Abstract 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.
Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may remain undiagnosed and untreated with immunotherapy. To investigate specific features and responses to immunotherapy of ...atypical anti-NMDAR antibody positivity patients, the authors reviewed and evaluated previous case reports/series including patients without seizure, involuntary movement, hypoventilation, or tumor. Of 22 patients identified, 21 responded to immunotherapy. Two patients had neurological/motor symptoms with few/no psychiatric/cognitive symptoms, and eight had both. Twelve patients presented with psychiatric/cognitive symptoms with few/no neurological/motor symptoms, and ≥1 had memory impairment, catatonia, abnormal MRI or electroencephalogram results. The authors recommend lumbar puncture and examination of anti-NMDAR antibodies for patients with these features.
Rationale
Adequate immunotherapies for anti-NMDAR encephalitis during pregnancy produce a relatively good clinical outcome for pregnant mothers and their infants, but there are no reports about the ...future growth of their babies. The damage of anti-NMDAR antibodies to early neuronal development is still unknown.
Objectives
Serum or cerebrospinal fluid from one patient with anti-NMDAR encephalitis (the index patient) and one patient with schizophrenia (the control patient) was administered to primary cultures of dissociated rat cortical neurons, and dendritic outgrowth, centrosome elimination, and branching of dendrites were investigated. For rescue experiments, serum of the index patient was replaced with normal culture media after 3 days’ administration of the index patient.
Results
Serum and cerebrospinal fluid of the index patient statistically significantly impaired dendritic outgrowth of cultured rat cortical primary neurons. Serum of the index patient also statistically significantly delayed centrosome elimination. Impaired dendritic outgrowth and delayed centrosome elimination were not perfectly rescued by changing to normal culture media. Serum of the index patient also statistically significantly reduced the branching of dendrites.
Conclusions
This is the first demonstration of the damage by anti-NMDAR antibodies on early dendritic development in vitro. As a strategy to protect embryonic neurons, our findings may support the efficacy of early immunotherapy for anti-NMDAR encephalitis in pregnancy.
Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but ...with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian EAS and European EUR) populations and/or that of trans-diseases (SCZ, bipolar disorder BD, and major depressive disorder MDD) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.
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.
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.
Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and ...function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo. These results explain why Rac1 and its activator (Kal-7) serve as important mediators of spine enlargement and why constitutive Rac1 activation decreases spine size. This mechanism likely underlies disturbances in glutamatergic neurotransmission that have been frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a signalosome involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.
Rationale
Depression in schizophrenia is an important symptom. We investigated whether depression and suicidal symptoms in the chronic phase are related to remote future clinical outcomes in patients ...with schizophrenia and whether psychotropics improved clinical outcomes.
Objectives
The subjects included 462 outpatients of working age (15 to 64 years old) with schizophrenia treated at Okayama University Hospital from January 2010 to December 2011. We investigated the relationship between the Clinical Global Impression-Severity score at the last visit (average 19.2 years) and the existence of previous depression, suicidal ideas, and suicide attempts. We adjusted by several possible confounders including medical history using multiple regression analysis or logistic regression analysis.
Results
Of 462 patients, 168 (36.4%) presented with depression 2 years after schizophrenia onset. A history of suicidal ideas and attempts was related to worse clinical outcome. In males, a history of depression was related to worse clinical outcome, but not in females. Lithium carbonate was related to better clinical outcome in all schizophrenia patients with depression, especially in males. Treatment with antidepressants was related to better clinical outcome only in males.
Conclusions
A history of depression or suicidal symptoms in the chronic phase predicted the future worse clinical outcome in patients with schizophrenia. The administration of lithium carbonate or antidepressants might be recommended, especially to male schizophrenia patients with depression.
Nalmefene is the only medication marketed to reduce the consumption of alcohol in patients with alcohol dependence, but it remains unclear which patients could most benefit from it. This study aimed ...to identify clinical moderators that affect treatment response to nalmefene in patients with alcohol dependence.
In a multicenter, randomized, controlled, double-blind, phase 3 study of nalmefene on Japanese patients with alcohol dependence, the relationship between the reduction of heavy drinking days (HDD) and total alcohol consumption (TAC) at 12 and 24 weeks of treatment and baseline variables of the participants were analyzed in a linear regression and multiple adjusted analysis.
Age < 65, no family history of problem drinking, age at onset of problem drinking ≥ 25, and not currently smoking were possible positive moderators. Nalmefene showed a significant HDD reduction in patients with age < 65 or no family history of problem drinking, and a significant TAC reduction in patients with age at onset of problem drinking ≥ 25 or who were not currently smoking. After multiple adjusted analyses, age < 65 (p = .028), no family history of problem drinking (p = .047), and age at onset of problem drinking ≥ 25 (p = .030) were statistically significant. Not currently smoking (p = .071) was marginally significant. In combination, these moderators indicated synergistic effects.
Alcohol-dependent patients with favorable prognostic factors such as non-smoking status, no family history of problem drinking, and a late-onset of problem drinking selectively benefit from nalmefene. Further research is needed to validate these exploratory results.
•No family history and late onset of problem drinking were positive moderators for nalmefene.•Not currently smoking moderated nalmefene’s effect positively.•Nalmefene may work selectively among alcoholics with favorable prognostic factors.•Positive moderators of nalmefene were opposite those previously reported for naltrexone.
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