佐々木 剛

22q11.2欠失症候群(以下,本疾患)は先天性心疾患や特徴的顔貌,そして精神疾患の合併が多いことで知られている。今回我々は,神経発達症や統合失調症として治療が行われ,先天性心疾患の既往や特徴的顔貌を欠くも後に本疾患と診断された症例を経験したので報告する。症例は20代前半女性。薬物療法を行うも,精神病症状,特に爆発性や衝動性を伴う滅裂な言動は改善せず,治療に難渋した。本疾患を疑い遺伝子診療科にコンサルトしたが,先天性心疾患の既往と特徴的顔貌を欠き疑いにくいとされた。翌年再度コンサルトを行い,遺伝子検査で本疾患との診断が確定した。本疾患は先天奇形の既往がないと診断されにくいとの報告があり,本邦で本症例のような経過での報告は,管見の限り初出である。先天奇形の既往が無くとも,神経発達症と精神病症状が存在し,特に爆発性や衝動性を伴う精神運動興奮が前景に立つ場合には,本疾患を鑑別することが望ましい。(著者抄録)

We describe the case of an unvaccinated 21-year-old Japanese male who experienced psychotic symptoms attributed to encephalopathy, known as post-acute COVID-19 syndrome (PACS). One week after his discharge following the remission of a SARS-CoV-2 infection, he experienced hyperactive delirium and unexpected movements of his limbs. As COVID-19-associated encephalopathy was suspected as a cause of the psychotic symptoms, he was admitted to the Department of Neurology. He received antiviral and steroid pulse therapy, but his psychiatric symptoms did not improve completely. Consequently, he was admitted to our psychiatric ward with a diagnosis of a primary psychotic disorder. Although he did not take psychopharmacotherapy, he gradually achieved a remission of psychiatric symptoms. At three months post-SARS-CoV-2 infection, single-photon emission computed tomography (SPECT) revealed hypoperfusion in the bilateral cerebellar dentate nuclei and occipital lobes. However, no abnormal findings were observed on fluorine-18 fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) at six months after the infection. This case indicates that (1) brain perfusion SPECT can be effective for detecting functional alterations in post-acute COVID-19-associated encephalopathy, and (2) it is necessary to carefully monitor patients' progress instead of quickly diagnosing a primary psychotic disorder.

We describe a 32-year-old Japanese female with hypersomnia and bipolar disorder. She had developed hypersomnia and sleep attacks in her teens. She was misdiagnosed with narcolepsy at a neurology department and then received methylphenidate (MPH) for many years. After giving birth, she developed postpartum depression and suffered from mood swings and irritability. Following 10-year treatment with methylphenidate, she experienced MPH-induced psychosis when she was in a manic state. Her psychosis improved rapidly with the cessation of methylphenidate. Furthermore, brexpiprazole treatment ameliorated her manic symptoms and hypersomnolence. Post-discharge, she was diagnosed with idiopathic hypersomnia based on nocturnal polysomnography and a multiple sleep latency test. This case indicates that brexpiprazole as a serotonin dopamine activity modulator might provide therapeutic effects against not only the patient's manic symptoms but also idiopathic hypersomnia.

Background: Several studies have reported that a switch to the dopamine partial agonist (DPA) aripiprazole (ARP), especially when the switch is abrupt, is likely to fail and sometimes worsen psychosis in schizophrenia patients already under high-dose antipsychotic treatment. Such a switching failure is speculated to be related to be the dopamine supersensitivity state. The risks of switching to the DPA brexpiprazole (BREX) have not been reported. Aims and Methods: We retrospectively analyzed the cases of 106 patients with schizophrenia to identify any factors related to the success or failure of switching to BREX. Results: The comparison between the patients with dopamine supersensitivity psychosis ( n = 44) and those without ( n = 62) revealed no significant difference in the switching failure judged at the sixth week. A comparison of the patients with successful switching ( n = 80) and those who failed ( n = 26) revealed that patients with treatment-resistant schizophrenia (TRS) were significantly more likely to fail. A logistic regression analysis also revealed that patients with past failure of switching to ARP are likely to succeed in switching to BREX. The 2-year follow-up of the patients with successful switching to BREX suggested that the patients who were treated with BREX, even temporarily, experienced some improvement in their Global Assessment of Functioning and Clinical Global Impression-Severity scores. Conclusions: Overall, the results indicate that patients with schizophrenia can be switched more safely to BREX compared to ARP. However, the failure of switching to BREX could be higher in patients with TRS, and thus, starting BREX treatment in refractory patients warrants careful monitoring.

