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.

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.

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.

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.

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.

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.

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis.

Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients with once- vs. multiple-daily dosing in the Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (AGATE dataset), and the Department of Psychiatry, Lausanne University Hospital, Switzerland, using non-parametric tests. Effectiveness and safety outcomes were available in the AGATE dataset. We performed a systematic review in PubMed/Embase until February 2022, meta-analyzing studies comparing clozapine once- vs. multiple-daily-dosing. We estimated a pooled odds ratio for adverse drug-induced reactions (ADRs) and meta-analyzed differences regarding clinical symptom severity, age, percentage males, smokers, clozapine dose, and co-medications between patients receiving once- vs. multiple-daily dosing. Study quality was assessed using the Newcastle-Ottawa-Scale. Of 1494 and 174 patients included in AGATE and Lausanne datasets, clozapine was prescribed multiple-daily in 74.8% and 67.8%, respectively. In the AGATE cohort, no differences were reported for the clinical symptoms severity or ADR rate (p > 0.05). Meta-analyzing eight cohorts with a total of 2810 clozapine-treated individuals, we found more severe clinical symptoms (p = 0.036), increased ADR risk (p = 0.01), higher clozapine doses (p < 0.001), more frequent co-medication with other antipsychotics (p < 0.001), benzodiazepines (p < 0.001), anticholinergics (p = 0.039), and laxatives (p < 0.001) in patients on multiple- vs. once-daily dosing. Of six studies, five were rated as good, and one as poor quality. Patients responding less well to clozapine may be prescribed higher doses multiple-daily, also treated with polypharmacy, potentially underlying worse safety outcomes. Patient preferences and adherence should be considered during regimen selection.

Antipsychotic Monotherapy for Major Depressive Disorder: A Systematic Review and Meta-Analysis.

Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.

Does short-term antipsychotic discontinuation of up to 3 weeks worsen symptoms in acute schizophrenia? A pooled analysis of placebo washout data.

AIM: This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia. METHODS: The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored. RESULTS: Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P = 0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation. CONCLUSIONS: Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

Combination Therapy of Long-Acting Injectable Second-Generation Antipsychotics and Oral Antipsychotics: A Retrospective Chart Review and Prescribers' Attitude Survey.

BACKGROUND: Although long-acting injectable antipsychotics (LAI-APs) have been considered as a monotherapeutic option in the maintenance treatment of schizophrenia, it has been recently reported that the combination therapy of LAI-APs and oral antipsychotics (OAPs) is common. METHODS: We conducted a retrospective chart review to examine the situation of the combination therapy of LAI second-generation antipsychotics (LAI-SGAs) and OAPs, and a questionnaire survey to investigate prescribers' attitudes toward the combination therapy. We included patients who received any LAI-SGAs for 1 month or longer and classified them into monotherapy and combination therapy groups. We collected information on age, sex, primary psychiatric diagnosis, and concomitant psychotropic medications. RESULTS: Of the 132 patients, 39 (29.5%) received the combination therapy of LAI-SGAs and OAPs. Long-acting injectable risperidone was significantly associated with receiving the combination therapy compared with LAI aripiprazole. Olanzapine was the most common OAP in combination with LAI-SGAs. Only 8 patients (20.5%) concurrently received the same type of OAPs as LAI-SGAs. More than 60% of the patients received OAP polypharmacy before the initiation of LAI-SGAs. The psychiatrists in charge prescribed LAI-SGAs mainly because of a concern about adherence, and OAPs mainly because of insufficient dose of LAI-SGAs, to patients in the combination therapy group. They estimated that adherence to OAPs in two thirds of the patients in the combination therapy group was 80% or higher. CONCLUSIONS: The present study showed that the combination therapy of LAI-SGAs and OAPs is often conducted in real-world clinical practice. Considering the reason for the introduction of LAI-APs, clinicians should carefully monitor patients' adherence to OAPs concurrently used with LAI-APs.

Trazodone and Mianserin for Delirium: A Retrospective Chart Review.

