No adverse events were observed in clozapine-treated patients on extended hematologic monitoring intervals during the coronavirus pandemic in four psychiatric centers in Japan.

AIM: As an emergency measure during the coronavirus disease pandemic, the monitoring interval for clozapine use was temporarily extended beyond the regulatory requirement in Japan, which is the safest monitoring interval worldwide. In this study, we aimed to explore the effect of this measure on patients undergoing clozapine treatment. METHODS: This retrospective chart review study included patients with treatment-resistant schizophrenia (TRS) who were undergoing clozapine treatment at four psychiatric institutions in Japan. Demographic characteristics and clinical information of these patients were collected on April 27, 2020, when Japanese psychiatrists were virtually allowed to prescribe clozapine beyond the regulatory requirement. Furthermore, information of adverse events related to the emergency measure was collected and analyzed. RESULTS: Of the 41 patients with TRS included in this study, 19 patients underwent extended hematological monitoring during clozapine treatment. No psychiatric or hematological adverse events were observed in the patients during the extended monitoring interval. CONCLUSION: This study suggested that there were few adverse events of clozapine-treated patients related to emergency measures in Japan. However, hematological monitoring intervals during clozapine treatment have been emergently extended worldwide; hence, it is necessary to verify the results of these measures.

Improvement of functional independence of patients with acute schizophrenia through early occupational therapy: a pilot quasi-experimental controlled study.

OBJECTIVE: To clarify whether early occupational therapy for patients with acute schizophrenia improves their functional independence. DESIGN: Quasi-experimental controlled study. SETTING: A university hospital in Japan. SUBJECTS: Forty-six out of 85 eligible patients with schizophrenia. INTERVENTION: Participants were allocated into an intervention group or a control group according to the month of admission. Activities in one-on-one and mainly non-verbal occupational therapy were provided for the intervention group immediately after admission, and not for the control group. MAIN MEASURES: Functional independence was measured using the Functional Independence Measure (FIM), at admission, at one month and at three months after admission. Psychiatric symptoms were also measured by the Brief Psychiatric Rating Scale. RESULTS: Patients in both groups showed improved FIM total scores at one month and three months after admission. In the intervention group, the medians (interquartile ranges) were 89.0 (44.5) at admission, 113.0 (18.5) at one month, and 121.0 (6.5) at three months. In the control group, they were 88.0 (32.0), 107.0 (39.5), and 111.0 (17.0). At three months, the total FIM scores were significantly higher in the intervention group than in the control group (p = 0.016). In the FIM cognitive domain, the scores were significantly higher in the intervention group than in the control group at one month (p = 0.038) and, three months (p = 0.012). Both groups showed improvement in Brief Psychiatric Rating Scale total scores, while no significant differences were observed between the groups at any points. CONCLUSION: The results suggest that early occupational therapy may improve functional independence in patients with acute schizophrenia.

Association analysis of putative cis-acting polymorphisms of interleukin-19 gene with schizophrenia.

BACKGROUND: Genome-wide association studies (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with multifactorial diseases, such as schizophrenia, are significantly more likely to be associated with expression quantitative trait loci (eQTL). It was recently suggested that an immune system imbalance plays an important role in the pathogenesis of schizophrenia. Interleukin-19 is a novel cytokine that may play multiple roles in immune regulation and various diseases. METHOD: We selected eight tag SNPs in the eQTL of the IL-19 gene. Seven of the SNPs are putative cis-acting SNPs. Then, we conducted a case-control study using two independent samples. The first sample comprised 567 schizophrenia patients and 710 controls, and the second sample comprised 677 schizophrenia patients and 667 controls. RESULT: We identified the TGAA haplotype as being significantly associated with schizophrenia (p=0.0036 and corrected p=0.0264), although a combined analysis of the TGAA haplotype with the replication samples exhibited a nominally significant difference (p=0.022 and corrected p=0.235). CONCLUSIONS: These results suggest that the IL-19 gene might slightly contribute to the genetic risk of schizophrenia. Thus, further research on the association of eQTL SNPs with schizophrenia is warranted.

Haplotype analysis of the DISC1 Ser704Cys variant in Japanese suicide completers.

