Real-World Effectiveness of High-Dose Olanzapine and Clozapine for Treatment-Resistant Schizophrenia in Japan: A Retrospective Bidirectional Mirror-Image Study.

BACKGROUND: Clozapine is considered the gold standard medication for treatment-resistant schizophrenia (TRS). However, given that clozapine treatment is associated with the burden of regular blood monitoring and the risk of life-threatening adverse effects, high-dose olanzapine can serve as an alternative treatment. We conducted a bidirectional mirror-image study to evaluate the effectiveness of high-dose olanzapine compared with clozapine. METHODS: We included patients with TRS who switched from olanzapine to clozapine or switched from clozapine to olanzapine, and received high-dose (>20 mg/d) olanzapine treatment for ≥4 weeks at Yamanashi Prefectural Kita Hospital. We obtained data on hospitalization, seclusion, and modified electroconvulsive therapy (mECT) during the clozapine phase and the olanzapine phase. RESULTS: A total of 44 patients were included. When patients switched from high-dose olanzapine to clozapine (n = 32), significant reductions were found in the total days of seclusion, the total number of mECT, and the number of patients who received mECT at least once. When patients switched from clozapine to high-dose olanzapine (n = 12), a significant reduction was found in the number of patients who received mECT at least once. When data from both directions of treatment were combined, significant reductions were found in the total days of seclusion, the total number of mECT, and the number of patients who received mECT at least once in favor of clozapine. CONCLUSIONS: Findings suggest that high-dose olanzapine may not be as effective as clozapine for patients with TRS in real-world practice. However, it should be noted that there are unique circumstances that restrict the use of clozapine in Japan.

Mortality in patients with schizophrenia in Japan.

PURPOSE: Patients with schizophrenia have a higher mortality risk than the general population. However, no recent studies have investigated mortality in patients with schizophrenia in Japan. Therefore, we conducted a retrospective study to evaluate excess mortality and risk factors for mortality in patients with schizophrenia in Japan. METHODS: We included patients diagnosed with schizophrenia or schizoaffective disorder at Yamanashi Prefectural Kita Hospital between January 1, 2013, and December 31, 2017. Standardized mortality ratios (SMRs) were used to compare mortality rates between patients with schizophrenia and the general population. Logistic regression analysis was performed to estimate risk factors associated with mortality. RESULTS: Of the 1,699 patients with schizophrenia (893 men and 806 women), 104 (55 men and 49 women) died during the study period. The all-cause SMR (95% confidence interval [CI]) was 2.18 (1.76-2.60); the natural- and unnatural-cause SMRs were 2.06 (1.62-2.50) and 5.07 (2.85-7.30), respectively. Men (adjusted odds ratio [OR] = 2.24, 95% CI = 1.10-4.56), age (adjusted OR = 1.12, 95% CI = 1.09-1.16), and barbiturate use (adjusted OR = 8.17, 95% CI = 2.07-32.32) were associated with the risk of mortality. CONCLUSION: The mortality rate remains high in patients with schizophrenia in Japan. Further studies are needed to evaluate mortality trends in this population.

Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment. METHOD: Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis. RESULTS: A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs. CONCLUSION: This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

Once-daily versus divided dosing regimens of clozapine: A cross-sectional study in Singapore.

INTRODUCTION: Clozapine is recognized as the gold standard medication for treatment-resistant schizophrenia. Despite the general recommendation of administering in a divided dosing regimen, clozapine is often prescribed once daily at night in clinical practice. This study aims to compare patient characteristics, psychiatric symptoms, side effects, and plasma concentration of clozapine between once-daily dosing and divided dosing regimens. METHODS: This cross-sectional study included 159 participants with treatment-resistant schizophrenia or schizoaffective disorder. Participant's demographic information, anthropometric data, and medical history were collected. Their psychiatric symptoms, cognition, functioning, and side effects were evaluated. RESULTS: Once-daily dosing regimen was associated with younger age and competitive employment. Lower clinical symptom severity, better functioning and cognitive performance were observed in the once-daily dosing group. Lower daily dose of clozapine, trough plasma concentrations of clozapine and norclozapine were also significantly associated with once-daily dosing regimen. CONCLUSION: The study results support once-daily dosing of clozapine as a viable option to selected patients in clinical practice, as no association of severe symptoms or side effects were associated with once-daily dosing regimen. More studies are needed to examine the relationship between clinical outcomes and clozapine dosing regimen.

