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.

Changes in Plasma Clozapine Levels after Smoking Cessation in Japanese Inpatients with Schizophrenia: A Retrospective Cohort Study.

Although reported for Caucasians, changes in plasma clozapine levels after smoking cessation in East Asians remain unclear. We here investigated plasma clozapine levels before and after smoking cessation in Japanese inpatients with schizophrenia. We conducted a retrospective chart review of 14 inpatients with schizophrenia who were being treated with clozapine between June 1, 2019, and July 31, 2019 and who were smokers as of July 1, 2019, the day on which a smoking ban was instituted in the tertiary public psychiatric hospital. The primary outcome was individual differences in plasma clozapine levels between before and after the smoking ban, which were compared using paired t-tests. The mean plasma clozapine level was significantly increased, by 213.4 ng/mL (95% CI 119.9-306.8; p<0.01) or 53.2%. Four of the 14 inpatients experienced clinically significant side effects, such as myoclonus, drooling, and amnesia, due to the development of high plasma clozapine levels. Our findings indicated that close monitoring of plasma clozapine levels before and after smoking cessation and prior dose adjustment of clozapine may be necessary, to prevent a significant risk of developing high plasma clozapine levels, even in Japanese patients.

Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus.

The mortality rate of patients with schizophrenia is high, and life expectancy is shorter by 10 to 20 years. Metabolic abnormalities including type 2 diabetes mellitus (T2DM) are among the main reasons. The prevalence of T2DM in patients with schizophrenia may be epidemiologically frequent because antipsychotics induce weight gain as a side effect and the cognitive dysfunction of patients with schizophrenia relates to a disordered lifestyle, poor diet, and low socioeconomic status. Apart from these common risk factors and risk factors unique to schizophrenia, accumulating evidence suggests the existence of common susceptibility genes between schizophrenia and T2DM. Functional proteins translated from common genetic susceptibility genes are known to regulate neuronal development in the brain and insulin in the pancreas through several common cascades. In this review, we discuss common susceptibility genes, functional cascades, and the relationship between schizophrenia and T2DM. Many genetic and epidemiological studies have reliably associated the comorbidity of schizophrenia and T2DM, and it is probably safe to think that common cascades and mechanisms suspected from common genes' functions are related to the onset of both schizophrenia and T2DM. On the other hand, even when genetic analyses are performed on a relatively large number of comorbid patients, the results are sometimes inconsistent, and susceptibility genes may carry only a low or moderate risk. We anticipate future directions in this field.

The relationship between plasma clozapine concentration and clinical outcome: a cross-sectional study.

OBJECTIVE: There is no report that statistically evaluates the therapeutic reference (350-600 ng/ml) and adverse drug reaction (ADR) range (>1000 ng/ml) of clozapine (CLZ) recommended by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) consensus guidelines in an isolated and large sampling study. METHODS: We administered CLZ to 131 Japanese patients with treatment-resistant schizophrenia in a multicenter cross-sectional study. Plasma CLZ concentrations were assayed by high-performance liquid chromatography using trough sampling. The Brief Psychiatric Rating Scale (BPRS) and severe dose-dependent ADR (sedation, myoclonus, and seizures) were analyzed statistically after adjusting for possible confounders. RESULTS: The daily CLZ dosage showed a moderately positive relationship with the plasma concentration (r = 0.49, p < 0.001). Every 100 ng/ml increase in plasma CLZ concentration improved the total BPRS score 1.95% (95% CI: 0.89-3.01, p < 0.001) and the odds ratio (OR) 1.38 (95% CI: 1.14-1.66, p = 0.001) for BPRS response. Compared with concentrations below 350 ng/ml CLZ, 350-600 ng/ml (11.12%; 95% CI: 2.52-19.72, p = 0.012) and 600-1000 ng/ml (11.05%; 95% CI: 2.40-19.71, p = 0.013) showed significant improvement in the total BPRS score. Dosages above 1000 ng/ml showed greater improvement (25.36%; 95% CI: 13.08-37.64, p < 0.001) of the total BPRS score but more severe ADRs than dosages below 1000 ng/ml (OR: 31.72; 95% CI: 1.04-968.81, p = 0.048). CONCLUSION: The AGNP therapeutic reference range (350-600 ng/ml) is useful, and a dose above 1000 ng/ml is potentially more effective but carries the risk of severe ADRs in the central nervous system.

