Psychometrics of rating scales for externalizing disorders in Japanese outpatients: The ADHD-Rating Scale-5 and the Disruptive Behavior Disorders Rating Scale.

OBJECTIVES: This study validated the Japanese version of the Attention-Deficit/Hyperactivity Disorder-Rating Scale-5 (ADHD-RS-5) and the Disruptive Behavior Disorders Rating Scale. We extended the ADHD-RS-5 by adding the oppositional defiant disorder and conduct disorder subscales to compare the two rating scales psychometrically. METHODS: We examined the internal consistency, test-retest reliability, construct validity and criterion validity of the two rating scales in 135 Japanese outpatients aged 6-18 years. RESULTS: The internal consistency and test-retest reliability were good for all the subscales of the two rating scales except for the conduct disorder subscale of the ADHD-RS-5 extended. Good construct validity was revealed by expected correlational patterns between subscales from the two rating scales and the Children Behavior Checklist. The criterion validity was good for all the subscales of the two rating scales rated by parents, while teacher-ratings revealed substantially lower predictive ability for all the subscales. Agreement between parent- and teacher-ratings of the two rating scales was generally moderate and using predictive ratings alone of both ratings showed the best predictive ability among the integration methods examined. CONCLUSION: The two rating scales have sound psychometric properties and will aid in screening and severity assessment of externalizing disorders in Japanese clinical settings.

Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study.

BACKGROUND: To assess the safety and efficacy of long-term administration of guanfacine extended-release (GXR) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this open-label, long-term, phase 3 extension study in Japan, 150 patients transitioned from a double-blind trial, and 41 newly enrolled patients received once daily GXR (starting dose 2 mg/day, maintenance dose 4-6 mg/day) for 50 weeks. Primary outcome measures were the frequency and nature of treatment-emergent adverse events (TEAEs); secondary outcome measures included the change from week 0 in ADHD Rating Scale IV with Adult Prompts (ADHD-RS-IV; Japanese version) total and subscale scores, Conners' Adult ADHD Rating Scales (CAARS), Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression-Improvement (PGI-I) scales, and quality of life (QoL) and executive functioning measures. RESULTS: Of all patients, 94.2% (180/191) reported ≥1 TEAE and 19.9% (38/191) discontinued because of a TEAE. Most TEAEs were mild to moderate in severity; there were two serious TEAEs and no deaths. Commonly reported TEAEs (≥10% of patients) were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia, malaise, constipation, and dizziness. Mean changes from week 0 in ADHD-RS-IV total and subscale scores and CAARS subscale scores were significantly improved in former placebo or GXR patients and new patients at last observation (p < .0001), and the percentage of patients with very much or much improved CGI-I and PGI-I scores increased. CONCLUSIONS: There were no major safety concerns during long-term GXR administration in adults with ADHD. After long-term treatment, patients had significant improvements from baseline in ADHD symptoms, QoL, and executive functioning. TRIAL REGISTRATION: Japan Primary Registries Network ( https://rctportal.niph.go.jp/en/ ): JapicCTI-163232, registered 04/21/2016.

Efficacy and Safety of Guanfacine Extended-Release in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To assess guanfacine extended-release (GXR) efficacy and safety in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: This phase 3, double-blind, placebo-controlled study (conducted between October 2016 and July 2017) included Japanese patients aged ≥ 18 years with ADHD (DSM-5). Patients received GXR (n = 101) or placebo (n = 100) titrated from 2 mg/d to 4-6 mg/d (dose-optimization; 5 weeks), followed by 4-6 mg/d (dose-maintenance; 5 weeks), then tapered doses to 2 mg/d (2 weeks). Primary endpoint was change from baseline in total score on the Japanese version of the ADHD-Rating Scale IV with adult prompts (ADHD-RS-IV) at week 10. Other measures were ADHD-RS-IV subscales, Clinical Global Impression-Improvement scale (CGI-I) and Patient Global Impression-Improvement scale (PGI-I) (percentage of patients very much improved/much improved), treatment-emergent adverse event (TEAE) incidences, and TEAEs leading to discontinuation. RESULTS: Compared with placebo, there was statistically significantly greater improvement in ADHD-RS-IV total score reduction with GXR (least squares mean ± SE: GXR vs placebo, -11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005; effect size 0.52). There were significantly greater improvements in GXR for ADHD-RS-IV inattention (-7.39 ± 0.79 vs -4.89 ± 0.76; P = .0032) and hyperactivity-impulsivity (-3.84 ± 0.54 vs -2.10 ± 0.52; P = .0021) subscale scores, CGI-I scores (48.1% vs 22.6%; P = .0007), and PGI-I scores (25.3% vs 11.8%; P = .0283). More patients in the GXR versus the placebo group reported TEAEs (81.2% vs 62.0%) and discontinued due to TEAEs (19.8% vs 3.0%). The main TEAEs in the GXR group were somnolence, thirst, blood pressure decrease, nasopharyngitis, postural dizziness, and constipation; most TEAEs were mild to moderate in severity. CONCLUSIONS: In Japanese adults with ADHD, GXR improved ADHD symptoms without any major safety concerns. Trial Registration: Japan Primary Registries Network (https://rctportal.niph.go.jp/en): JapicCTI-163231

