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.

Slower clozapine titration is associated with delayed onset of clozapine-induced fever among Japanese patients with schizophrenia.

Clozapine-induced fever marks the beginning of its inflammatory and potentially life-threatening adverse effects, such as myocarditis. We retrospectively analyzed the correlation between clozapine titration rate and fever onset date in 254 Japanese patients, including 55 with treatment-resistant schizophrenia who developed clozapine-induced fever. Pearson's product-moment correlation indicated a significant delay in the fever onset date with slower titration. Most fever onset cases occurred within 4 weeks, even with slow titration. Therefore, clinicians should remain vigilant in monitoring clozapine-induced fever within 4 weeks of clozapine initiation, regardless of the titration rate.

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.

Comparison between olanzapine and aripiprazole treatment for 104 weeks after hospital discharge in schizophrenia spectrum disorders: a multicenter retrospective cohort study in a real-world setting.

RATIONALE: The long-term effectiveness of olanzapine and aripiprazole in real clinical conditions at flexible doses in patients after hospital discharge has not been evaluated yet. OBJECTIVES: This study was a multicenter retrospective cohort study. Patients with schizophrenia (n = 398) were prescribed olanzapine (n = 303) or aripiprazole (n = 95) at hospital discharge. The continuation of olanzapine or aripiprazole at 26, 52, or 104 weeks after the hospital discharge were compared using a Cox proportional hazards model and adjusted for possible confounders. RESULTS: The Kaplan-Meier survival curves revealed that the continuation of olanzapine at 26 (P = 0.001) and 52 weeks (P = 0.018) was significantly higher than that of aripiprazole but not at 104 weeks. Olanzapine was better than aripiprazole in efficacy at 26 (hazard ratio: 0.321, 95% confidence interval: 0.159-0.645, P = 0.001), 52 (hazard ratio: 0.405, 95% confidence interval: 0.209-0.786, P = 0.008), and 104 weeks (hazard ratio: 0.438, 95% confidence interval: 0.246-0.780, P = 0.005). Aripiprazole was better than olanzapine in tolerability at 104 weeks (hazard ratio: 4.574, 95% confidence interval: 1.415-14.787, P = 0.011). Rates after two years continuation of olanzapine and aripiprazole were not significantly different in patients with less than five years' duration of illness, but olanzapine was more commonly maintained for more than two years in those patients who had been ill for over five years' due to its greater efficacy. CONCLUSION: Olanzapine treatment showed better continuation rates at 26 and 52 after hospital discharge than aripiprazole, whereas maintenance with the two antipsychotics did not differ significantly at 104 weeks, due reduced tolerability of long-term olanzapine treatment.

The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms.

Anti-NMDAR encephalitis has a psychotic presentation that is difficult to distinguish from primary psychosis. An atypical psychosis that is similar to schizophrenia, mood disorder, and epilepsy is unique, and the original diagnostic criteria exist only in Japan. The clinical symptoms and courses of anti-NMDAR encephalitis and atypical psychosis are very similar. We investigated whether the diagnostic criteria of atypical psychosis are useful to increase the detection rate of anti-NMDAR encephalitis with psychiatric symptoms. The presence of anti-NR1/NR2B IgG antibodies in the cerebrospinal fluid of 218 newly admitted inpatients initially diagnosed with schizophrenia (n = 151), mood disorder (n = 47), or epilepsy with psychiatric symptoms (n = 20) was assessed by cell-based assay. Of 218 patients, 123 (36.3 years ± SD 17.2, 69.9 % females) fulfilled the diagnostic criteria of category B for atypical psychosis. All 12 patients (9.8 %, 12/123) with anti-NR1/NR2B IgG antibodies fulfilled category B of atypical psychosis statistically better than the patients without anti-NR1/NR2B IgG antibodies (P = 0.0009). Of the 12 patients with anti-NMDAR antibodies, two did not fulfill either criteria of catatonia (DSM-5) or Graus' diagnostic criteria of anti-NMDAR encephalitis during the time course, and 11 patients showed good prognosis with early immunotherapies. In ROC analysis, abnormal electroencephalogram findings showed the highest sensitivity (0.833) for detection of anti-NR1/NR2B IgG antibodies, and 31.3 % of patients with category B atypical psychosis and abnormal electroencephalogram findings had anti-NMDAR antibodies. Lumbar puncture and detection of anti-NMDAR antibodies should be considered for patients who fulfill atypical psychosis diagnosis criteria with an abnormal electroencephalogram.

