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bipolar disorder. However, psycho-education is essential to help the patient understand the illness and to encourage and assist acceptance of the illness by paying attention to the patient’s mental reactions to it17). Psycho-education aims to help patients understand the nature of the disease, the effects and side effects of medications, as well as to help them and their families understand and share what the first signs of relapse are. Therefore, it is important to discuss and confirm the initial signs of relapse with the family and share them with the patient and the family. It is also meaningful to predict in advance the stressors that are likely to trigger relapse and to learn how to cope with them.It is also important to keep a regular life in the treatment of bipolar disorder, as even one-night sleep deprivation can trigger a manic state. Inter-personal social rhythm therapy is reported to be effective in preventing episodes in bipolar disorder. However, it is difficult to receive this treatment in Japan, and usually, the essence of social rhythm therapy is included in psychoeducation; e.g., avoiding staying up all night, get some sunlight in the morning, light exercise such as taking a walk in the morning, and avoiding excessive social stimula-tion when the mood is unstable.Cognitive-behavioral therapy (CBT), which is widely used for depression, has also been reported to be effective in preventing the recurrence of bipolar disorder. CBT is available at least in urban areas in Japan.Bipolar disorder has a higher concordance rate in monozygotic twins than in dizygotic twins, so there is no doubt that genomic factors are involved18). On the other hand, even in monozygotic twins with almost the same genome, not all of them develop the disease, and it is considered that non-genetic factors such as environmental factors are also involved19). Perinatal factors, such as perinatal complications, influenza infection during preg-nancy, and smoking of mothers, are reported as environmental factors that pose a risk of bipolar disorder. Early developmental adversity has been reported to have a negative impact on symptoms and course. Stress is said to trigger the onset and recurrence, but it cannot be said to be the cause.As mentioned above, genome-wide association studies (GWAS) have been conducted because of the involvement of genetic factors in bipolar disorder20). Sixty-four relevant genomic loci were identified in a GWAS of 41,917 bipolar patients21). Among these, FADS2 (Fatty Acid Desaturase 2) and FADS1, which were first found in a GWAS of approximately 3,000 Japanese patients22), are genes for enzymes involved in the metabolism of unsatu-rated fatty acids, and their reduced activity has been associated with bipolar disorder. In addition to the calcium (Ca2+) channel gene CACNA1C, which was one of the first genes found in the GWAS for bipolar disorder, a new association was found with another Ca2+ channel gene, CACNB2. The risk genes for bipolar disorder included many genes involved in synapses, Ca2+ signaling, and neurogenesis. In addition, many genes encoding target proteins of antipsychotics, antiepileptic drugs, and other drugs were included.We performed exome analysis in 354 trio families (patients and their parents) of bipolar disorder and analyzed de novo mutations, i.e., mutations that were not present in the parents23). As a result, we found that de novo mutations were more common in genes with few loss-of-function mutations in the general population. The loss-of-function de novo mutations were more common in genes such as presynaptic active zones and ion channels. In addi-tion, somatic mosaic mutations were frequently found in genes that cause neurodevelopmental disorders, indicating that the presence of genes that cause neurodevelopmental disorders in a somatic mosaic state may be a risk factor for bipolar disorder.Although various pathological hypotheses for bipolar disorder have been proposed, the calcium hypothesis, which has been previously reported to be associated with high intracellular Ca2+ levels and has been found to be relevant in recent genomic studies, is the most likely. However, since intracel-lular Ca2+ affects many cells, it is difficult to under-stand the pathogenesis of bipolar disorder by itself11).We have been focusing on the relationship between mitochondria and bipolar disorder based 21EtiologyGenome researchNeurobiological studies