Introduction Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have demonstrated differences in extensive brain structure, activity and network. However, there remains heterogeneity and inconsistency across these findings, presumably because of the diversity of the disorders themselves, small sample sizes, and site and parameter differences in MRI scanners, and their overall pathogenesis remains unclear. To address these gaps in the literature, we will apply the travelling-subject approach to correct site differences in MRI scanners and clarify brain structure and network characteristics of children with ADHD and ASD using large samples collected in a multi-centre collaboration. In addition, we will investigate the relationship between these characteristics and genetic, epigenetic, biochemical markers, and behavioural and psychological measures. Methods and analysis We will collect resting-state functional MRI (fMRI) and T1-weighted and diffusion-weighted MRI data from 15 healthy adults as travelling subjects and 300 children (ADHD, n=100; ASD, n=100; and typical development, n=100) with multi-dimensional assessments. We will also apply data from more than 1000 samples acquired in our previous neuroimaging studies on ADHD and ASD. Ethics and dissemination The study protocol has been approved by the Research Ethics Committee of the University of Fukui Hospital (approval no: 20220601). Our study findings will be submitted to scientific peer-reviewed journals and conferences.

BACKGROUND AND OBJECTIVE: The possibility of combination therapy with atomoxetine (ATO) and oxybutynin (OXY) has been suggested for obstructive sleep apnoea (OSA). However, the effectiveness of this treatment remains uninvestigated in Japanese OSA patients. Therefore, we performed a randomized, crossover, phase II, single-centre prospective trial to examine the effects of ATO-OXY therapy in Japanese OSA patients. METHODS: In total, 17 OSA patients participated in this study. The effects of one night of 80-mg ATO plus 5-mg OXY administration were compared with those of no medication administered before sleep. The primary and secondary outcomes comprised the apnoea-hypopnoea index (AHI) and nadir SpO2 , SpO2 drop time and sleep architecture, respectively. The safety endpoints included drug side effects and adverse events. RESULTS: The values of AHI, nadir SpO2 , 3% oxygen desaturation index (ODI), 4% ODI, and SpO2 drop time of <90% did not significantly differ between patients receiving ATO-OXY administration and no medication. Sleep architecture exhibited a significant change: ATO-OXY increased sleep stage N1 (p < 0.0001) and decreased stage N2 (p = 0.03), rapid eye movement (p < 0.0001) and sleep efficiency (p = 0.02). However, the subanalysis demonstrated an obvious decrease in AHI in five responder patients. Total sleep time and basal sleep efficiency tended to be lower in the responders compared with nonresponders (p = 0.065). No patients experienced severe adverse events or side effects. CONCLUSION: Overall, ATO-OXY therapy does not reduce AHI in Japanese OSA patients, although AHI was decreased in a proportion of patients. Future studies for identifying treatment response group characteristics are warranted.

