Multiple-time measurements of multidimensional psychiatric states from immediately before the COVID-19 pandemic to one year later: A longitudinal online survey of the Japanese population

The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected the mental health of both infected and uninfected people. Although most psychiatric disorders have highly overlapping genetic and pathogenic backgrounds, most studies investigating the impact of the pandemic have examined only single psychiatric disorders. It is necessary to examine longitudinal trajectories of factors that modulate psychiatric states across multiple dimensions. 2274 Japanese citizens participated in online surveys presented in December 2019 (before the pandemic), August 2020, Dec 2020, and April 2021. These surveys included nine questionnaires on psychiatric symptoms, such as depression and anxiety. Multi-dimensional psychiatric time series data were then decomposed into four principal components. We used generalized linear models to identify modulating factors for effects of the pandemic on these components. The four principal components can be interpreted as general psychiatric burden, social withdrawal, alcohol-related problems, and depression/anxiety. Principal components associated with general psychiatric burden and depression/anxiety peaked during the initial phase of the pandemic. They were further exacerbated by the economic burden of the pandemic. In contrast, principal components associated with social withdrawal showed a delayed peak, with human relationships as an important risk modulating factor. In addition, being elderly and female were risk factors shared across all components. Our results show that COVID-19 has imposed a large and varied burden on the Japanese population since the commencement of the pandemic. Although components related to the general psychiatric burden remained elevated, peak intensities differed between components related to depression/anxiety and those related to social anxiety. These results underline the importance of using flexible monitoring and mitigation strategies for mental problems, according to the phase of the pandemic.

Japanese Project for Telepsychiatry Evaluation during COVID-19: Treatment Comparison Trial (J-PROTECT): Rationale, design, and methodology

IntroductionThe COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date. MethodsThe targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a "telepsychiatry group" (at least 50% of visits to be conducted using telemedicine, with at least one face-to-face treatment [FTF] every six months) or an "FTF group" (all visits to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group. DiscussionThis study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry. Trial RegistrationjRCT1030210037, Japan Registry of Clinical Trials (jRCT)

Clozapine Is Better Tolerated in Younger Patients: Risk Factors for Discontinuation from a Nationwide Database in Japan

Objective@#The effectiveness of clozapine is clearly superior to other antipsychotics in the treatment of refractory schizophrenia. Clozapine leads to various side effects, and therefore many patients are forced to discontinue. In this study, we analyzed the registry database of all cases in Japan to identify risk factors for discontinuation of clozapine. @*Methods@#The Clozaril patient monitoring service® (CPMS) database from July 31, 2009 to January 26, 2020 was acquired. We defined the following exclusion criteria: patients who had ever taken clozapine by a non-CPMS method, such as an individual import or clinical trial, patients who did not receive clozapine after being enrolled in CPMS, and patients with initial doses other than 12.5 mg (outside the current protocol). Therefore, all patients in this study are new users. Multivariate Cox regression analysis was used to investigate independent risk factors associated with time to discontinuation of clozapine. @*Results@#We identified 8,263 patients as the study population. Clozapine discontinuation was significantly associated with age 40 and older [hazard ratio (HR)=1.66, p<0.001], intolerance to olanzapine (HR=1.31, p=0.018), previous treatment with clozapine (HR=1.30, p=0.001), and leukocyte counts <6,000/mm3 (HR=1.24, p<0.001). The Kaplan-Meier curves for clozapine discontinuation by age group revealed that older age at the time of clozapine introduction tended to have lower continuation rates. @*Conclusion@#Careful administration is important because patients with these factors have a high risk of discontinuation. In addition, the initiation of clozapine during the younger period was more effective and more tolerated.

PTSD symptoms related to COVID-19 as a high risk factor for suicide - Key to prevention

