Combination therapy of modified electroconvulsive therapy and long-acting injectable aripiprazole for dopamine supersensitivity psychosis: a case report.

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

Subjective achievement from psychiatry rotation in the Japanese postgraduate residency system: a longitudinal questionnaire study.

BACKGROUND: Psychiatry rotation has been mandatory in the Japanese postgraduate residency system since 2020. Some psychiatry-related competency items are stipulated as mandatory for residents. The current study aimed to clarify whether psychiatry rotation affected residents' subjective achievement of these competency items. METHODS: This longitudinal study was conducted among postgraduate residents who completed a rotation in the psychiatry department at Nagasaki University Hospital across two academic years (2020-2021). The survey was administered at the start and at the end of the psychiatry rotation. Residents evaluated their subjective understanding and confidence regarding initiating treatment for these competency items using a six-point Likert scale. The average scores for each item were compared between pre-rotation and post-rotation. RESULTS: In total, 99 residents (91.7%) responded to this survey. Residents had significantly higher scores at post-rotation compared with pre-rotation in all psychiatry-related competency items in both subjective understanding and confidence in initiating treatment. Additionally, strong effect sizes were found for many items. CONCLUSION: Residents improved learning about psychiatry-related competency items through psychiatry rotation. This finding suggests that it is reasonable for psychiatry rotation to be mandatory in the current Japanese postgraduate residency system. The importance of psychiatry is likely to increase in both undergraduate and postgraduate medical education in the future. It is necessary to continuously update educational strategies to meet changing social needs over time. As this study was conducted at a single institution, a multi-center study is needed to expand the current findings.

The effectiveness of lamotrigine for persistent depressive disorder: A case report.

AIM: Persistent depressive disorder (PDD) was first introduced in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), which encompasses numerous different conditions, including dysthymia, recurrent major depressive disorder, double depression, and chronic major depression. SSRIs are the first-line drugs for treatment of PDD; however, not all patients respond to SSRI treatment. CASE PRESENTATION: We describe a woman who was diagnosed with PDD. At the age of 38, the patient presented with anxiety, reduced energy, marked tiredness, and sleep disturbances. She was prescribed with three antidepressants (paroxetine, duloxetine, and mirtazapine), which were not effective in relieving her symptoms. She was also prescribed bromazepam, which was also not effective. Subsequently, she was switched to lamotrigine, which resulted in a marked improvement in symptoms. The antidepressants and bromazepam were gradually tapered and discontinued. CONCLUSION: This case demonstrates that lamotrigine may be effective for treating patients with antidepressant resistant PDD and suggests that it may be a promising alternative to combination therapy of antidepressants and benzodiazepines in the treatment of PDD.

Intracranial calcification and psychotic symptoms after irradiation in a patient with Fanconi anemia: A case report.

Background: Patients with Fanconi anemia (FA) are at high risk for the development of malignancies, and are often treated with radiation therapy. Radiation therapy during childhood can cause intracranial calcification after a latent period, which has been associated with psychiatric symptoms. Despite the high sensitivity of patients with FA to radiation, intracranial calcification has rarely been reported in these patients. Case Presentation: A 17-year-old girl presented with psychiatric symptoms and cognitive impairment. She had been diagnosed with FA at 3 years old, and had received a bone marrow transplant at 5 years old with a preparative regimen that included total body irradiation. Results of IQ tests revealed a characteristic pattern of decline between the ages of 15 and 17 years. Computed tomography indicated multiple intracranial calcifications in regions associated with psychotic symptoms, including the frontal lobe and thalamus. The patient's psychiatric symptoms improved with the administration of blonanserin. Limitations: The patient did not have regular intracranial imaging, making it difficult to confirm a direct relationship between intracranial calcification, psychiatric symptoms, and cognitive impairment. It is unclear whether the intracranial calcification in this case can be explained entirely by irradiation. Conclusion: This case suggests a link between FA, intracranial calcification, and psychosis, in which intracranial calcification may have caused psychiatric symptoms. At present, evidence regarding the characteristics of psychiatric symptoms of intracranial calcification and its treatment is lacking. The current case will be helpful for elucidating the pathogenesis of this disorder and developing appropriate treatment protocols.

Game-related behaviors among children and adolescents after school closure during the COVID-19 pandemic: A cross-sectional study.

Aim: Increased exposure to digital gaming content among youth in recent years has raised serious health concerns. Social restrictions such as school closures, imposed worldwide because of the ongoing COVID-19 pandemic, may increase exposure to gaming and lead to addictive gaming behavior in young people. In this study, we investigated gaming behaviors among Japanese students during COVID-19 school closures. Methods: Students completed questionnaires regarding their living conditions, game-related behaviors, diagnosis of Internet addiction, psychological difficulties, and the impact of the COVID-19 pandemic. We compared differences between the responses of potentially at risk for gaming disorder (potentially at risk for gaming disorder; defined in this paper with reference to the ICD-11 MMS criteria for gaming disorder [PGD]) students who met the criteria for a diagnosis of gaming disorder in ICD-11 MMS and those of control students. Logistic regression analysis was performed to predict the extent of factors contributing to potential gaming disorder. Results: Four thousand and forty-eight participants completed the survey. Compared with control students (93%), potentially at risk for gaming disorder (defined in this paper with reference to the ICD-11 MMS criteria for gaming disorder, PGD) students (7%) reported playing games for longer times, spending more money on in-game purchases, were of younger age at the start of game playing, showed a tendency toward Internet dependence, practised school avoidance or absenteeism, and demonstrated the need for psychological support. Moreover, participants in the PGD group reported more anxiety about COVID-19 than control participants, as well as an increase in game-playing time and amount of money spent on games during the COVID-19 pandemic. Conclusion: These results indicate that young people classified as having a gaming disorder not only exhibit characteristic game-related behaviors but may be psychologically and socially vulnerable and need special support, especially during the ongoing COVID-19 pandemic.