BACKGROUND: Several lines of evidence suggest that glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor plays a role in certain behavioral manifestations common to Post-Traumatic Stress Disorder (PTSD). Ifenprodil tartrate is a neuroprotective agent that binds to the GluN2B subunit of the NMDA receptor. The aim of this study is to confirm whether ifenprodil tartrate is effective in the adolescent PTSD patients. METHODS: This is a randomized, double-blind, placebo-controlled trial. Ten adolescent (13 to 18 years old) PTSD patients were randomized into two arms: placebo (n = 4), 40 mg/day ifenprodil tartrate (n = 6) for 4 weeks. All of the patients were assessed by IES-R-J (Primary outcome measure), TSCC-J, CDRS-R, DSRS-C-J and CGI-I. RESULTS: A comparison of baseline IES-R-J total scores and 4-week end-point scores showed a mild trend of improvement (p = 0.0895) and the difference score was -9.314. A comparison of baseline scores and 2-week intermediate-point scores showed that IES-R-J hyperarousal subscores and TSCC-J subscores (dissociation subscores, sexual concerns subscores) improved significantly. A comparison of baseline TSCC-J sexual concerns subscores and 4-week end-point scores improved significantly. CONCLUSIONS: Our study may prove to be an short-term effective alternative safe treatment for adolescent patients with PTSD.

AIM: No effective pharmacological interventions have been developed for patients with methamphetamine use disorder. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels, which play a key role in the mechanism of action of addictive substances. We conducted a randomized, double-blind, exploratory, dose-ranging, placebo-controlled trial to examine the clinical efficacy of ifenprodil for the treatment of methamphetamine use disorder. METHODS: Participants were assigned to three groups: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. The drug administration period was 84 days. The primary outcome was the use or nonuse of methamphetamine during the drug administration period in the placebo group vs 120 mg/d ifenprodil group. We also assessed drug use status, relapse risk based on the Stimulant Relapse Risk Scale (SRRS), drug craving, and methamphetamine in urine as secondary outcomes. We further evaluated drug use status and SRRS subscale scores in patients who were not taking addiction medications during the study. RESULTS: Ifenprodil did not affect the primary or secondary outcomes. However, the additional analyses showed that the number of days of methamphetamine use during the follow-up period and scores on the emotionality problems subscale of the SRRS improved in the 120 mg/d ifenprodil group. The safety of ifenprodil was confirmed in patients with methamphetamine use disorder. CONCLUSION: The present findings did not confirm the efficacy of ifenprodil for methamphetamine use disorder treatment based on the primary or secondary outcomes, but we found evidence of its safety and efficacy in reducing emotionality problems. CLINICAL TRIAL REGISTRATION: The study was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000030849) and Japan Registry of Clinical Trials (no. jRCTs031180080). The main registration site is jRCT (https://jrct.niph.go.jp/).

<title>Abstract</title><sec> <title>Background</title> To control the spread of the new SARS-CoV-2 infection's disease (COVID-19), appropriate precautionary behaviors by the public should be promoted. There are international differences in public cognitive and behavioral pattern, attitudes toward information sources, and anxiety about COVID-19. Information about these differences could increase understanding of the patterns of epidemic-related anxiety and behavior, and would help optimize future policies for preventing the next wave of the epidemic. </sec><sec> <title>Methods</title> To examine between-country differences in perception, attitude, and precautionary behaviors toward COVID-19, we conducted a cross-sectional study using an online questionnaire survey. Participants were adults who had been registered in Cross Marketing Group Inc. and living in the UK, Spain, or Japan. A total of 8,000 people stratified by age were recruited on a first-come, first-serve basis. Knowledge of and anxiety about COVID-19, the frequency of access and perceived credibility of several information sources, and the frequency of each precautionary behavior were examined on March 27–28, 2020, in Japan and April 17–21, 2020, in the UK and Spain. </sec><sec> <title>Results</title> Knowledge, anxiety, and the frequency of precautionary behaviors were higher in the UK and Spain than in Japan. Participants with infected acquaintances were more concerned about COVID-19. However, participants in the UK rarely wore a medical mask. Participants in the UK and Spain were more eager to obtain information about COVID-19 than those in Japan. Participants in Spain tended not to trust official information and to believe specialists’ comments instead. </sec><sec> <title>Conclusion</title> The rapidity of the spread of COVID-19, cultural background, and recent political situations seemed to contribute to the international differences here. </sec>

