A Pharmacovigilance Study on Clozapine in the Food and Drug Administration Adverse Event Reporting System: A Regional Comparative Analysis.

Objective: This pharmacovigilance study evaluated the profile of clozapine-related adverse events by region using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We categorized each case into five regions (America, Europe/West Asia, Oceania, Asia, and Africa) based on the reporting country information in the FAERS database. The number of clozapine-related adverse events reported in each region was aggregated according to the preferred term (PT) and the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). Results: A total of 101,872 clozapine-related adverse events were registered in the FAERS database. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs by relative reporting rate. However, Asia had higher relative reporting rates of pyrexia and salivary hypersecretion (13.91% and 10.85%, respectively). Regarding the SMQ, the relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively), with significant differences even after adjusting for confounding factors using multivariate logistic regression analysis. Conclusion: Spontaneous reports of adverse events associated with clozapine show regional disparities, particularly in Asia, where concentration-dependent adverse events are more frequently reported. However, the spontaneous reporting system has several limitations, requiring further research for validation.

Comprehensive signal detection of delirium-associated medication using the Food and Drug Administration Adverse Event Reporting System.

OBJECTIVE: Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system. METHOD: The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates. RESULTS: After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64-1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21-4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20-2.71). CONCLUSIONS: These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications.

Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis.

In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression.

Antidepressants available in Japan for older people with major depressive disorder: A systematic review and meta-analysis.

AIM: To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta-analysis of double-blind, randomized, placebo-controlled trials of available antidepressants in Japan for older adults with MDD. METHODS: Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all-cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random-effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). RESULTS: Nine double-blind, randomized, placebo-controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta-analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = -0.62 [-0.92, -0.33], p < 0.0001). However, antidepressants were associated with a higher discontinuation rate due to adverse events (RR [95% CI] = 1.94 [1.30, 2.88], p = 0.001) and a higher incidence of at least one adverse event (RR [95% CI] = 1.11 [1.02, 1.21], p = 0.02) compared to placebo. The groups did not differ significantly in terms of remission rate or all-cause discontinuation. CONCLUSIONS: Our meta-analysis concluded that treatment with antidepressants available in Japan is only weakly recommended for moderate to severe MDD in older adults.

Newer antidepressant for Japanese adults with major depressive disorder: A systematic review and meta-analysis.

INTRODUCTION: The question remains to be elucidated: "Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?" It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random-effects pairwise meta-analysis including these nine double-blind, randomized, placebo-controlled trials. METHODS: We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI). RESULTS: Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = -0.20 (-0.27, -0.12), p < 0.00001], response to treatment [RR (95% CI) = 1.23 (1.13, 1.32), p < 0.00001], and remission rate [RR (95% CI) = 1.30 (1.16, 1.45), p < 0.00001]. Although all-cause discontinuation was not significantly different between the treatment groups, the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001]. DISCUSSION: We concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals.

Clinical Laboratory Data in Japan: A Comparative Study of Patients with Psychiatric Disorders and the General Population.

Purpose: Several nationwide population-based studies have reported that patients with psychiatric disorders are at higher risk of developing chronic kidney disease, chronic liver disease, and metabolic syndrome than the general population; however, there are insufficient studies in the Japanese population. Thus, we aimed to clarify the influence of psychiatric disorders on clinical laboratory data in the Japanese population. Patients and Methods: This cross-sectional study was based on medical records from the Department of Psychiatry at Fujita Health University Hospital and the 6th National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan (specific health checkups in 2018) in the Ministry of Health, Labor and Welfare. The primary endpoint was the incidence of clinical laboratory abnormalities in patients with psychiatric disorders and the general Japanese population. Results: Compared to the general Japanese population, patients with psychiatric disorders had significantly higher rates of the following clinical laboratory abnormalities: estimated glomerular filtration rate, alanine transaminase, aspartate aminotransferase (AST), body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), triglycerides, and hemoglobin A1c (HbA1c). In the age-specific analysis, AST, BMI, HDL-C, and HbA1c levels were more frequently abnormal in patients with psychiatric disorders only in the 40-49 and 50-59 age groups. Conclusion: Our results showed that patients with psychiatric disorders have higher rates of various clinical laboratory abnormalities than the general Japanese population, with stronger influences in the middle-aged group. These data suggest the importance of monitoring and preventing chronic diseases in patients with psychiatric disorders in Japan.

Serotonin 3 receptor antagonists for obsessive-compulsive disorder: A systematic review and pairwise meta-analysis.