Phase II/III Study of Lisdexamfetamine Dimesylate in Japanese Pediatric Patients with Attention-Deficit/Hyperactivity Disorder.

Objective: To further define the efficacy and safety profiles of lisdexamfetamine dimesylate (LDX) in Japanese pediatric patients with attention-deficit/hyperactivity disorder (ADHD). Methods: This was a multicenter, randomized, double-blind, placebo-controlled study of LDX 30, 50, or 70 mg/day for 4 weeks in 76 patients 6-17 years of age with ADHD in Japan. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to 4 weeks. Secondary efficacy endpoints were: Conners' Third Edition (Japanese version) Parent Rating Scale (Conners 3), Clinical Global Impression-Improvement (CGI-I) scale, and Parent Global Assessment (PGA) scale. Results: Change in the ADHD-RS-IV total score from baseline to 4 weeks was significantly greater (p < 0.0001) in all LDX dosage groups versus placebo (30 mg, -16.38; 50 mg, -18.10; 70 mg, -16.47; placebo, -2.78). At all time points, improvements (decreases) in the ADHD-RS-IV total score were significantly greater in all LDX groups versus placebo. At weeks 3 and 4, improvements from baseline in Conners 3 inattention plus hyperactivity/impulsivity subscale scores were significantly greater (p ≤ 0.0082) for all LDX dosages versus placebo. At week 4, the proportion of LDX-treated patients "much improved" or "very much improved" was 61%-71% on the CGI-I scale (p ≤ 0.0019) and 56%-65% on the PGA scale (p ≤ 0.0170). LDX was generally well tolerated. The most frequent treatment-emergent adverse events (AEs) were decreased appetite, headache, and initial insomnia. No severe/serious AEs occurred, and no AEs specific to Japanese patients were evident. Conclusions: The superiority of LDX 30, 50, and 70 mg/day over placebo was confirmed in Japanese pediatric patients with ADHD, and no major safety or tolerability concerns were identified.

Long-term study of lisdexamfetamine dimesylate in Japanese children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: As an extension of a phase 2/3 study evaluating the efficacy and safety of lisdexamfetamine dimesylate (LDX) 30, 50, or 70 mg/d for 4 weeks in Japanese patients aged 6-17 years with attention-deficit/hyperactivity disorder (ADHD), this study evaluated its long-term safety and efficacy. METHODS: This was a multicenter, open-label study of LDX for 53 weeks. Safety was assessed by regular medical examination for treatment-emergent adverse events (TEAEs); regular recording of body weight, vital signs, and laboratory test values; and completion of dependence questionnaires. Efficacy was assessed using Japanese versions of the ADHD-Rating Scale-IV (ADHD-RS-IV) and Conners' 3rd edition Parent Rating Scale (Conners 3); plus Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity, and Parent Global Assessment (PGA) scales. RESULTS: Of 132 enrolled patients, 104 completed the trial. Most frequent treatment-related TEAEs were decreased appetite (73.5%), initial insomnia (39.4%), and weight decrease (22.0%). Most TEAEs were mild (82.6% of patients). There were no serious or severe TEAEs or deaths. No treatment-related TEAEs were associated with blood pressure or pulse rate, and no patient had a QTcF interval >500 ms. Statistically significant improvement from baseline to week 53 was observed in the mean ADHD-Rating Scale-IV total score and mean Conners 3 subscale scores. Most patients showed improvement on the CGI-I (78%) and PGA (76.5%) scales. CONCLUSIONS: No significant safety issues were observed with LDX 30, 50, or 70 mg/d administered for 1 year in Japanese children and adolescents with ADHD. LDX was associated with long-term reductions in ADHD symptoms and severity.