<title>Abstract</title><sec> <title>Background</title> Incomplete clinical trials for pediatric drug development result in a lack of adequate scientific evidence for providing appropriate medication to pediatric populations; this is especially true for Japan. Thus, using the European Clinical Trials Database (EudraCT), this study aimed to identify the factors related to the study design and administration that lead to incompletion of clinical trials that included pediatric patients. </sec><sec> <title>Methods</title> We focused on clinical trials that included patients under the age of 18 registered in the database, named as the European Clinical Trials Database between January 1, 2014, and December 31, 2018. Two groups of trials were identified: “all cases completed” and “not all cases completed,” reflecting whether they were completed in all participating countries/regions or not. To identify the factors of the occurrence of “not all cases completed,” a logistic regression analysis was performed to calculate the odds ratios and 95% confidence intervals. In total, 142 clinical trials (95 “all cases completed” and 47 “not all cases completed”) were analyzed. </sec><sec> <title>Results</title> The logistic regression analysis showed the number of countries in which a clinical trial was conducted to be the only significant factor (odds ratio: 1.3; 95% confidence interval: 1.1-1.5); this was identified as the primary factor for the occurrence of “not all cases completed” in the clinical trials that included pediatric patients. </sec><sec> <title>Conclusion</title> Our findings suggest that the feasibility of clinical trials that include pediatric patients, such as whether the countries in which the trial is to be conducted are suitable, must be considered prior to the trial. </sec>

ナルコレプシー患者が抱えている顕在または潜在ニーズの実態を明らかにすることを目的に、当該患者257名(男性93名、女性164名、平均年齢30.9±11歳)を対象に、「ナルコレプシーに罹患したことで困った点」「ナルコレプシーに罹患して行った対策」「誰かに伝えたい想い」の自由記述を含むアンケート調査を行った。顕在ニーズに対する設問である「ナルコレプシーに罹患したことで困った点」では、98.4%が「困ったことがある」と回答した。自由記述を内容分析し、WHOが定義した3つの健康概念(「社会的」「肉体的」「精神的」)に分類した結果、最も記録単位が多かった健康概念「社会的」では【社会の理解】のカテゴリが最も多くを占めた。また、潜在ニーズに対する設問である「伝えたい想い」には68.1%が「伝えたい想いがある」と回答し、自由記述を内容分析した結果、最も記録単位が多かったカテゴリは【疾患の状態を理解してほしい】であった。

Glial cell line-derived neurotrophic factor (GDNF) may play an important role in attention. We investigated the association between serum GDNF levels and clinical status in unmedicated adults with attention deficit/hyperactivity disorder (ADHD) (n = 16) and healthy controls (n = 33); the levels were comparable between the ADHD and control groups (107.2 ± 31.7 vs. 110.5 ± 40.0 pg/mL, respectively; p = 0.77). In the ADHD group, higher GDNF serum levels were associated with severe subjective inattention (r = 0.528, p = 0.035). These preliminary results suggest that the serum GDNF level may not be a suitable biomarker for adult ADHD, although it may be associated with the pathophysiology of persistent inattention in adult ADHD.

Dopamine supersensitivity psychosis (DSP) in patients with schizophrenia is induced by treatment with a high dosage of antipsychotics for a long time period, and it is characterized by unstable psychotic symptoms. The upregulation of dopamine D2 receptor (DRD2) provoked by antipsychotics underlies DSP. Aripiprazole does not cause an excessive blockade of DRD2 and is less likely to upregulate DRD2 by aripiprazole's dopamine partial agonistic profile. Aripiprazole; however, has a potential risk of inducing severe rebound psychosis in patients who have already developed dopamine supersensitivity. Recently, an animal model study suggested that aripiprazole could attenuate established dopamine supersensitivity. The present study was conducted to examine whether very slowly switching to aripiprazole could help patients with schizophrenia with dopamine supersensitivity while avoiding rebound psychosis. This study was a single-armed and open-labeled study in which patients were observed over a period of 2 years. Only 11 patients were ultimately recruited. Five patients were successfully switched to a sufficient dose of aripiprazole and completed the study protocol. These five patients did not present with severe DSP over the study period, but only one patient showed a large improvement in psychopathology. Five patients dropped out of the study, and one of these five showed a severe worsening of psychosis. The present study indicated that the introduction of aripiprazole in patients with DSP was difficult, but suggested that aripiprazole could contribute to attaining a stable state in psychosis if it was applied with careful observation.

