Preliminary efficacy of cognitive-behavioral therapy on emotion regulation in adults with autism spectrum disorder: A pilot randomized waitlist-controlled study.

Previous studies have demonstrated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in children on the autism spectrum. However, no studies have elucidated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in autistic adults. The aim of the present pilot study was to explore the preliminary clinical utility of a group-based cognitive-behavioral therapy program designed to address emotion regulation skills in autistic adults. We conducted a clinical trial based on a previously reported protocol; 31 participants were randomly allocated to the intervention group and 29 to the waitlist control group. The intervention group underwent an 8-week program of cognitive-behavioral therapy sessions. Two participants from the intervention group withdrew from the study, leaving 29 participants (93.5%) in the group. Compared with the waitlist group, the cognitive-behavioral therapy group exhibited significantly greater pre-to-post (Week 0-8) intervention score improvements on the attitude scale of the autism spectrum disorder knowledge and attitude quiz (t = 2.21, p = 0.03, d = 0.59) and the difficulty describing feelings scale of the 20-item Toronto Alexithymia Scale (t = -2.07, p = 0.04, d = -0.57) in addition to pre-to-follow-up (Week 0-16) score improvements on the emotion-oriented scale of the Coping Inventory for Stressful Situations (t = -2.14, p = 0.04, d = -0.59). Our study thus provides preliminary evidence of the efficacy of the group-based cognitive-behavioral therapy program on emotion regulation in autistic adults, thereby supporting further evaluation of the effectiveness of the cognitive-behavioral therapy program in the context of a larger randomized clinical trial. However, the modest and inconsistent effects underscore the importance of continued efforts to improve the cognitive-behavioral therapy program beyond current standards.

Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

AIM: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. METHODS: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. RESULTS: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.