An open-label extension long-term study of the safety and efficacy of aripiprazole for irritability in children and adolescents with autistic disorder in Japan.

AIM: The purpose of this study was to evaluate the long-term safety and efficacy of aripiprazole in treating irritability in pediatric patients (6-17 years) with autistic disorder (AD) in Japan. METHODS: In this open-label extension study, patients who had completed a previous randomized, double-blind, placebo-controlled 8-week study were enrolled and were flexibly dosed with aripiprazole (1-15 mg/day) until the new indication of irritability in pediatric autism spectrum disorder was approved in Japan. RESULTS: Seventy (81%) out of 86 enrolled patients completed week-48 assessments. The mean duration of treatment was 694.9 days. The mean daily dose of aripiprazole over the treatment period was 7.2 mg and the mean of the final dose was 8.5 mg. The most common treatment-emergent adverse events (TEAE; ≥20%) included nasopharyngitis, somnolence, influenza, and increased weight. The majority of these TEAE were mild or moderate in severity, and there were no deaths, and no clinically relevant findings in laboratory values except prolactin decrease, vital signs, height, or ECG parameters. At week 48 (observed case), the mean change from baseline in the Irritability subscale score for the Aberrant Behavior Checklist Japanese Version was -6.3 in prior placebo patients and -2.6 in prior aripiprazole patients. CONCLUSION: Aripiprazole was generally safe, well tolerated, and effective in the long-term treatment of irritability associated with AD in Japanese pediatric patients.

Efficacy and Safety of Atomoxetine Hydrochloride in Asian Adults With ADHD.

OBJECTIVE: The efficacy and safety of atomoxetine was assessed in adult ADHD patients from Japan, Korea, and Taiwan in this first placebo-controlled Asian clinical study in adults of an ADHD medication. METHOD: Atomoxetine was compared with placebo (195 atomoxetine, 196 placebo) over 10 weeks. The change from baseline to endpoint and changes over time in the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version total score (CAARS-Inv: SV total score) were assessed along with changes in quality of life (QoL) and executive function. RESULTS: Atomoxetine treatment resulted in a mean reduction of -14.3 (placebo, -8.8) in CAARS-Inv: SV total score and a steady increase of between-group differences from Week 2. Improvements in QoL and executive functioning were also observed. Treatment-emergent adverse events leading to discontinuation were infrequent (atomoxetine: 5.2%, placebo: 1.5%). CONCLUSION: Atomoxetine was tolerable and effective in improving QoL and executive function as well as ameliorating core ADHD symptoms in adult Asian patients.

Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorder in Japan: A Randomized, Double-blind, Placebo-controlled Study.

We evaluated the efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents (6-17 years) with autism spectrum disorder (ASD) in a randomized, double-blind, placebo-controlled 8-week study in Japan. Patients received flexibly dosed aripiprazole (1-15 mg/day) or placebo. Ninety-two patients were randomized to placebo (n = 45) or aripiprazole (n = 47). Aripiprazole produced a significant improvement in the mean parent/caregiver-rated Aberrant Behavior Checklist Japanese Version irritability subscale score relative to placebo from week 3 through week 8. Administration of aripiprazole provided significantly greater improvement in the mean clinician-rated Clinical Global Impression-Improvement scores than placebo from week 2 through week 8. All patients randomized to aripiprazole completed the study, and no serious adverse events were reported. Three patients in placebo group discontinued. Aripiprazole was effective and generally safe and well-tolerated in the treatment of irritability associated with ASD in Japanese children and adolescents.

Long-term safety and tolerability of atomoxetine in Japanese adults with attention deficit hyperactivity disorder.