BackgroundRising rates of suicide, the most dreadful consequence of mental health effects elicited by the coronavirus pandemic (COVID-19) are cause for grave concern. However, the exact association between mental health problems and suicide remains largely unknown in relation to COVID-19. MethodsTo determine the impact of COVID-19 on suicide trajectory, we used an interrupted time-series design to analyze monthly suicides rates extracted from Japans national database. We next used mixed-effects regression models to investigate the relationship between the nationwide suicide increase in August 2020 and psychiatric states of 4,348 individuals from an online survey performed immediately before (December 2019) and during (August 2020) the pandemic. Psychiatric states included depression, anxiety, and COVID-19-related PTSD, a form of severe event-related stress. FindingsIn Japan, suicides had gradually decreased before COVID-19 ({beta} = -0{middle dot}7x10-3, t57 = -14{middle dot}2, p = 8{middle dot}6x10-46), but increased drastically after a state of emergency was declared in April 2020 ({beta} = 0{middle dot}9x10-2, t57 = 17{middle dot}3, p = 2{middle dot}3x10-67). We found that PTSD symptoms reliably predict COVID-19s impact on suicide rates ({beta} = 6{middle dot}3x10-4, t3936 = 5{middle dot}96, p = 2{middle dot}7x10-9). In contrast, depression scores are a reliable indicator of stress vulnerability (i.e. future suicide increases, {beta} = 0{middle dot}001, t3936 = 6{middle dot}6, p = 4{middle dot}5x10-11). Simulations revealed that a one-point reduction in PTSD score could decrease suicides by up to 3{middle dot}1 per ten million people per month in Japan. InterpretationPTSD symptoms may help to identify high-risk groups so as to increase efficacy of prevention policies. FundingKDDI collaborative research contract, the Innovative Science and Technology Initiative for Security (JPJ004596), ATLA and AMED (JP20dm0307008). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on December 2, 2020, for "COVID" and "suicid*" in the titles or abstracts of published articles and obtained 269 hits. No language restrictions were applied to the search. Nearly all previous articles on suicide and COVID-19 have reported simulation studies of suicide counts and rates in case studies, editorials, letters, and commentaries. To date, no study has analyzed the association between psychiatric states and suicide increases in the context of the COVID-19 pandemic. Added value of this studyTo the best of our knowledge, this is the first study reporting a concrete approach to predict suicide rate increases from psychiatric states during the COVID-19 pandemic. Our findings indicate that PTSD symptoms are a reliable surrogate endpoint of pandemic-related suicide increase. Implications of all available evidenceThis work provides a new perspective on preparing guidelines for suicide prevention. Efforts should focus on reducing PTSD severity for single individuals and populations to reduce the overall suicide risk.

fNIRS Assessment during an Emotional Stroop Task among Patients with Depression: Replication and Extension

OBJECTIVE: Accumulated evidence collected via functional near-infrared spectroscopy (fNIRS) has been reported with regard to mental disorders. A previous finding revealed that emotional words evoke left frontal cortex activity in patients with depression. The primary aim of the current study was to replicate this finding using an independent dataset and evaluate the brain region associated with the severity of depression using an emotional Stroop task. METHODS: Oxygenized and deoxygenized hemoglobin recording in the brain by fNIRS on 14 MDD patients and 20 normal controls. RESULTS: Hyperactivated oxygenized hemoglobin was observed in the left frontal cortex on exposure to unfavorable stimuli, but no significant difference was found among patients with depression compared with healthy controls on exposure to favorable stimuli. This result is consistent with previous findings. Moreover, an evoked wave associated with the left upper frontal cortex on favorable stimuli was inversely correlated with the severity of depression. CONCLUSION: Our current work using fNIRS provides a potential clue regarding the location of depression symptom severity in the left upper frontal cortex. Future studies should verify our findings and expand them into a precise etiology of depression.

Comparative Analysis of the WISC between Two ADHD Subgroups

OBJECTIVE: The prevalence of attention deficit/hyperactivity disorder (ADHD) in school-age children is 7.2%, and ADHD is divided into clinical subtypes. METHODS: The current study explored whether specific cognitive profiles as assessed using the Wechsler Intelligence Scale for Children (WISC)-IV could be obtained for each clinical ADHD subtype (ADHD-Inattentive type and ADHD-Combined type) and investigated the correlation between WISC scores and parental age at their children’s birth or birthweight. The enrolled sample comprised 12 ADHD-I and 15 ADHD-C subjects. RESULTS: An impaired Processing Speed Index was found in ADHD-I. The age of the father at the child’s birth and birthweight positively correlated with the full scale intelligence quotient (FSIQ) score in the WISC assessment. CONCLUSION: Inattentiveness within the behaviors of the children with ADHD-I is partly due to the impaired processing speed, therefore effective support for ADHD will be conducted if educator decreases their speaking speed. Since biological basis of ADHD is still largely unknown, future studies using both psychological and biological methods will reveal the etiology of ADHD. These scientific assessments will provide information for more effective approaches in the care of children with ADHD.