The benefits of serotonin 3 receptor antagonists (5-HT3R-As) in obsessive-compulsive disorder (OCD) treatment remain unclear. Thus, this study aimed to perform a systematic review and a random-effects meta-analysis, including double-blind, randomized, placebo-controlled trials (DBRPCTs). The outcomes include the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score (primary), Y-BOCS obsession subscale score, Y-BOCS compulsive subscale score, treatment response, remission rate, all-cause discontinuation, and incidence of individual adverse events (nervousness/restlessness/anxiety, insomnia, headache, dizziness/lightheadedness, decreased appetite, constipation, nausea/vomiting, diarrhea, dry mouth, sweating/increased perspiration, itching/pruritus, tremor, and sexual dysfunction/decreased libido). The mean differences (MD) for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CIs) were calculated. Our study included 10 DBRPCTs (n = 628). Pooled 5-HT3R-As outperformed placebo regarding Y-BOCS total score (MD = -5.08, 95% CI = -7.04, -3.12, N = 9, n = 560), Y-BOCS obsession subscale score, Y-BOCS compulsive subscale score, treatment response, and remission rate. Individually, all 5-HT3R-As outperformed placebo regarding Y-BOCS total score (granisetron: MD = -5.59, 95% CI = -8.79, -2.39, N = 3, n = 178, ondansetron: MD = -5.72, 95% CI = -8.06, -3.37, N = 6, n = 331, tropisetron: MD = -2.87, 95% CI = -5.19, -0.550, N = 1, n = 96). However, all-cause discontinuation and incidence of individual adverse events between pooled 5-HT3R-As and placebo were not significantly different. In conclusion, our meta-analysis suggested 5-HT3R-As as efficacious for symptom improvement in individuals with OCD. However, the number of individuals included in each study was small; thus, a replication randomized trial of 5-HT3R-As should be conducted using a larger sample size.

Long-term outcomes of delayed clozapine initiation in treatment-resistant schizophrenia: a multicenter retrospective cohort study.

BACKGROUND: Clozapine is the only antipsychotic medication with proven efficacy against treatment-resistant schizophrenia. This multicenter retrospective cohort study aimed to evaluate the impact of a delay in clozapine initiation on long-term outcomes. METHODS: Patients who initiated clozapine treatment between July 2009 and December 2018 were included in this study. According to the length of time from the diagnosis of schizophrenia to clozapine initiation, the patients were categorized into one of three groups: early (≤ 9 years), intermediate (10-19 years), and late (≥ 20 years) initiation. The endpoints were psychiatric rehospitalization and all-cause clozapine discontinuation within 3 years. Hazard ratios (HR) and 95% confidence interval (CI) were estimated using the Fine and Gray method or the Cox proportional hazards model. RESULTS: The incidence rates of rehospitalization within three years, according to the cumulative incidence function, were 32.3% for early, 29.7% for intermediate, and 62.2% for late initiation, respectively. Late initiation had a significantly higher risk of psychiatric rehospitalization than early initiation (HR, 2.94; 95% CI, 1.01- 8.55; P = 0.016 by the Gray's test). The risk of psychiatric rehospitalization was not significantly different between the early and intermediate initiation groups. The incidence rate of all-cause clozapine discontinuation within three years using the Kaplan-Meier method was 13.0% for early, 10.6% for intermediate, and 20.1% for late initiation. The risk of all-cause clozapine discontinuation was not significantly among the groups. The late initiation group had more patients discontinuing because of death due to physical diseases than the other groups. CONCLUSIONS: The study suggests that clozapine should be initiated promptly in patients with treatment-resistant schizophrenia to prevent psychiatric rehospitalization during long-term treatment. Further prospective studies with appropriate consideration of confounding factors and large sample sizes are needed to strengthen the evidence.

Subjective assessment of brexpiprazole in patients with schizophrenia: a prospective observational study.

Objectives: To investigate the subjective assessments of an antipsychotic treatment with brexpiprazole. Methods: This was a 14-week prospective observational study. Nineteen patients participated in the study between February 2019 and January 2020. Results: Patients had a mean age of 40.6±14.2 years and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score of 4.6±1.2 at the initiation of brexpiprazole treatment. The Subjective Well-being under Neuroleptic drug treatment Short form, Japanese version (SWNS-J) total score significantly improved from 68.1±22.3 in week 2 to 79.5±21.0 in week 14 (p=0.0084). The SWNS-J subscales of self-control and social integration status also significantly improved from 14.0±4.7 and 13.9±6.0 in week 2 to 17.0±4.7 and 16.0±5.1 in week 14, respectively (p=0.0053 and 0.012, respectively). No significant improvements were observed in any other SWNS-J subscales or the Drug Attitude Inventory-10 (DAI-10) in the 14-week observation period. Moreover, the SWNS-J total score did not correlate with the DAI-10 (r=0.31, p=0.19), or CGI-S (r=-0.18, p=0.47) scores. Conclusions: The present results suggest that brexpiprazole might improve subjective well-being, although this may not necessarily reflect psychopathological improvements. To enhance medication adherence, it is important to perform subjective assessments on patients over time.