INTRODUCTION: The primary aim of this study was to evaluate the long-term safety/tolerability of atomoxetine in Japanese adults with attention deficit hyperactivity disorder (ADHD). METHODS: This 48-week, open-label extension study involved participants with ADHD who completed a 10-week randomized controlled trial of atomoxetine. Participants received atomoxetine 40 mg/day, followed by step-wise titration to a maximum of 120 mg/day. The primary outcome was safety/tolerability. Secondary outcomes were symptoms of ADHD (Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version 18-item total score), quality of life (Adult Attention-Deficit/Hyperactivity Disorder Quality of Life scale), and executive function (Behavior Rating Inventory of Executive Function-Adult Version: Self-report). RESULTS: Of the 39.5% of participants overall who discontinued the study, 15.9% (37/233) of participants discontinued because of adverse events (AEs), primarily nausea (4.3%; 10/233). Overall, 93.6% (218/233) of participants experienced treatment-emergent AEs (TEAEs), most commonly nausea (56.2%; 131/233), nasopharyngitis (25.3%; 59/233), thirst (19.3%; 45/233), headache (17.2%; 40/233), and decreased appetite (16.3%; 38/233). Most TEAEs (70.8%; 165/233) were mild in intensity. Overall, 79.8% (186/233) of participants experienced ≥1 adverse drug reaction, primarily nausea (55.4%; 129/233). Five participants experienced serious AEs during the open-label extension; none was related/possibly related to treatment. There were statistically significant increases in vital signs and decreases in body weight that were not considered clinically significant. Symptoms of ADHD, quality of life, and executive function were significantly improved from baseline to endpoint (P < 0.05). DISCUSSION: Despite discontinuations due to the long-term, open-label design, AE related discontinuations were modest, suggesting that atomoxetine has acceptable long-term safety and tolerability in Japanese adults with ADHD. Symptoms of ADHD improved and remained improved throughout the study.

[Introduction to child and adolescent psychiatry].

Child and adolescent psychiatry used to be a part of adult psychiatry. In adult psychiatry, patients with schizophrenia are common, and their problems arise after puberty. However, we cannot overlook their problems in the developmental stage. In child and adolescent psychiatry, the constitution of diseases changes gradually. Diseases developing in adulthood, such as schizophrenia, are rare, and those developing in infants, such as PDD or ADHD, are very common. I divided child and adolescent psychiatric diseases into 3 types (developing in infants, children, and adolescents), and described them. In child and adolescent psychiatry, multi professional staff, such as doctors, nurses, clinical psychologists, psycho-social-workers, and school teachers, need to collaborate with each other for effective treatment.

Reliability and validity of autism diagnostic interview-revised, Japanese version.

To examine the inter-rater reliability of Autism Diagnostic Interview-Revised, Japanese Version (ADI-R-JV), the authors recruited 51 individuals aged 3-19 years, interviewed by two independent raters. Subsequently, to assess the discriminant and diagnostic validity of ADI-R-JV, the authors investigated 317 individuals aged 2-19 years, who were divided into three diagnostic groups as follows: autistic disorder (AD), pervasive developmental disorder not otherwise specified, and other psychiatric diagnosis or no diagnosis, according to the consensus clinical diagnosis. As regards inter-rater reliability, intraclass correlation coefficients of greater than 0.80 were obtained for all three domains of ADI-R-JV. As regards discriminant validity, the mean scores of the three domains was significantly higher in individuals with AD than in those of other diagnostic groups. As regards diagnostic validity, sensitivity and specificity for correctly diagnosing AD were 0.92 and 0.89, respectively, but sensitivity was 0.55 for individuals younger than 5 years. Specificity was consistently high regardless of age and intelligence. ADI-R-JV was shown to be a reliable tool, and has sufficient discriminant validity and satisfactory diagnostic validity for correctly diagnosing AD, although the diagnostic validity appeared to be compromised with respect to the diagnosis of younger individuals.

Brain region-specific altered expression and association of mitochondria-related genes in autism.

BACKGROUND: Mitochondrial dysfunction (MtD) has been observed in approximately five percent of children with autism spectrum disorders (ASD). MtD could impair highly energy-dependent processes such as neurodevelopment, thereby contributing to autism. Most of the previous studies of MtD in autism have been restricted to the biomarkers of energy metabolism, while most of the genetic studies have been based on mutations in the mitochondrial DNA (mtDNA). Despite the mtDNA, most of the proteins essential for mitochondrial replication and function are encoded by the genomic DNA; so far, there have been very few studies of those genes. Therefore, we carried out a detailed study involving gene expression and genetic association studies of genes related to diverse mitochondrial functions. METHODS: For gene expression analysis, postmortem brain tissues (anterior cingulate gyrus (ACG), motor cortex (MC) and thalamus (THL)) from autism patients (n=8) and controls (n=10) were obtained from the Autism Tissue Program (Princeton, NJ, USA). Quantitative real-time PCR arrays were used to quantify the expression of 84 genes related to diverse functions of mitochondria, including biogenesis, transport, translocation and apoptosis. We used the delta delta Ct (∆∆Ct) method for quantification of gene expression. DNA samples from 841 Caucasian and 188 Japanese families were used in the association study of genes selected from the gene expression analysis. FBAT was used to examine genetic association with autism. RESULTS: Several genes showed brain region-specific expression alterations in autism patients compared to controls. Metaxin 2 (MTX2), neurofilament, light polypeptide (NEFL) and solute carrier family 25, member 27 (SLC25A27) showed consistently reduced expression in the ACG, MC and THL of autism patients. NEFL (P = 0.038; Z-score 2.066) and SLC25A27 (P = 0.046; Z-score 1.990) showed genetic association with autism in Caucasian and Japanese samples, respectively. The expression of DNAJC19, DNM1L, LRPPRC, SLC25A12, SLC25A14, SLC25A24 and TOMM20 were reduced in at least two of the brain regions of autism patients. CONCLUSIONS: Our study, though preliminary, brings to light some new genes associated with MtD in autism. If MtD is detected in early stages, treatment strategies aimed at reducing its impact may be adopted.