Switching from blonanserin tablets to blonanserin transdermal patches improves tardive dyskinesia: A case report.

Tardive dyskinesia (TD) is a common side effect of antipsychotics, and it remains a persistent and challenging problem. The blonanserin transdermal patch, developed in Japan and launched in September 2019, is the first antipsychotic transdermal treatment. Here, we describe a patient with schizophrenia who exhibited markedly improved orofacial dyskinesia after switching from blonanserin tablets to blonanserin transdermal patches. We speculate that the patch formulation might have led to more stable plasma blonanserin levels, thus reducing the side effects. Specifically, the patch formulation might have contributed to stable plasma levels via the continuous and direct absorption of blonanserin through the skin.

A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models.

Genetic and epidemiological evidence has suggested that genetic factors are important in schizophrenia, although its pathophysiology is poorly understood. This study used whole-exome sequencing to investigate potential novel schizophrenia-causing genes in a Japanese family containing several members affected by severe or treatment-resistant schizophrenia. A missense variant, chr12:132064747C>T (rs200626129, P2805L), in the E1A-binding protein P400 (EP400) gene completely segregated with schizophrenia in this family. Furthermore, numerous other EP400 mutations were identified in the targeted sequencing of a schizophrenia patient cohort. We also created two lines of Ep400 gene-edited mice, which had anxiety-like behaviours and reduced axon diameters. Our findings suggest that rs200626129 in EP400 is likely to cause schizophrenia in this Japanese family, and may lead to a better understanding and treatment of schizophrenia.

Genetic and epigenetic analyses of panic disorder in the post-GWAS era.

Panic disorder (PD) is a common and debilitating neuropsychiatric disorder characterized by panic attacks coupled with excessive anxiety. Both genetic factors and environmental factors play an important role in PD pathogenesis and response to treatment. However, PD is clinically heterogeneous and genetically complex, and the exact genetic or environmental causes of this disorder remain unclear. Various approaches for detecting disease-causing genes have recently been made available. In particular, genome-wide association studies (GWAS) have attracted attention for the identification of disease-associated loci of multifactorial disorders. This review introduces GWAS of PD, followed by a discussion about the limitations of GWAS and the major challenges facing geneticists in the post-GWAS era. Alternative strategies to address these challenges are then proposed, such as epigenome-wide association studies (EWAS) and rare variant association studies (RVAS) using next-generation sequencing. To date, however, few reports have described these analyses, and the evidence remains insufficient to confidently identify or exclude rare variants or epigenetic changes in PD. Further analyses are therefore required, using sample sizes in the tens of thousands, extensive functional annotations, and highly targeted hypothesis testing.

Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies.

Twin studies of psychiatric disorders such as schizophrenia and autism spectrum disorder have employed epidemiological approaches that determine heritability by comparing the concordance rate between monozygotic twins (MZs) and dizygotic twins. The basis for these studies is that MZs share 100% of their genetic information. Recently, biological studies based on molecular methods are now being increasingly applied to examine the differences between MZs discordance for psychiatric disorders to unravel their possible causes. Although recent advances in next-generation sequencing have increased the accuracy of this line of research, there has been greater emphasis placed on epigenetic changes versus DNA sequence changes as the probable cause of discordant psychiatric disorders in MZs. Since the epigenetic status differs in each tissue type, in addition to the DNA from the peripheral blood, studies using DNA from nerve cells induced from postmortem brains or induced pluripotent stem cells are being carried out. Although it was originally thought that epigenetic changes occurred as a result of environmental factors, and thus were not transmittable, it is now known that such changes might possibly be transmitted between generations. Therefore, the potential possible effects of intestinal flora inside the body are currently being investigated as a cause of discordance in MZs. As a result, twin studies of psychiatric disorders are greatly contributing to the elucidation of genetic and environmental factors in the etiology of psychiatric conditions.

Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities.

OBJECTIVE: To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH. METHODS: We performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene. Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus. RESULTS: In WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 encoding cilia- and flagella-associated protein is preferentially expressed in the testis. Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia. CONCLUSION: Our results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.

Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder.

Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case-control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case-control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.

Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease.

Monozygotic (MZ) twins have been thought to be genetically identical. However, recent studies have shown discordant variants between them. We performed whole-exome sequencing (WES) in five MZ twin pairs with discordant neurodevelopmental disorders and one healthy control MZ twin to detect discordant variants. We identified three discordant variants confirmed by deep sequencing after analysis by personalized next-generation sequencing (NGS). Three mutations in FBXO38 (chr5:147774428;T>G), SMOC2 (chr6:169051385;A>G) and TDRP (chr8:442616;A>G), were detected with low allele frequency of mutant alleles on deep sequencing, suggesting that these loci are mosaic due to somatic mutations in a developmental stage. Our results suggest that deep sequencing analysis would be an adequate method to detect discordant mutations in candidate genes responsible for heritable diseases.