<title>Abstract</title> <bold>Objective:</bold> The coronavirus disease 2019 pandemic has caused school closures worldwide. Japan's Prime Minister declared a state of emergency based on the coronavirus pandemic for Tokyo, Chiba, and other prefectures on April 7, 2020. Children with ADHD are particularly vulnerable to the distress caused by the pandemic and physical distancing measures, and they might display increased behavioral problems. We surveyed 15 children with ADHD, aged 11.8 ± 2.8 years old; 13 were males and 2 were females (combined subtype, n=12; inattentive subtype, n=3). The children's ADHD-RS scores were assessed by their mother (n=12), father (n=1), or nursing home staff (n=2) from before the emergency declaration (in February or March 2020) to after the emergency declaration (April or May 2020). There were no changes of treating physician, drug type or quantity, or psychotherapy or assessment person from January 2020 to May 2020. <bold>Results:</bold> A comparison of the baseline scores and secondary outcomes reveals that the ADHD-RS total score and inattentive subscore worsened significantly during this period, whereas the hyper/impulsive subscore did not. In conclusion, we suggest that policymakers, healthcare providers and families should be mindful of the potential development of inattentiveness among children with ADHD who are quarantined because of COVID-19.

It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06-1.45, p < 0.001) for rs4680, 1.73 (95% CI 1.47-2.02, p < 0.0001) for rs1800497, and 1.79 (95% CI 1.35-2.36, p < 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (p < 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59-2.19, p < 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.

Background: The novel corona virus infection (COVID-19) quickly became a pandemic state. Identifying characteristics of "possible super spreaders", suggested as a dominant cause of rapid spreading transmission, will help us to design proper prevention strategies. Methods: We conducted a nation-wide online survey to investigate the relationship of perception and anxiety levels about COVID-19 to the possible risk behaviors for spread of the virus in Japan. We recruited a total of 4,000 citizens, who responded to the questionnaire including several questions regarding the level of fear and anxiety about COVID-19, infection preventive behaviors and access to media with trust level about the virus as well as some demographic and socioeconomic data during March 27th and 28th, 2020. Findings: Thirteen-point-three percent of the participants rated "1" on a nine-point Likert with respect to the knowledge about COVID-19. Ten-point-one percent and 11.7% presented no anxiety of being infected and transmission to others. Ten-point-eight percent showed no worry about symptomatic aggravation. Eight-point-one percent had no serious concern about expanding infection. The distribution of these items was highly correlated with each other. Participants with the low level of knowledge about COVID-19 were likely to less frequently access any information sources and neither trust them. They were less anxious about their health status, and less likely to put precautionary behaviors such as washing hands and avoiding crowded spaces, suggested by statistical analyses. Interpretation: The present study suggests that it is greatly important to enlighten those have no concerns about this crisis of COVID-19 and modify their risk behavior via various ways, in order to prevent and control this viral pandemic. Funding: This study was funded by the management grand provided to Chiba University Graduate School of Medicine and the Japan Society for the Promotion of Science KAKENHI grants.

