efficacy information in clinical trials for antidepressants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02918318. Registered: 28 September 2016.

Early Improvement of Psychiatric Symptoms with Long-Acting Injectable Antipsychotic Predicts Subsequent Social Functional Remission in Patients with Schizophrenia.

PURPOSE: The aim of this study was to clarify whether early symptomatic improvement in response to a long-acting injectable antipsychotic (LAI) contributes to subsequent social functional remission in patients with schizophrenia using the previous clinical trial data (EudraCT registration number: 2011-004889-15). Associations between other factors and social functional remission were also explored. PATIENTS AND METHODS: We analyzed 428 patients with schizophrenia in which the personal and social performance scale (PSP) and the involvement evaluation questionnaire (IEQ) at the time of the base line were recorded. Social functional remission was defined as participants who scored PSP >70 at the end of 65 weeks. Logistic regression analyses were done to examine associations between social functional remission and clinical and demographic characteristics including early symptomatic response evaluated by Positive and Negative Syndrome Scale (PANSS) at week one. RESULTS: One hundred out of 428 patients showed social functional remission at the end of the observation period. Shorter duration of illness, higher baseline score of supervision evaluated by IEQ and higher baseline PSP were significantly associated with the social functional remission. Improvement of positive subscale of PANSS at one week was significantly associated with later social functional remission when baseline PSP scores were excluded from predictive variables. CONCLUSION: Shorter duration of illness, residual type of schizophrenia, higher baseline score of supervision and higher baseline social functioning were predictors of subsequent social functional remission. Although its effect seems to be limited, early symptomatic improvement could be also was a predictor of social functional remission.

The Effects of Paliperidone Palmitate 1 Month on the Employment Status and Social Functioning of Patients with Schizophrenia.

Objective: We sought to evaluate the effects of a one-month paliperidone palmitate formulation (PP1M) on employment status, social function, symptomatology, and safety and conducted a two-year postmarketing surveillance study of Paliperidone Palmitate 1 Month (PP1M). Methods: Patients diagnosed with schizophrenia participated in the study. Employment status was recorded at baseline and changes were measured at one and two years. Social functioning and symptomatology were assessed using the Social and Occupational Functioning Assessment Scale (SOFAS) and the Clinical Global Impression-Schizophrenia (CGI-SCH). Data on adverse events were also collected. Results: A total of 1,319 patients were enrolled in this investigation, including 1,306 who were evaluable for safety and 1,279 who were evaluable for efficacy. The maintenance rate during the observation period was 49.4 percent. During the observation period, the percentages of patients reporting employment significantly increased: 24.3 percent of patients were employed in some capacity at baseline, 32.5 percent of patients were employed at one year, and 34.6 percent of patients were employed at two years. Significant improvements were observed in both SOFAS and CGI-SCH scores during the observation period. The percentage of patients with socially functional remission also significantly increased. A strong association between the improvement of social function, gender, and monotherapy versus polypharmacy and the improvement of employment status was observed. A total of 29.3 percent of patients experienced at least one adverse event. There were no unexpected findings from long-term treatment and a safety profile, including mortality. Conclusion: PP1M treatment appears to improve not only schizophrenic symptoms but also functional outcomes.

Budget impact analysis of long acting injection for schizophrenia in Japan.

Aims: To estimate the budgetary impact of providing additional reimbursement for long acting injections for schizophrenia patients in psychiatric hospital settings in Japan to improve patient outcomes in schizophrenia.Methods: Budget impact analysis of change in reimbursement policy using a prevalence-based model over a five-year time horizon. The results are reported as net change in expenditure and consequent cost/savings in Japanese yen at the time of analysis.Results: The budget impact analysis shows that an increase in reimbursement for LAIs could lead to cumulative savings of an estimated 36.6 billion JPY over five years. These savings result from a decrease in hospitalization costs and an increased usage of LAI (assumed to be 10%). Based on the sensitivity analysis, the saving estimates are most sensitive to change in market share of generic and branded oral antipsychotics.Limitations: Historical data were used to estimate the future costs of drug and hospitalization; however, it is not the best predictor of future, hence a source of potential bias. A good level of treatment adherence with oral antipsychotics was assumed, which is generally not the case; therefore, we might have overestimated the effectiveness of oral atypical antipsychotics. Additionally, the drug cost due to reimbursement might have also been overestimated because in clinical setting, the increase of LAI use may not have reached 10% of the market share. Lastly, patients' behavior was derived from models, which may have loosely approximated the reality.Conclusions: An additional reimbursement for the use of LAI in schizophrenia patients is likely to be cost neutral/cost saving and should be considered as a policy option to improve patient outcomes and budget sustainability.