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder.

AIMS: The main purpose of this first atomoxetine study in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8-week treatment regimen. METHODS: This was an open-label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM-IV-defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) scores. RESULTS: Thirty-nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS-Inv:SV-J total ADHD symptom scores decreased in a time-dependent manner; the mean change from baseline to endpoint was -15.0 (P<0.001). CONCLUSIONS: This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients.

Replication study of Japanese cohorts supports the role of STX1A in autism susceptibility.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from Japanese trios with autistic probands. In TDT analysis, rs69510130 (p=0.027) showed nominal associations with autism; modest haplotype association was also observed. We further compared STX1A mRNA expression between the autistic and control groups in the postmortem brain. In the anterior cingulate gyrus region, STX1A expression in the autism group was found to be significantly lower than that of the control group. Thus, we suggest a possible role of STX1A in the pathogenesis of autism.

Further evidence for the role of MET in autism susceptibility.

MET receptor tyrosine kinase (MET)-mediated signaling has been implicated in multiple aspects of neocortical and cerebellar neuronal growth and maturation. A promoter functional SNP (rs1858830) that disrupts the transcription of MET has been reported to be strongly associated with autism spectrum disorders (ASD) in the Caucasian population. Here, we performed a trio association study of MET with ASD in Japanese subjects (n=126 trios). Based on the HapMap data on the Japanese population, 15 SNPs were chosen for the association study. One SNP located in intron 1, rs38841, showed a nominal association with autism (p=0.044; OR=1.61) when analyzed using the transmission disequilibrium test. To the best of our knowledge, this is the first replication study of the association of MET with autism, in any non-Caucasian population. Association of rs38841 with autism was further confirmed in 252 Caucasian trios from AGRE (p=0.0006). An interesting observation is that all three SNPs of MET (rs1858830, rs38845 and rs38841) shown to be associated with autism in three independent studies including the present one, are located towards the 5'end of the gene at a span of 9.4 kb. Our results provide further evidence for a possible role of MET in the pathogenesis of ASD.

A randomized, double-blind, placebo-controlled study of atomoxetine in Japanese children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVES: Until the recent approval of methylphenidate (MPH), Japan had no approved treatment for attention-deficit/hyperactivity disorder (ADHD). The need still exists for an effective, safe, nonstimulant treatment. This first placebo-controlled Japan study of an ADHD nonstimulant therapy assessed atomoxetine efficacy and safety to determine the optimal dose for controlling ADHD symptoms in children and adolescents. METHODS: A total of 245 Japanese children and adolescents, aged 6-17 years and diagnosed with ADHD, were randomly assigned to receive placebo or one of three atomoxetine doses (0.5, 1.2, and 1.8 mg/kg per day) over 8 weeks. Symptoms were assessed with the Japanese Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator scored and integrated with teacher reports (ADHD RS-IV-J:I/Sch). Adverse events, vital signs, laboratory tests, and electrocardiograms (ECGs) were obtained for safety analysis. RESULTS: In all, 234 patients completed the study. Atomoxetine at 1.8 mg/kg per day was significantly superior to placebo in reducing ADHD symptoms (p = 0.01; one-sided). Decreased appetite and vomiting were significantly greater in the atomoxetine treatment groups; however, no clinically significant differences were observed. Two patients discontinued due to affect lability and headache. A linear dose-response and vital signs similar to those from other atomoxetine studies were observed. CONCLUSION: Atomoxetine provides an effective and safe nonstimulant option for the treatment of Japanese pediatric patients with ADHD.