Clinical Utility and Safety of Slower-than-Recommended Titration of Clozapine for Treatment-Resistant Schizophrenia: a Retrospective Cohort Study.

Slow titration of clozapine is recommended given the risk of serious adverse effects. However, the utility and safety of slower-than-recommended titration of clozapine remain unclear. Consequently, we aimed to investigate the clinical utility and safety of slower-than-recommended titration of clozapine for treatment-resistant schizophrenia. We conducted a retrospective chart review of 152 inpatients with treatment-resistant schizophrenia who had been newly started on clozapine in a tertiary psychiatric public hospital between April 2012 and March 2018. The primary outcome was clozapine continuation for the first 18 weeks. We performed multivariate logistic regression to identify the association between the rate of clozapine dose titration and clozapine continuation for the first 18 weeks. Among the 152 inpatients, 122 (80%) could continue clozapine for the first 18 weeks. There was no significant association between the rate of clozapine dose titration and clozapine continuation for the first 18 weeks (adjusted odds ratio 1.23; 95% CI 0.29-5.26; p = 0.78). Our findings indicate that slower-than-recommended titration of clozapine may not improve toward clozapine continuation for the first 18 weeks. Therefore, it may not be a beneficial option in terms of safe clozapine continuation when starting clozapine for treatment-resistant schizophrenia.

Change in smoking cessation stage over 1 year in patients with schizophrenia: a follow up study in Japan.

BACKGROUND: We performed a follow up study about willingness and behaviors to quit smoking among smokers with schizophrenia in Japan. METHODS: Participants were outpatients with schizophrenia aged 20-69 years who had been visiting the hospital for ≥1 year as of April 1, 2016, and had visited the hospital more than once in the previous 6 months. A baseline survey on smoking behaviors including current smoking status and smoking cessation stage, was administered in 420 participants that were randomly extracted from a patient pool (n = 680) in 2016, and a follow-up survey was administered in 2017. We calculated the distribution and change in smoking cessation stage, number of smokers and nonsmokers after 1 year, and quitting rate from a naturalistic 1-year smoking-cessation follow up. RESULTS: The number of baseline respondents was 350; 113 current smokers and 68 former smokers. Among the 113 current smokers, 104 (92.0%) were followed for 1 year, 79 (70.0%) were interested in smoking cessation, and only 7 had received smoking cessation treatments at baseline. Among the tracked 104 participants, only 6 (5.8%) stopped smoking after 1 year. Among the 25 participants who had intentions to quit smoking within 6 months at baseline, 6 (24.0%) maintained their intention to quit smoking for 1 year, and 16 (64.0%) did not maintain their intention to quit smoking. CONCLUSIONS: Our findings showed that many smokers with schizophrenia were interested in quitting smoking, but few patients received treatment and actually quit smoking. Timely intervention, including the option to receive smoking cessation treatment, is necessary for those patients with schizophrenia who smoke. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000023874, registered on August 31, 2016).

Optimal Dosing of Risperidone and Olanzapine in the Maintenance Treatment for Patients With Schizophrenia and Related Psychotic Disorders: A Retrospective Multicenter Study.