BACKGROUND: Although antipsychotics are commonly used for delirium, their adverse effects are a serious concern in light of extrapyramidal symptoms and cardiovascular disturbances. In clinical practice, sedative antidepressants are frequently used as an alternative treatment for delirium; however, there is scarce evidence. Thus, we conducted a retrospective chart review to examine the use and effectiveness of trazodone and mianserin for delirium. METHODS: Patients who were admitted to a university hospital during 4 years and received either trazodone or mianserin on a regular schedule as monotherapy for the treatment of delirium were included. The rates of and times to the improvement of delirium were compared. RESULTS: Among 3971 patients who developed delirium, 379 (9.5%) and 341 (8.6%) patients received trazodone and mianserin on a regular schedule; 52 and 46 patients met the eligibility criteria (ie, monotherapy) for trazodone and mianserin, respectively. The percentages of patients 65 years or older were 86.5% (n = 45) for trazodone and 89.1% (n = 41) for mianserin. The rates of the improvement of delirium were 63.5% for trazodone and 50.0% for mianserin. Times to the improvement of delirium were 5.3 days (95% confidence interval, 3.2-7.4 days) for trazodone and 9.3 days (95% confidence interval, 5.3-13.3 days) for mianserin. There were no significant differences in the primary outcomes between the 2 groups ( P = 0.17 and P = 0.13, respectively). CONCLUSION: Considering potentially serious, sometimes lethal, adverse effects of antipsychotics, sedative antidepressants such as trazodone and mianserin may be a treatment option for delirium, especially in the elderly.

Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan.

OBJECTIVE: Clozapine is generally recommended to be prescribed in a divided dosing regimen based on its relatively short plasma half-life. However, there has been little evidence to support the superiority of divided dosing of clozapine over once-daily dosing. To our knowledge, there have been no studies examining differences in actual plasma concentrations or adverse effects between the 2 dosing strategies of clozapine. We aimed to compare actual plasma concentrations of clozapine between once-daily and divided dosing regimens, and to examine the relationships of these regimens with psychiatric symptoms and adverse effects of clozapine. METHODS: We analyzed data from 108 participants of a previous study conducted in 2 hospitals in Japan. A population pharmacokinetic model was used to estimate the peak and trough plasma concentrations of clozapine based on actual plasma concentrations. We evaluated psychiatric symptoms with the Brief Evaluation of Psychosis Symptom Domains and adverse effects of clozapine with the Glasgow Antipsychotic Side-effects Scale for Clozapine. RESULTS: The estimated peak and trough plasma concentrations of clozapine did not differ significantly between once-daily and divided dosing regimens. There were no significant differences in psychiatric symptoms except for depression/anxiety or subjective adverse effects of clozapine between the 2 dosing strategies. CONCLUSIONS: Our findings tentatively support the feasibility and clinical utility of once-daily dosing of clozapine in clinical practice. Further studies are needed to replicate these findings and determine causality between dosing strategies and clinical outcomes.

Drug Combinations for Mood Disorders and Physical Comorbidities That Need Attention: A Cross-Sectional National Database Survey.

INTRODUCTION: This study investigated combined prescriptions of drugs for mood disorders and physical comorbidities that need special attention in the light of frequent physical comorbidities in patients with mood disorders. METHODS: We used the claims sampling data of 581,990 outpatients in January 2015 from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Fisher's exact test was performed to compare the prescription rates of non-steroidal anti-inflammatory drugs (NSAIDs), loop/thiazide diuretics, angiotensin-converting enzyme inhibitors, and/or angiotensin II receptor blockers between lithium users and age- and sex-matched non-lithium users; NSAIDs, antiplatelet drugs, and/or anticoagulants between selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) users and non-users; warfarin between mirtazapine users and non-users; and the proportions of patients in the two groups with a diagnosis of somatic conditions for which these medications were indicated and actually received them. A Bonferroni corrected p-value of<0.05/3 was considered statistically significant. RESULTS: Prescriptions of the above-mentioned medications were less frequent in lithium and mirtazapine users and comparable in SSRI/SNRI users, compared to non-users (18.3 vs. 31.9%, p=7.6×10-10; 0.78 vs. 1.65%, p=0.01; 23.1 vs. 24.1%, p=0.044). In a subgroup of patients with somatic diseases for which these medications were indicated, the prescription rates were comparable in lithium and mirtazapine users and higher in SSRI/SNRI users compared to non-users (28.0 vs. 29.4%, p=0.73; 4.7 vs. 7.4%, p=0.28; 35.6 vs. 33.4%, p=0.0026). DISCUSSION: Pharmacotherapy with drugs for mood disorders and physical comorbidities that require attention was commonly observed in clinical practice.

Clinical Outcomes after Clozapine Discontinuation in Patients with Schizophrenia: A Systematic Review.

INTRODUCTION: Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation. METHODS: A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation* OR cease* OR withdraw* OR discontinu* OR halt* OR stop* OR switch*) AND (schizophreni* OR schizoaffective)). RESULTS: A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group. DISCUSSION: Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

Pharmacological interventions for prevention of weight gain in people with schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem. OBJECTIVES: To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia. SEARCH METHODS: The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI. MAIN RESULTS: Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (> 5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants; > 7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence. AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.