We describe the case of a 49-year-old Japanese male patient successfully treated with a paliperidone rechallenge following 2-year treatment with clozapine for treatment-resistant schizophrenia. He had responded well to conventional antipsychotic treatment for the initial psychotic episode but gradually developed dopamine supersensitivity; even treatment with paliperidone and another antipsychotic medication (a total up to 1700 mg in chlorpromazine-equivalent dose) had not improved his psychotic symptoms. Clozapine treatment produced temporary symptomatic relief, but the clozapine dose could not be increased to &gt; 150 mg due to the patient’s intolerance. Following low-dose clozapine treatment for 2 years, a rechallenge with paliperidone monotherapy ameliorated his psychotic symptoms. This suggests that clozapine may have the potential to release the dopamine supersensitivity state. Our patient’s case indicates that for patients with dopamine supersensitivity psychosis, a rechallenge with a previously ineffective antipsychotic after clozapine treatment may be successful.

BACKGROUND:Patients with adolescent idiopathic scoliosis (AIS) under brace treatment perceive stress, not only from scoliosis, but from wearing the brace itself. The Bad Sobernheim Stress Questionnaire-Brace (BSSQbrace) was developed to assess the level of psychological stress induced by brace treatment for AIS. However, a Japanese version of BSSQbrace had not yet been developed. METHODS:We developed a Japanese adaptation of the Bad Sobernheim Stress Questionnaire-Brace (JBSSQ-brace) through a guideline-based process to adapt assessment of the psychological effect of brace treatment for AIS in Japanese patients. We administered the JBSSQ-brace to 71 patients with AIS under brace treatment in our clinic. Internal consistency and reproducibility were analyzed using Cronbach's alpha and a test-retest method. RESULTS:We included 44 patients that responded adequately. JBSSQ-brace achieved excellent internal consistency (Cronbach's alpha = 0.84 for the first questionnaire, and 0.87 for the second) and substantial reproducibility (interclass correlation coefficient = 0.75). The average score for JBSSQ-brace was 16.5 and 16.8, and almost 40% of AIS patients felt a moderate-to-high stress from brace treatment. CONCLUSIONS:JBSSQ-brace is an effective instrument with which to evaluate the stress level from brace treatment in Japanese patients with AIS.

AIMS: Pharmacotherapy for methamphetamine dependence has not yet been developed in Japan or elsewhere in the world. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels that play a key role in the mechanism of action of addictive substances. Our aim is to examine the safety, efficacy, and outcomes of ifenprodil for the treatment of methamphetamine dependence in a randomized, double-blind, placebo-controlled trial. METHODS: The recruitment of outpatients with methamphetamine dependence began in January 2018. The patients will be randomized into three arms: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. Placebo or ifenprodil will be taken for 84 days. We will use Cerocral fine granule 4%® (ifenprodil tartrate). Follow-up assessments will be conducted for 84 d after the drug administration period. All of the patients will be assessed by self-administered questionnaires and urine tests. The primary outcome will be the presence or absence of methamphetamine use during the 84-day administration period in the 120 mg/d ifenprodil and placebo groups. Secondary outcomes will include the number of days and percentage of days of abstinence from methamphetamine use, positive urine for methamphetamine, relapse risk, and drug craving. DISCUSSION: This study is the first clinical trial of ifenprodil treatment for methamphetamine dependence and is designed as an intervention test with off-label drug use. The present study is expected to provide evidence of the effects of ifenprodil treatment on methamphetamine dependence. TRIAL REGISTRY: This trial was registered in the UMIN clinical trial registry (UMIN000030849; date of registration: January 17, 2018).