The Mechanism of Anti-Epileptogenesis by Levetiracetam Treatment is Similar to the Spontaneous Recovery of Idiopathic Generalized Epilepsy during Adolescence

OBJECTIVE: The anti-epileptogenic drug levetiracetam has anticonvulsant and anti-epileptogenesis effects. Synergy between cell death and inflammation can lead to increased levels of apoptosis inhibitory factors and brain-derived neurotrophic factor, aberrant neurogenesis and extended axon sprouting. Once hyperexcitation of the neural network occurs, spontaneous seizures or epileptogenesis develops. This study investigated whether the anti-epileptogenic effect of levetiracetam is due to its alternate apoptotic activity. METHODS: Adult male Noda epileptic rats were treated with levetiracetam or vehicle control for two weeks. mRNA quantification of Bax, Bcl-2 and GAPDH expression were performed from prefrontal cortex and hippocampus tissue samples. RESULTS: The levetiracetam-treated group showed a significant increase of Bax/Bcl-2 mRNA expression ratio in the prefrontal cortex than the control group, but no change in the Bax/Bcl-2 mRNA expression ratio in hippocampus. CONCLUSION: Idiopathic generalized epilepsy including childhood absence epilepsy develop at childhood and recover spontaneously during adolescence. The aberrant neural excitable network is pruned by a neural-maturing action. This study suggests the mechanism of acquired anti-epileptogenesis by levetiracetam treatment may be similar to spontaneous recovery of idiopathic generalized epilepsy during adolescence.

Association between Medication Adherence and Duration of Outpatient Treatment in Patients with Schizophrenia

OBJECTIVE: Medication adherence is important in the treatment of schizophrenia, and critical periods during treatment may be associated with relapse. However, the relationship between adherence and duration of outpatient treatment (DOT) remains unclear. The authors aimed to clarify the relationship between adherence and DOT at a psychiatric hospital in Japan. METHODS: For outpatients with schizophrenia who regularly visit Shin-Abuyama hospital, the authors conducted a single questionnaire survey (five questions covering gender, age, DOT, medication shortages, and residual medication) over one month period. Participants were divided into two groups whether DOT were from more than one year to within five years or not. Mantel-Haenszel analysis and logistic regression analysis were performed on the data regarding the medication adherence. RESULTS: Effective answers were received for 328 patients. The residual medication rate was significantly higher among those receiving outpatient treatment from more than one year to within five years than five years than those receiving outpatient treatment for more than five years or less than one year (p=0.016). CONCLUSION: This survey suggests that there are critical periods during which patients are most prone to poor adherence. Because poor adherence increases the risk of relapse, specific measures must be taken to improve adherence during these periods.

Increases in iPS Transcription Factor (Oct4, Sox2, c-Myc, and Klf4) Gene Expression after Modified Electroconvulsive Therapy

OBJECTIVE: Electroconvulsive therapy (ECT) is a reasonable option for intractable depression or schizophrenia, but a mechanism of action has not been established. One credible hypothesis is related to neural plasticity. Three genes (Oct4, Sox2, c-Myc) involved in the induction of induced pluripotent stem (iPS) cells are Wnt-target genes, which constitute a key gene group involved in neural plasticity through the TCF family. Klf4 is the other gene among Yamanaka's four transcription factors, and increases in its expression are induced by stimulation of the canonical Wnt pathway. METHODS: We compared the peripheral blood gene expression of the four iPS genes (Oct4, Sox2, c-Myc, and Klf4) before and after modified ECT (specifically ECT with general anesthesia) of patients with intractable depression (n=6) or schizophrenia (n=6). Using Thymatron ten times the total bilateral electrical stimulation was evoked. RESULTS: Both assessments of the symptoms demonstrated significant improvement after mECT stimulation. Expression of all four genes was confirmed to increase after initial stimulation. The gene expression levels after treatment were significantly different from the initial gene expression in all twelve cases at the following treatment stages: at the 3rd mECT for Oct4; at the 6th and 10th mECT for Sox2; and at the 3rd, 6th and 10th mECT for c-Myc. CONCLUSION: These significant differences were not present after correction for multiple testing; however, our data have the potential to explain the molecular mechanisms of mECT from a unique perspective. Further studie should be conducted to clarify the pathophysiological involvement of iPS-inducing genes in ECT.

Genetic Polymorphisms in Dopamine- and Serotonin-Related Genes and Treatment Responses to Risperidone and Perospirone

We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.

An Association Study of the Signal Transducer and Activator of Transcription 6 Gene With Periodic Psychosis

OBJECTIVE: Recent molecular and genetic investigations have suggested that the current nosology for major psychiatric disorders, based on the "two-entities-principal" is not accurate with respect to clinical observations; patient groups that do not fit to the current operative diagnostic boundaries are readily identified. We aimed to perform an investigation of the signal transducer and activator of transcription 6 (STAT6) gene (located on 12q13), which has an important role in the apoptotic cascade, with patients suffering from periodic psychosis. METHODS: Genetic association study has been employed for the current work. Investigated six tag-SNPs were chosen from Hapmap database. RESULTS: Among six tag-SNPs, one marker (rs10783813), located in the STAT6 gene, showed modest association (p<0.05), although no marker or haplotype block showed association after Bonferroni's correction. CONCLUSION: Future studies will reveal the etiological role of STAT6, and of other genes of the apoptotic cascade, in major psychiatric disorders.