OBJECTIVES: This study aims to determine the optimal tolerability dose ranges of risperidone (RIS) and olanzapine (OLZ) administered during schizophrenia maintenance phase. METHODS: Two-year continuation rates of prescription at discharge were examined using a retrospective cohort study method. Adult patients with schizophrenia and related psychotic disorders, receiving antipsychotic monotherapy with RIS or OLZ at discharge, were included. The primary outcome measures were the time to treatment discontinuation and 2-year continuation rates at 4 modal dose ranges of each drug. We estimated the optimal tolerability dose ranges by comparing the continuation rates at various modal doses. RESULTS: Of 648 patients, 344 received RIS and 304 received OLZ. The RIS 2-year continuation rates at 4 daily modal dose ranges were significantly different (0.5-2.5 mg: 46.0%, 3.0-5.0 mg: 40.0%, 5.5-7.5 mg: 30.0%, and 8.0-10.0 mg: 28.0%), with the difference favoring RIS at lower doses (0.5-5.0 mg) more than higher doses (5.5-10.0 mg). In contrast, there were no significant differences among OLZ 4 modal dose ranges (2.5-7.5 mg: 49.1%, 10.0-15.0 mg: 42.6%, 17.5-22.5 mg: 40.9%, and 25.0-30.0 mg: 39.0%). The time to treatment discontinuation significantly favored OLZ over RIS. However, it did not significantly differ between RIS and OLZ at lower doses. CONCLUSIONS: It is suggested that the optimal tolerability dose range during maintenance treatment is 0.5 to 5.0 mg/d for RIS and 2.5 to 30 mg/d for OLZ, and that RIS at lower doses is comparable with OLZ at lower doses.

Effect of concomitant use of valproic acid during clozapine initiation on clozapine-induced inflammation among Japanese patients with schizophrenia.

During clozapine initiation, titration speed and concomitant valproate administration have been reported as risk factors for clozapine-induced fever and myocarditis. We tested the risk of concomitant valproate administration by stratifying patients according to titration rate. Concomitant valproate use was only associated with increased inflammatory adverse events in the slower titration group. The frequency of inflammatory adverse events was approximately 30 % during faster titration, regardless of concomitant valproate administration. However, the faster titration group with valproate had a higher frequency of severe adverse effects such as myocarditis. Clinicians should avoid concomitant valproate administration during clozapine initiation, regardless of titration rate.

Impact of clozapine once-daily versus multiple-daily dosing regimen on relapse in patients with treatment-resistant schizophrenia: A 1-year retrospective cohort study.

RATIONALE: Clozapine, the standard treatment for treatment-resistant schizophrenia (TRS), is generally recommended in a multiple-daily dosing regimen. However, it is commonly administered once daily in clinical practice. Few studies have compared the longitudinal clinical outcomes of these two dosing regimens. OBJECTIVE: To investigate the effect of once-daily versus multiple-daily dosing regimens of clozapine on relapse in patients with TRS. METHODS: This retrospective cohort study included patients with TRS who commenced treatment with clozapine during hospitalization and were discharged between April 2012 and January 2022 from a tertiary psychiatric hospital in Japan. Relapse, defined as a psychiatric exacerbation requiring re-hospitalization within the first-year post-discharge, was analyzed. Multivariable Cox proportional hazards regression analysis compared the relapse risk between once-daily and multiple-daily dosing regimens. A subgroup analysis was conducted to examine the potential interactions between dosing regimen and dose category (low versus high dose). RESULTS: Among 179 patients, 107 (59.8%) received clozapine once daily. No significant difference in the relapse risk was observed between once-daily and multiple-daily dosing regimens (adjusted hazard ratio [aHR]: 1.16; 95% confidence interval [CI]: 0.68-1.99; p = 0.58). However, in patients receiving high doses of clozapine (> 300 mg/day), multiple-daily dosing increased the relapse risk compared to once-daily dosing (aHR: 2.23; 95% CI: 1.00-4.97; p = 0.049). CONCLUSIONS: Once-daily clozapine dosing may not be associated with an increased relapse risk. The increased relapse risk in high-dose multiple-daily dosing may be confounded by unmeasured non-adherence. Further randomized controlled trials are required to validate these findings.