OBJECTIVE: 'Treatment-resistant depression' is depression that does not respond to an adequate regimen of evidence-based treatment. Treatment-resistant depression frequently becomes chronic. Children with treatment-resistant depression might also develop bipolar disorder (BD). The objective of this study was to determine whether serum levels of oxytocin (OXT) in treatment-resistant depression in adolescents (TRDIA) differ from non-treatment-resistant depression in adolescents (non-TRDIA) or controls. We also investigated the relationships between serum OXT levels and the clinical symptoms, severity, and familial histories of adolescent depressive patients. METHODS: We measured serum OXT levels: TRDIA (n = 10), non-TRDIA (n = 27), and age- and sex- matched, neurotypical controls (n = 25). Patients were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and the Depression Self-Rating Scale for Children-Japanese Version (DSRS-C-J). The patients were also assessed retrospectively using the following variables: familial history of major depressive disorder and BD (1st degree or 2nd degree), history of disruptive mood dysregulation disorder, recurrent depressive disorder (RDD), history of antidepressant activation. RESULTS: Serum levels of OXT among the TRDIA and non-TRDIA patients and controls differed significantly. Interestingly, the rates of a family history of BD (1st or 2nd degree), RDD and a history of antidepressant activation in our TRDIA group were significantly higher than those of the non-TRDIA group. CONCLUSIONS: Serum levels of OXT may play a role in the pathophysiology of TRDIA.

Dopamine supersensitivity psychosis (DSP) resulting from antipsychotic treatment is related to treatment-resistant schizophrenia (TRS), and its treatment has not been established to date. Maintaining thoroughly stable occupancy of the dopamine D2 receptor by risperidone long-acting injectable (RLAI) is one strategy for treatment. In this study, RLAI was given as an adjunctive medication to oral antipsychotic(s), which were switched partially and gradually to RLAI in 108 treatment-resistant patients for an additional 1-year follow-up in a 2-year study, and to compare the effects in 72 patients with a DSP history (DSP group) and 36 patients without this history (NonDSP group). Although both groups showed significant improvements in the total Brief Psychotic Rating Scale (BPRS) score during the follow-up period, greater improvement was observed for the DSP group than the NonDSP group. High doses (&gt; 850 mg chlorpromazine-dose combined of oral antipsychotics and RLAI) did not significantly change in both groups throughout the study period; however, extrapyramidal symptoms, including tardive dyskinesia, were significantly improved only in the patients with DSP. This study strongly suggested that the RLAI treatment, even with only partial switching, provides relief from refractory symptoms, particularly for patients with a history of DSP. Clinical trial registration: http://www.umin.ac.jp/:UMIN000008487

<sec id="S0924270815000599_abs1" sec-type="general"><title>Objective</title>Glutamatergic neurotransmission via the <italic>N</italic>-methyl-<sc>d</sc>-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. </sec><sec id="S0924270815000599_abs2" sec-type="general"><title>Method</title>We measured the serum levels of <sc>d</sc>-serine, <sc>l</sc>-serine, glycine, glutamate and glutamine in patients with depression (<italic>n</italic>=70), and age-matched healthy subjects (<italic>n</italic>=78). </sec><sec id="S0924270815000599_abs3" sec-type="results"><title>Results</title>Serum levels of <sc>d</sc>-serine and <sc>l</sc>-serine in patients with depression were significantly higher than those of healthy controls (<italic>p</italic>&lt;0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of <sc>l</sc>-serine to glycine in patients was significantly higher than that of healthy controls (<italic>p</italic>&lt;0.001). </sec><sec id="S0924270815000599_abs4" sec-type="conclusion"><title>Conclusion</title>This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the <sc>d</sc>-serine-<sc>l</sc>-serine-glycine cycle plays a role in the pathophysiology of depression. </sec>