Effect of smoking habits and concomitant valproic acid use on relapse in patients with treatment-resistant schizophrenia receiving clozapine: A 1-year retrospective cohort study.

INTRODUCTION: No study has investigated the impact of smoking habits and concomitant valproic acid (VPA) use on clinical outcomes in maintenance treatment with clozapine. Thus, we aimed to examine the effect of smoking habits and concomitant VPA use on relapse during the first year after discharge in patients with treatment-resistant schizophrenia (TRS) receiving clozapine. METHODS: This retrospective cohort study included patients with TRS who were initiated on clozapine during hospitalization and discharged between April 2012 and January 2021 in two tertiary psychiatric hospitals in Japan. Relapse was defined as rehospitalization due to psychiatric exacerbation during the first year after discharge. A multivariable Cox proportional hazards regression analysis was performed to analyze the effect of smoking habits and concomitant VPA use on relapse. Subgroup analyses were also conducted to examine potential interactions between smoking habits and concomitant VPA use. RESULTS: Among the included 192 patients, 69 (35.9%) met the criteria of relapse. While smoking habits (adjusted hazard ratio [aHR], 2.27; 95% confidence interval [CI], 1.28-4.01; p < 0.01) independently increased the risk of relapse, a significant interaction for relapse risk was found between smoking habits and concomitant VPA use (p-interaction = 0.015). Concomitant VPA use may be an effective modifier of the increased relapse risk associated with smoking habits. Among patients who smoked, those using VPA concomitantly exhibited a higher risk of relapse (aHR, 5.32; 95% CI, 1.68-16.9; p < 0.01) than those not using VPA (aHR, 1.41; 95% CI, 0.73-2.70; p = 0.30). CONCLUSION: The findings suggest that the combination of smoking habits and concomitant VPA use may increase the risk of relapse after discharge. Future studies are required to elucidate the mechanisms underlying these findings, such as a decrease in clozapine blood levels.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Clozapine dosing patterns and clinical outcomes in patients with treatment resistant schizophrenia.

Clozapine is the only medication found to be effective for patients with treatment resistant schizophrenia-spectrum disorders (TRS) and its prescription patterns may impact on their outcomes. The study aims to explore the impact of clozapine dosing frequency, dose level and presence of pharmacological augmentation on the clinical, social and cognitive outcomes in patients with TRS. Patients with TRS and on clozapine were interviewed. Daily defined dose (DDD) and anticholinergic burden were calculated. Patients were categorized in three ways: the single daily dose (SDD) and multiple daily dose (MDD), ≤300 mg/day (LD) and >300 mg/day (HD) of clozapine, and clozapine monotherapy (MT) and augmentation therapy (AT). The impact of these clozapine prescription patterns and their interaction on patient outcomes were examined with ANOVA. Of 124 patients on clozapine, 98 patients (79%) had SDD, 59 patients (47.6%) received LD, and 58 patients (46.8%) had MT. Patients in the LD group had significantly better cognitive functions. Though no significant effect of clozapine dosing frequency on outcomes, among patients on LD, those on MDD had better processing speed, short-term and visual memory. Patients with MT had better motivation. Among patients on HD, those with MT had better motivation and vocational functioning. These results provide guidance to the clozapine prescription in a naturalistic setting to achieve optimizing outcomes for patients with TRS in social and cognitive functions. Further longitudinal studies are needed to verify the results.

Association of protein distribution and gene expression revealed by positron emission tomography and postmortem gene expression in the dopaminergic system of the human brain.