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.

Risk factors for clozapine-induced central nervous system abnormalities in Japanese patients with treatment-resistant schizophrenia.

The purpose of this study was to assess the risk factors for clozapine-induced central nervous system (CNS) abnormalities (i.e., electroencephalogram [EEG] abnormalities, myoclonus, and seizures). We retrospectively analyzed data from 106 patients with schizophrenia who received clozapine treatment through our hospital. A review of the EEG recordings showed that 71 of these patients (67.0 %) developed CNS abnormalities after initiating clozapine treatment. EEG abnormalities, myoclonus, and seizures occurred in 53.8 %, 38.7 %, and 8.5 % of the patients, respectively. Multivariate logistic regression analysis showed that the risk factors for clozapine-induced CNS abnormalities were concomitant lithium usage (odds ratio, 4.560; 95 % confidence interval, 1.750-11.900) and shorter illness durations before clozapine initiation (odds ratio, 0.796; 95 % confidence interval, 0.649-0.976). However, plasma clozapine levels and the usage of antiepileptics did not exhibit associations with the risks of CNS abnormalities. Clinicians should monitor their patients for incident CNS abnormalities when administering lithium in combination with clozapine regardless of plasma clozapine levels or the usage of antiepileptics. This is especially true for patients with short illness durations.

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.

Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole.

RATIONALE: Changing antipsychotics of patients with chronic schizophrenia involves several risks. Switching to aripiprazole is especially difficult. We investigated switching methods and related factors for successful switching patients with chronic schizophrenia to aripiprazole. OBJECTIVES: This study was a multi-center historical cohort study and approved by the research ethics committee of Okayama University Hospital and Okayama Psychiatric Medical Center. We compared survival proportions of 178 chronic schizophrenia patients who continued aripiprazole monotherapy for 6 months after non-direct switching (add-on switching (n = 45), cross switching (n = 62)) or direct switching (n = 71). We adjusted possible confounders using a Cox proportional hazards model. RESULTS: Of patients with chronic schizophrenia, 56.7% (101/178) were switched to aripiprazole monotherapy, and 55.0% (98/178) showed improvement in symptoms as demonstrated by the Clinical Global Impression Severity score. Kaplan-Meier survival curves showed that non-direct switching had a higher survival proportion than direct switching (log-rank test, p = 0.012). Even after adjusting for several variables using a Cox proportional hazards model, add-on switching had a significantly lower hazard at 6 months than direct switching (hazard ratio 0.42, 95% confidence interval 0.21-0.82, P = 0.01). In cases of switching to aripiprazole for psychiatric symptoms, non-direct switching had a lower hazard than direct switching (hazard ratio 0.41, 95% confidence interval 0.21-0.81, P = 0.01) but was not significant for adverse reaction. When aripiprazole was switched from olanzapine, add-on switch showed the lowest hazard ratio for continuation (hazard ratio 0.29, 95% confidence interval 0.07-1.11, P = 0.07). CONCLUSIONS: Flexibility in strategies when switching to aripiprazole may induce a better outcome for patients with chronic 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).

Anti-NMDA-receptor antibody in initial diagnosis of mood disorder.

Anti-NMDAR encephalitis is increasingly recognized as one etiology of psychiatric symptoms, but there is not enough evidence on patients with mood disorder. We assayed anti-NR1/NR2B IgG antibodies in serum and/or cerebrospinal fluid of 62 patients initially diagnosed with mood disorder by a cell-based assay. We also investigated the specific patient characteristics and psychotic symptoms. At first admission, the patients showed only psychiatric symptoms without typical neurological signs or abnormal examination findings. Four of the 62 patients had anti-NR1/NR2B IgG antibodies. The anti-NR1/NR2B IgG antibody-positive patients showed more super- or abnormal sensitivity (P = 0.00088), catatonia (P = 0.049), and more conceptual disorganization (P < 0.0001), hostility (P = 0.0010), suspiciousness (P < 0.0001), and less emotional withdrawal (P < 0.0001) and motor retardation (P < 0.0001) on the Brief Psychiatric Rating Scale than the antibody-negative patients. During the clinical course, anti-NR1/NR2B IgG antibody-positive patients showed more catatonia (P = 0.0042) and met Graus's criteria for diagnosis of anti-NMDAR encephalitis, but negative patients did not. Immunotherapy was effective for anti-NR1/NR2B IgG antibody-positive patients, and there was the weak relationship (R²â€¯= 0.318) between the anti-NR1/NR2B IgG antibody titer in the cerebrospinal fluid and the Brief Psychiatric Rating Scale score.