Analysis of clozapine-induced seizures using the Japanese Adverse Drug Event Report database.

Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP ß-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.

Effectiveness of Clozapine on Employment Outcomes in Treatment-Resistant Schizophrenia: A Retrospective Bidirectional Mirror-Image Study.

Purpose: Clozapine is more effective than other antipsychotics and is the only antipsychotic approved for treatment-resistant schizophrenia. The objective of this study is to reveal the effect of clozapine on employment using a bidirectional mirror-image model. Patients and Methods: This design was a retrospective observational study that investigated the employment status of patients with treatment-resistant schizophrenia based on medical records. The bidirectional mirror-image model consisted of 1) switching from other antipsychotics to clozapine and 2) switching from clozapine to other antipsychotics. The observation period was 1 year for each pre- and post-clozapine initiation and discontinuation. Results: We included 36 patients in the bidirectional mirror-image model. The regular employment plus employment support rate was significantly higher in the clozapine phase than in the other antipsychotic phase in the bidirectional mirror-image model (30.6% vs 11.1%, P = 0.039). The days of regular employment plus employment support were also significantly longer in the clozapine phase (61.3 ± 106.2 vs 24.7 ± 82.7 days, P = 0.032). As per the unidirectional mirror-image model, switching to clozapine resulted in significantly higher regular employment plus employment support rates in the clozapine phase than those in the other antipsychotic phase (33.3% vs 10.0%, P = 0.039). Switching from clozapine to other antipsychotics did not exhibit significant differences in any outcomes. Conclusion: The results suggest that clozapine is superior to other antipsychotics with respect to achieving employment in patients with treatment-resistant schizophrenia. However, biases specific to the mirror-image model need to be considered.

Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis.

A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.

Neutrophil-Lymphocyte Ratio Is Associated With Occurrence of Febrile Neutropenia in Patients Treated With 5-Fluorouracil and Cisplatin.

BACKGROUND/AIM: This study aimed to determine whether a high neutrophil-lymphocyte ratio (NLR) was associated with the occurrence of febrile neutropenia (FN). PATIENTS AND METHODS: Japanese patients with esophageal cancer who had been treated with first-line 5-fluorouracil and cisplatin therapy at Fujita Health University from April 2016 to March 2021 were enrolled in this retrospective cohort study. The primary outcome was the identification of independent risk factors for FN. RESULTS: One hundred and fourteen patients were enrolled. Advanced cancer (hazard ratios (HR)=6.731) and an NLR ≥3 (HR=4.849) were identified as risk factors for FN. Furthermore, FN occurred earlier in patients with high NLR than in patients with low NLR. CONCLUSION: Advanced cancer and a high NLR might be predictors of the occurrence of severe neutropenia and FN in patients treated with 5-fluorouracil and cisplatin therapy.

Efficacy of a Pharmacist Team Clinical Medication Review in Older Adults: A Prospective and Retrospective Observational Study.

Polypharmacy in older adults causes problems such as increased adverse drug reactions, overdose or duplication, and poor medication adherence. We have established a "medication review team" organized by pharmacists. This prospective and retrospective observational study evaluated the effectiveness of the pharmacist-led team-based approach for reducing polypharmacy as compared to the individual pharmacist approach. Data on the individual pharmacist approach were collected retrospectively, but prospectively for the pharmacist-led team approach. The study included patients who were admitted to the nephrology, orthopedic surgery, and psychiatry wards. Characteristics for patient included in each study group were adjusted using the propensity score method. The pharmacist-led team approach had a significantly higher medication change rate compared to that of the individual pharmacist approach (odds ratio (OR), 2.28; 95% confidence interval (CI), 1.21 to 4.46; p = 0.009). The rate of patients with two or more medication discontinuations and the rate of patients with intervention by young clinical pharmacist were also significantly higher in the pharmacist-led team approach (OR, 2.19; 95% CI, 1.06 to 4.74; p = 0.03 and OR, 5.67; 95% CI, 1.22 to 53.15; p = 0.02, respectively). The rate of patients with discontinuation of potentially inappropriate medications was not significantly different between the two groups (OR, 2.07; 95% CI, 0.86 to 5.33; p = 0.11). Our results suggest that it is possible to improve the quality of medication review by conducting team conferences even with only pharmacists.