PURPOSE: The topological distribution of dopamine-related proteins is determined by gene transcription and subsequent regulations. Recent research strategies integrating positron emission tomography with a transcriptome atlas have opened new opportunities to understand the influence of regulation after transcription on protein distribution. Previous studies have reported that messenger (m)-RNA expression levels spatially correlate with the density maps of serotonin receptors but not with those of transporters. This discrepancy may be due to differences in regulation after transcription between presynaptic and postsynaptic proteins, which have not been studied in the dopaminergic system. Here, we focused on dopamine D1 and D2/D3 receptors and dopamine transporters and investigated their region-wise relationship between mRNA expression and protein distribution. METHODS: We examined the region-wise correlation between regional binding potentials of the target region relative to that of non-displaceable tissue (BPND) values of 11C-SCH-23390 and mRNA expression levels of dopamine D1 receptors (D1R); regional BPND values of 11C-FLB-457 and mRNA expression levels of dopamine D2/D3 receptors (D2/D3R); and regional total distribution volume (VT) values of 18F-FE-PE2I and mRNA expression levels of dopamine transporters (DAT) using Spearman's rank correlation. RESULTS: We found significant positive correlations between regional BPND values of 11C-SCH-23390 and the mRNA expression levels of D1R (r = 0.769, p = 0.0021). Similar to D1R, regional BPND values of 11C-FLB-457 positively correlated with the mRNA expression levels of D2R (r = 0.809, p = 0.0151) but not with those of D3R (r = 0.413, p = 0.3095). In contrast to D1R and D2R, no significant correlation between VT values of 18F-FE-PE2I and mRNA expression levels of DAT was observed (r = -0.5934, p = 0.140). CONCLUSION: We found a region-wise correlation between the mRNA expression levels of dopamine D1 and D2 receptors and their respective protein distributions. However, we found no region-wise correlation between the mRNA expression levels of dopamine transporters and their protein distributions, indicating different regulatory mechanisms for the localization of pre- and postsynaptic proteins. These results provide a broader understanding of the application of the transcriptome atlas to neuroimaging studies of the dopaminergic nervous system.

Development and acceptability testing of a decision aid for considering whether to reduce antipsychotics in individuals with stable schizophrenia.

AIM: Continued antipsychotic treatment is the key to preventing relapse. Maintenance antipsychotic monotherapy and optimal dose use are recommended for individuals with stable schizophrenia because of their undesirable effects. Decision aids (DAs) are clinical conversation tools that facilitate shared decision-making (SDM) between patients and health-care providers. This study aimed to describe the development process and results of acceptability testing of a DA for individuals with stable schizophrenia, considering (i) whether to continue high-dose antipsychotics or reduce to the standard dose and (ii) whether to continue two antipsychotics or shift to monotherapy. METHODS: A DA was developed according to the guidelines for the appropriate use of psychotropic medications and International Patient Decision Aid Standards (IPDAS). First, a DA prototype was developed based on a previous systematic review and meta-analysis conducted for identifying the effects of continuing or reducing antipsychotic treatment. Second, mixed-method survey was performed among individuals with schizophrenia and health-care providers to modify and finalize the DA. RESULTS: The DA consisted of an explanation of schizophrenia, options to continue high-dose antipsychotics or reduce to the standard dose, options to continue two antipsychotics or shift to monotherapy, pros and cons of each option, and a value-clarification worksheet for each option. The patients (n = 20) reported acceptable language use (75%), adequate information (75%), and well-balanced presentation (79%). Health-care providers (n = 20) also provided favorable overall feedback. The final DA covered six IPDAS qualifying criteria. CONCLUSION: A DA was successfully developed for schizophrenia, considering whether to reduce antipsychotics, which can be used in the SDM process.

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

[Pharmacological Treatment of Tardive Dyskinesia].

Tardive dyskinesia (TD) is a serious, intractable, and potentially disabling side effect. Adjunctive drug treatment is used after optimizing the causative drugs. This article describes valbenazine, the first drug for treating TD that was recently approved in Japan, clonazepam, and vitamin E.

Appendicitis Associated With Clozapine: Analyses Based on a Spontaneous Reporting System Database in Japan.

BACKGROUND: An association between appendicitis and clozapine has recently been reported; however, few studies other than case reports have investigated this association. Therefore, we aimed to investigate the association between appendicitis and clozapine, using a large spontaneous reporting database in Japan. METHODS: Japanese Adverse Drug Event Report data were used in this study, and patients who had received clozapine or nonclozapine second-generation antipsychotics (NC-SGAs) available in Japan were included. To compare the reporting frequency of appendicitis associated with clozapine and NC-SGAs, we calculated the adjusted reporting odds ratio using logistic regression models, adjusting for age group, sex, and anticholinergic use. We conducted a time-to-event analysis to examine the time to onset of appendicitis associated with clozapine. RESULTS: In total, 8921 patients were included in this study, of whom 85 (1.0%) had appendicitis. Of these, 83 patients had received clozapine. Appendicitis was significantly more frequently reported with clozapine than with NC-SGAs. Time-to-event analysis showed that the risk of developing appendicitis associated with clozapine increased over time. CONCLUSIONS: Clozapine was associated with a higher risk of appendicitis than NC-SGAs, which increased with time. These findings suggest that clinicians need to pay greater attention to the risk of developing appendicitis during clozapine treatment.