Two-year effectiveness of risperidone and aripiprazole in the maintenance treatment of patients with recent-onset or chronic schizophrenia and related psychotic disorders: a retrospective multicenter study.

This study aimed to assess the comparative effectiveness of risperidone (RIS) versus aripiprazole (ARP) in patients with recent-onset or chronic schizophrenia during maintenance treatment and to examine the interaction between illness duration and the effectiveness of the treatment. All adult patients with schizophrenia and related disorders discharged from four psychiatric hospitals between 2006 and 2012 were screened and the 2-year continuation rates of monotherapy using RIS or ARP after discharge were examined retrospectively. The treatment continuation of the two drugs in patients with recent-onset (illness duration <5 years) or chronic schizophrenia (illness duration ≥5 years) and the moderator effect of illness duration on the effectiveness of the treatment were analyzed. Of 328 patients, 233 received RIS and 95 received ARP. No significant difference was found between the two drugs in the treatment continuation for the entire sample. However, there was a significant difference favoring ARP in the recent-onset subgroup mainly because of differences in tolerability, whereas RIS tended to present better outcomes in patients with chronic illness. Furthermore, there was a significant variation in the effectiveness of the treatment between recent-onset and chronic schizophrenia. Our results suggest that illness duration is an important moderator in terms of the long-term effectiveness of the two drugs.

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.

The critical treatment window of clozapine in treatment-resistant schizophrenia: Secondary analysis of an observational study.

Previous studies have suggested that a delay in initiating clozapine is one of the predictors of outcomes in treatment-resistant schizophrenia (TRS). However, whether there is a critical treatment window of clozapine in TRS and the duration of that window remain unclear. We conducted a secondary analysis of a previously published observational study using a retrospective chart review of 105 patients with TRS who were treated with clozapine. We included 90 patients who remained on clozapine for at least 3 months. The delay in initiating clozapine was an independent contributor to symptomatic improvement based on treatment with clozapine by multiple linear regression analysis. A receiver operating characteristic curve analysis (area under the curve: 0.78) confirmed 2.8 years was the best predictive cut-off value of delay in initiating clozapine for responses in patients treated with clozapine (sensitivity: 0.66, specificity: 0.84). In patients with a delay in initiating clozapine of ≤2.8 years and a delay in initiating clozapine of >2.8 years, the response rates were 81.6% and 30.8% (risk ratio=2.65; 95% confidence interval, 1.80, 3.63), respectively. Clinicians should reduce the delay in initiating clozapine to less than 3 years to improve symptomatic outcomes in TRS and to prevent clozapine-resistant schizophrenia.

Encephalitis With Antibodies to GluN2B During Administration of Clozapine.

Clozapine's immunomodulatory properties may contribute to its effect on schizophrenia as well as various adverse effects. However, a possible relationship between N-methyl-D-aspartate-type glutamate receptor antibodies, refractory schizophrenia, and clozapine has not been reported. We experienced a patient who developed refractory schizophrenia that mimicked an exacerbation of encephalitis with antibodies to N-methyl-D-aspartate-type glutamate receptor (GluN2B) after administration of clozapine for 26 days. We performed plasma exchange 5 times and subsequent steroid pulse therapy. The level of consciousness improved within a few weeks, but involuntary movement as well as psychotic symptoms remained. The production of anti-GluN2B antibodies may have contributed to the patient's resistance to the antipsychotic effects of clozapine in addition to mediating the encephalitis. When we administer clozapine to patients with refractory schizophrenia, we should be careful to differentiate between a diagnosis of refractory schizophrenia and encephalitis with antibodies to GluN2B.