Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Rare PDCD11 variations are not associated with risk of schizophrenia in Japan.

AIM: Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three-stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia. METHODS: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls. RESULTS: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His). CONCLUSION: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population.

The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder: A non-randomized prospective interventional study.

BACKGROUND: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ±â€Š.04 mg/kg [mean ±â€Šstandard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ±â€Š.31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ±â€Š32.3 ng/mL in 7 responders and was significantly higher than 29.5 ±â€Š23.9 ng/mL (P < .01) for the 29 non-responders. CONCLUSIONS: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

Influence of Atomoxetine on Relationship Between ADHD Symptoms and Prefrontal Cortex Activity During Task Execution in Adult Patients.

Objective: We conducted this non-randomized prospective interventional study to clarify the relationship between improved attention-deficit hyperactivity disorder (ADHD) symptoms and regional brain activity. Methods: Thirty-one adult patients underwent near-infrared spectroscopy examinations during a go/no-go task, both before and 8 weeks after atomoxetine administration. Results: Clinical symptoms, neuropsychological results of the go/no-go task, and bilateral lateral prefrontal activity significantly changed. A positive correlation was observed between right dorsolateral prefrontal cortex activity and Conners' Adult ADHD Rating Scales scores. Before atomoxetine administration, no correlations between prefrontal cortex activity and clinical symptoms were observed in all cases. When participants were divided into atomoxetine-responder and non-responder groups, a positive correlation was observed between prefrontal cortex activity and clinical symptoms in the non-responder group before treatment but not in the responder group, suggesting that non-responders can activate the prefrontal cortex without atomoxetine. Conclusions: Individuals with increased ADHD symptoms appear to recruit the right dorsolateral prefrontal cortex more strongly to perform the same task than those with fewer symptoms. In clinical settings, individuals with severe symptoms are often observed to perform more difficultly when performing the tasks which individuals with mild symptoms can perform easily. The atomoxetine-responder group was unable to properly activate the right dorsolateral prefrontal cortex when necessary, and the oral administration of atomoxetine enabled these patients to activate this region. In brain imaging studies of heterogeneous syndromes such as ADHD, the analytical strategy used in this study, involving drug-responsivity grouping, may effectively increase the signal-to-noise ratio.

Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD.

Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.

Whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder and a follow-up study.

Two truncating variations (WDR90 V1125fs and EFCAB5 L1210fs), identified by whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder (ASD), were not detected in 257 ASD patients, 677 schizophrenia patients or 667 controls in a follow-up study. Thus, these variations were exclusively identified in the family, suggesting that rare truncating variations may have a role in the genetic etiology of ASD, at least in a subset of ASD patients.

Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.

Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.