The social functional outcome of being naturalistically treated with paliperidone extended-release in patients with schizophrenia.

BACKGROUND: Social functioning is an important outcome for patients with schizophrenia. To evaluate the effects of paliperidone extended-release (PAL-ER) on social function, symptomatology, and safety in the routine clinical practice, we conducted a 1-year post-marketing surveillance study of PAL-ER. We also explored relationships between symptomatic improvement and socially functional outcome in patients with schizophrenia. PATIENTS AND METHODS: Patients with an established diagnosis of schizophrenia were allowed flexible 3-12 mg/day dosing during the surveillance. Patients were assessed on social functioning using the Social and Occupational Functioning Assessment Scale (SOFAS) and on symptomatology using the Clinical Global Impression-Schizophrenia scale. All adverse events (AEs) were also collected. RESULTS: A total of 1,429 patients were enrolled in the surveillance study, of whom 1,405 were evaluable for safety and 1,142 were evaluable for efficacy. The treatment discontinuation rate for any reason during the observation period was 34.66%. Significant improvements were observed on both Social and Occupational Functioning Assessment Scale and Clinical Global Impression-Schizophrenia scale during the observation period. The percentage of patients with socially functional remission (SOFAS ≥61) also increased significantly. A significant association between early improvements in positive symptoms, sex, severity of negative symptoms at baseline, and socially functional remission was observed. A total of 33.52% of patients had AEs and 8.75% of patients had serious AEs. Despite the recommendation of monotherapy with PAL-ER, 65.84% of patients were given additional antipsychotics (polypharmacy). Post hoc comparisons of monotherapy versus polypharmacy revealed that the monotherapy group had better outcomes and fewer AEs than the polypharmacy treated group. The improvement in social functioning and the rate of socially functional remission did not differ between groups. CONCLUSION: PAL-ER treatment showed effective symptom control and improvement in social functioning. The data suggest that early response to antipsychotic treatment should be important for functional outcomes.

Predicting pharmacokinetic stability by multiple oral administration of atypical antipsychotics.

Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.)

Effects of methylphenidate hydrochloride on the cardiovascular system in vivo and in vitro: a safety pharmacology study.

INTRODUCTION: : We examined the effects of methylphenidate hydrochloride (MPH) on the cardiovascular system using in vivo and in vitro study methods in accordance with the ICH-S7B guideline. METHODS: MPH was orally administered at doses of 3, 10 and 30 mg/kg to unrestrained conscious dogs implanted with a telemetry transmitter and attached with body surface electrodes, and electrocardiogram (ECG) leads. The QTcF interval was determined while heart rate (HR), and blood pressure (BP) were measured. Action potentials in isolated guinea-pig papillary muscle and the rapid component of the delayed rectifier potassium current (I(Kr)) in HEK-293 cells stably transfected with hERG were also investigated at concentrations of 0.1, 0.3 and 1 microg/mL (0.37, 1.1 and 3.7 micromol/L) of MPH. RESULTS: No ECG changes were observed except for a shortening of the QT interval due to a shortening of the RR interval at the maximum dose tested, 30 mg/kg. The only observed change was an elevation of BP in dogs at the dose of 30 mg/kg, which is approximately 10 times higher than the maximum therapeutic dose for use in children with attention deficit hyperactivity disorder (ADHD). Neither APD prolongation nor I(Kr) inhibition was observed by MPH in the in vitro studies up to the maximum concentration tested, 1 microg/mL (3.7 micromol/L), which is approximately 34 times higher than the clinically attainable unbound plasma MPH concentrations in children with ADHD. DISCUSSION: These results suggest that it is unlikely that MPH affects ventricular repolarization processes at the therapeutically recommended dose levels in patients with ADHD.