The present study investigated the genetic association of the disrupted-in-schizophrenia 1 (DISC1) gene with suicide using 398 Japanese completed suicides and 511 healthy controls. The functional Ser704Cys variant of DISC1 was nominally associated with completed suicide. Enhanced evidence of association was observed in a multi-marker sliding window haplotype analysis (the lowest p=0.002). These findings warrant further studies with a larger sample size to confirm the association of DISC1 with suicide.

Association analysis of the DISC1 gene with schizophrenia in the Japanese population and DISC1 immunoreactivity in the postmortem brain.

The Disrupted-in-Schizophrenia 1 (DISC1) gene plays a role in the regulation of neural development. Previous evidence from genetic association and biological studies implicates the DISC1 gene as having a role in the pathophysiology of schizophrenia. In the present study, we explored the association between DISC1 missense mutation rs821616 (Ser704Cys) single nucleotide polymorphism (SNP) and four other SNPs (rs1772702, rs1754603, rs821621, rs821624) in the related haplotype block and schizophrenia in the Japanese population. We could not find a significant association of selected SNPs with schizophrenia after correction for multiple testing. We performed a meta-analysis of the Ser704Cys variant in schizophrenia using data from the present study and five previous Japanese population studies, and found no association with schizophrenia. We also examined DISC1 immunoreactivity in postmortem prefrontal cortex specimens of schizophrenia patients compared to control samples. The immunoreactivity revealed a significant decrease of DISC1 protein expression in the schizophrenia samples after ruling out potential confounding factors. However, the Ser704Cys variant did not show effects on DISC1 immunoreactivity. These results provide evidence that this functional genetic variation of DISC1 do not underlie the pathophysiology of schizophrenia in the Japanese population.

A missense mutation in the ITGA8 gene, a cell adhesion molecule gene, is associated with schizophrenia in Japanese female patients.

BACKGROUND: Cell adhesion molecules (CAMs) play pivotal role in the development of the central nervous system (CNS) and have also been reported to play role in the pathophysiology of schizophrenia. Missense mutations in the CAMs genes might alter the binding of their ligands, increasing the vulnerability to develop schizophrenia. METHODS: We selected 15 missense mutations in the CAMs genes of the CNS reported in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and examined the association between these mutations and schizophrenia in 278 patients and 284 control subjects (first batch). We also genotyped the positive single nucleotide polymorphisms (SNPs) in 567 patients and 710 control subjects (second batch) and in 635 patients and 639 control subjects (replication samples). RESULTS: Genotypic and allelic distributions of rs2298033 in the ITGA8 gene between the schizophrenia and control groups were significantly different in the first batch (p=0.005 and 0.007, respectively). Gender-based analysis revealed that the allelic and genotypic distributions of rs2298033 in the ITGA8 were significantly different between the schizophrenia and control groups among females in both batches (p=0.010, 0.011 and 0.0086, 0.010, respectively) but not among males. Combine analysis of rs2298033 with the replication samples revealed a more significant differences (p=0.0032; 0.0035 in the overall subjects and p=0.0024; 0.0025 in the female subjects, respectively). The significant differences for rs2802808 of the NFASC gene were only observed in the female subgroup of the first batch. CONCLUSION: These results suggest that the ITGA8 gene might have gender-specific roles in the development of schizophrenia. Further replication and functional studies are required to confirm these findings.

Haplotypes in the expression quantitative trait locus of interleukin-1ß gene are associated with schizophrenia.

Recent genome-wide association study (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with complex diseases such as schizophrenia are significantly more likely to be associated with expression quantitative trait loci (eQTL). The interleukin-1ß (IL1B) gene has been strongly implicated in the susceptibility to schizophrenia. In order to test this association, we selected five tag SNPs in the eQTL of the IL1B gene and conducted a case-control study using two independent samples. The first sample comprised 528 schizophrenic patients and 709 controls and the second sample comprised 576 schizophrenic patients and 768 controls. We identified two SNPs and several haplotypes as being significantly associated with schizophrenia. Previous reports indicated that one major haplotype that was protective against schizophrenia reduced IL1B transcription, while two risk haplotypes for schizophrenia enhanced IL1B transcription. Therefore, we measured IL1B mRNA expression in PAXgene-stabilized whole blood from 40 schizophrenic patients and 40 controls to explore the possibility of using five tag SNPs as schizophrenic trait markers. A multiple regression analysis taking confounding factors into account revealed that the T allele of rs4848306 SNP, which is a protective allele for schizophrenia, predicted reduced change in IL1B mRNA expression, regardless of phenotype. Our results appear to support the previous hypothesis that IL1B contributes to the genetic risk of schizophrenia and warrant further research on the association of eQTL SNPs with schizophrenia.