Differential associations of dopamine synthesis capacity with the dopamine transporter and D2 receptor availability as assessed by PET in the living human brain.

BACKGROUND: The dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects. METHODS: First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[ß-11C]DOPA and [18F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[ß-11C]DOPA and [11C]raclopride, respectively, obtained from other previous dual-tracer assays. RESULTS: We found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum. CONCLUSION: The intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains.

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11 C]raclopride and [18 F]FE-PE2I, respectively, were acquired along with T1-weighted magnetic resonance imaging data in our previous studies, and were re-analyzed in this work. We quantified the binding potentials (BPND ) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BPND and regional GM volume were then examined by voxel-based morphometry. In line with the functional and anatomical connectivity, [11 C]raclopride BPND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BPND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BPND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18 F]FE-PE2I BPND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.

Olanzapine Reduction From High Dose to Standard Dose: A Retrospective Chart Review.

PURPOSE/BACKGROUND: Although high-dose olanzapine might be a treatment option in patients with treatment-resistant schizophrenia, it can be reduced to the standard dose after symptoms are stabilized. We examined the rate of olanzapine reduction from high to standard dose and whether this change was successful. METHODS/PROCEDURES: We included patients who received high-dose olanzapine (>20 mg/d) for 4 weeks or longer at our hospital. First, we retrospectively followed the patients for 6 years and estimated the percentage of those whose olanzapine was reduced from high to standard dose. Second, we followed patients who received olanzapine reduction for 1 year and estimated the rate of success based on the study-defined criteria for unsuccessful reduction. We also explored factors associated with the dose reduction and successful results. FINDINGS/RESULTS: Among 110 patients who received high-dose olanzapine treatment, 72 had their olanzapine dose reduced to the standard dose for 6 years; the duration of high-dose olanzapine treatment was significantly and negatively associated with a reduction in olanzapine (hazard ratio, 0.98; 95% confidence interval, 0.98-0.99). Among the patients whose olanzapine was reduced, 50 achieved successful reduction for 1 year. Among the reasons for the reduction, an unknown reason was significantly associated with successful reduction (hazard ratio, 4.93; 95% confidence interval, 1.55-22.8). IMPLICATIONS/CONCLUSIONS: The findings suggest that high-dose olanzapine can be reduced to the standard dose after stabilization of symptoms in most patients with schizophrenia.

Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms.

OBJECTIVE: There are only a few treatment algorithms for first-episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first-episode schizophrenia. METHODS: The algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia. RESULTS: The acute treatment algorithm focuses on drug-naïve patients with first-episode schizophrenia who are not old or very agitated and recommends first-line treatment with aripiprazole, second- or third-line treatment with risperidone/paliperidone or olanzapine, and fourth-line treatment with clozapine. Long-acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first-line treatment with lorazepam and second- or third-line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms. CONCLUSIONS: We hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment.

Effects of Discontinuation of Drugs Used for Augmentation Therapy on Treatment Outcomes in Depression: A Systematic Review and Meta-analysis.

INTRODUCTION: There has been no consensus on whether and how long add-on drugs for augmentation therapy should be continued in the treatment of depression. METHODS: Double-blind randomized controlled trials that examined the effects of discontinuation of drugs used for augmentation on treatment outcomes in patients with depression were identified. Meta-analyses were performed to compare rates of study withdrawal due to any reason, study-defined relapse, and adverse events between patients who continued augmentation therapy and those who discontinued it. RESULTS: Seven studies were included (n=841 for continuing augmentation therapy; n=831 for discontinuing augmentation therapy). The rate of study withdrawal due to any reason was not significantly different between the 2 groups (risk ratio [RR]=0.86, 95% confidence interval [CI]=0.69-1.08, p=0.20). Study withdrawal due to relapse was less frequent in the continuation group than in the discontinuation group (RR=0.61, 95% CI=0.40-0.92, p=0.02); however, this statistical significance disappeared when one study using esketamine as augmentation was excluded. Analysis of the data from 5 studies that included a stabilization period before randomization found less frequent relapse in the continuation group than in the discontinuation group (RR=0.47, 95% CI=0.36-0.60, p<0.01). This finding was repeated when the esketamine study was excluded. DISCUSSION: No firm conclusions could be drawn in light of the small number of studies included. Currently available evidence suggests that add-on drugs, other than esketamine, used for augmentation therapy for depression may be discontinued. This may not be the case for patients who are maintained with augmentation therapy after remission.