BACKGROUND: We assessed the effect of switching patients with major depressive disorder to milnacipran following an initial selective serotonin reuptake inhibitor treatment failure, and explored potential biomarkers in their blood. METHODS: We conducted a prospective, open-label, 24-week trial. Depression was assessed with the 17-item Hamilton Depression Rating Scale. Patients showing a ≥50% reduction in Hamilton Depression Rating Scale scores from baseline to final visit were considered responders. Regarding adverse effects (AEs), moderate-to-severe AEs were specifically identified as effects that required any medical treatment or that induced treatment withdrawals. We also measured blood levels of various molecules including inflammatory cytokines. RESULTS: Of the 30 participants who enrolled, 17 completed this study. The responder rate was 30% (n=10). Baseline serum levels of interleukin-6 (Z=-2.155; P=0.031) and interleukin-8 (Z=-2.616; P=0.009) were significantly higher when moderate-to-severe AEs were present (n=13 patients with moderate-to-severe AEs). Serum levels of macrophage inflammatory protein-1β showed a significant continuous decrease from the baseline level (Friedman's test: χ (2)=23.9, df=4, P<0.001) only in non-responders. CONCLUSION: These results demonstrate that serum levels of interleukin-6, interleukin-8, and macrophage inflammatory protein-1β as potential blood biomarkers could be utilized to identify the responsiveness of patients to serotonin and norepinephrine reuptake inhibitor like milnacipran, or to identify those patients who may experience AEs strong enough to warrant discontinuation of treatment.

The present case is of a 14-year-old female with trichotillomania (TTM) that was treated with a low dose of aripiprazole (ARP) 1.5 mg/day. To our knowledge, this is the first published report to show an improvement of pubertal TTM using an ultra-low dose of ARP. In this case, a 50-mg fluvoxamine monotherapy for 2 years and a subsequent 4-month comprehensive cognitive behavioral therapy (CBT) monotherapy did not improve her hair-pulling symptoms. However, the treatment with a low-dose ARP of 1.5 mg/day dramatically improved her TTM symptoms without extrapyramidal symptoms. In this regard, low-dose ARP treatment for TTM might be a safe alternative to antidepressants, which carry the risk of agitation with suicidal ideation in adolescents.

Attention Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorder (ASD) are highly comorbid, and both disorders share executive function deficits. Accumulating evidence suggests that ASD patients have significantly lower peripheral oxytocin (OXT) levels compared with their normal counterparts, and that the repetitive behavior seen in ASD is related to abnormalities in the OXT system. In this study, we investigated whether serum levels of OXT are altered in pediatric patients with ADHD. We measured serum OXT levels: drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22). Patients were evaluated using the ADHD-RS. Serum levels of OXT in total subjects with ADHD were significantly decreased compared with those of neurotypical controls, and serum levels of OXT in drug naive ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum OXT levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients. In conclusion, this study suggests that decreased levels of OXT may play a role in the pathophysiology of patients with ADHD and its inherent inattentiveness.

OBJECTIVE: Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti-oxidant and anti-inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia. METHODS: We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN-glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8. RESULTS: A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants. CONCLUSIONS: This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia.

Objective: Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP. Method: This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2. weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression-Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively. Results: While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥. 20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group. Conclusions: It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP.Clinical trials registration: UMIN (UMIN000008487). © 2014 The Authors.

BACKGROUND: Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this open-label trial was to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD. SUBJECTS AND METHODS: This was a 4-week, open-label, proof-of-efficacy pilot study for pediatric subjects with ADHD. Ten pediatric ADHD subjects (70% male; mean age, 9.9 years; combined [inattentive and hyperactive/impulsive] subtype, n=7; inattentive subtype, n=3; hyperimpulsive subtype, n=0) received tipepidine hibenzate taken orally at 30 mg/day for 4 weeks. All subjects were assessed using the ADHD Rating Scale IV (ADHD-RS), Japanese version, and the Das-Naglieri Cognitive Assessment System (DN-CAS), Japanese version. RESULTS: A comparison of baseline scores and 4-week end-point scores showed that all the ADHD-RS scores (total scores, hyperimpulsive subscores, and inattentive subscores) improved significantly (P<0.001). Furthermore, a comparison of baseline DN-CAS total scores and 4-week end-point scores showed a mild trend of improvement (P=0.093). Tipepidine was well tolerated, with no patients discontinuing medication because of side effects. CONCLUSION: Our pilot study suggests that tipepidine therapy may prove to be an effective alternative treatment for pediatric patients with ADHD. Nonetheless, more detailed randomized, double-blind trials are needed to confirm tipepidine's efficacy.