Association of FKBP5 gene haplotypes with completed suicide in the Japanese population.

BACKGROUND: The hypothalamus-pituitary-adrenal (HPA) axis is known to have a role in suicidal behaviors in patients with affective disorders. However, the incomplete overlapping of the genetic factors of suicidal behaviors and the genetic factors of affective disorders suggest that the genes associated with predisposition to suicidal behaviors and affective disorders are different. There is increasing evidence that genes regulating the HPA axis have effects on suicidal behaviors. To test this idea, we examined the association of three HPA axis-related genes (glucocorticoid receptor (NR3C1), mineralocorticoid receptors (NR3C2), and FK506 binding protein 5 (FKBP5)) with suicide. METHODS: We selected 3 SNPs of the FKBP5 (rs3800373, rs1360780, and rs2395635), 2 SNPs of the NR3C1 (rs6196 and rs10052957), and 3 SNPs of the NR3C2 genes (rs5525, rs5522, and rs2070951) based on their frequency in the Japanese population. Using TaqMan probe assays, we determined these SNPs in 219 completed suicide victims and 228 age- and gender-matched healthy control subjects. RESULTS: No significant differences in genotypic distribution or allelic frequency of any single SNPs between the completed suicide and control groups were observed. The distributions of TT, TC, and GT haplotypes of the FKBP5 gene (comprised of rs3800373 and rs1360780) between the completed suicide and control groups were significantly different (p<0.05 for each haplotype). The TC haplotype withstood correction for multiple comparisons (corrected p = 0.034). CONCLUSION: Our results suggest that haplotypes in FKBP5 gene are associated with completed suicide. This finding needs to be confirmed using rigorous SNPs selection in a larger sample.

Radiosynthesis and biodistribution in mice of a 18F-labeled analog of O-1302 for use in cerebral CB1 cannabinoid receptor imaging.

The suitability of an 18F-labeled form of N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4'-(5-fluoropentyl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide (1), a CB1 cannabinoid ligand with high binding affinity (Ki=0.91 nM) and moderate lipophilicity (log P7.4=2.9), as a radiotracer for positron emission tomography imaging was evaluated in mice. Ligand 1 was labeled with 18F (T1/2=109.7 min) by treatment of the corresponding tosyl derivative with [18F]fluoride ion in acetonitrile. Tissue distribution studies of the 18F-labeled form ([18F]1) in mice demonstrated low brain uptake with minimal specific binding in brain regions. Cyclosporin A (a modulator of P-glycoprotein) treatment significantly increased both the brain uptake and the brain-to-blood ratio of [18F]1, indicating the possibility that P-glycoprotein regulates the ability of [18F]1 to cross the blood brain barrier. Radioligand [18F]1 does not have the required properties for imaging the cerebral cannabinoid CB1 receptor in vivo.

Methoxy- and fluorine-substituted analogs of O-1302: synthesis and in vitro binding affinity for the CB1 cannabinoid receptor.

Methoxy and fluorine analogs substituted on the terminal carbon of the pentyl chain of N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide (O-1302) were synthesized in a multi-step process from 5-phenyl-1-pentanol, which was based on the 1,5-diarylpyrazole core template of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) through condensation of the respective amine with pyrazole carboxylic acid, in order to develop tracers for medical imaging. Their potency for inhibiting the binding of the CB1 antagonist [(3)H]SR141716 was evaluated with the aim of developing positron emission tomography (PET) ligands for the cerebral cannabinoid CB1 receptor. These analogs bearing a piperidinyl carboxamide at the C(3) of the pyrazole ring exhibited affinities comparable to those of the CB1 reference antagonist SR141716, which warrants further investigation using the radiolabeled form for biological imaging studies. A morpholine ring substituted at the C(3) of the pyrazole ring resulted in a reduction of the CB1 affinity.