CBSST appears to be an effective intervention to address these concerns that requires minimal resources and a relatively brief treatment interval, making it ideally suited to adaptation to a variety of clinical settings. Future studies will compare CBSST to standard outpatient care with a focus on additional outcomes, including quality of life and healthcare utilization.Bipolar disorder is a severe, chronic, and disabling mental illness characterized by recurrent episodes of hypomania or mania and depression. The evidence from twin, family, and adoption studies provide compelling evidence for a strong genetic predisposition to BPD with heritability estimated to be as high as ≥80% . Given BPD is a heterogeneous disease with substantial phenotypic and genetic complexities, the identification for BPD risk loci has proven to be difficult. Some researchers have proposed that dissecting BPD into clinical subgroups with distinct sub-phenotypes may result in genetically homogeneous cohorts to facilitate the mapping of BPD susceptibility genes . Among the subphenotypes, early-onset BPD is of particular interest as several independent cohort studies have demonstrated their existence. Comparing to the non-early-onset BPD, the early-onset subtype is associated with a more severe form of clinical manifestations characterized by frequent psychotic features, more mixed episodes, greater psychiatric comorbidity such as drug and alcohol abuse and anxiety disorders, higher risk of suicide attempt, worse cognitive performance, and poorer response to prophylactic lithium treatment. In addition, the pattern of disease inheritance seems to differ between early‐ and late‐onset BPD families, with the former involving greater heritability. These observations indicate that early-onset BPD may be a genetically homogenoussubset and thus could be used for genetic study to identify its susceptibility genes.
A number of BPD genes identified by genome-wide association study have been widely replicated and intensively studied,cannabis grow equipment but these studies did not include early-onset BPD. Over the past two decades, a host of studies have investigated genetic loci responsible for early-onset BPD through linkage-analyses, candidate–gene association, analyses of copy number variants , and GWAS, but findings are inconclusive. Candidate–gene association studies have identified a number of genes potentially associated with early-onset BPD, including glycogen synthase kinase 3-β gene, circadian clock gene Per 3, serotonin transporter gene, brain-derived neurotrophic factor gene, and gene coding synaptosomal-associated protein SNAP25. However, very few positive findings of these studies have been replicated independently. Findings from linkage studies suggested chromosomal regions harboring the susceptibility genes at 3p14 and 21q22, plus the loci at 18p11, 6q25, 9q34 and 20q11 with nominal significance. Studies of CNVs in early-onset BPD were based on relatively small effect sizes and were irreproducible, suggesting that CNVs are unlikely the major source of liability. Finally, GWAS failed to find any risk variant with genome-wide statistical significance in Caucasian populations, despite some variants showed suggestive significance. In previous genetic studies, the definition of early-onset in BPD typically ranged from 15 to 25 years of age. These association studies were largely conducted with small sample size and were under powered . Most of them compared early-onset BPD vs. healthy control. Such a case–control design is more likely to identify susceptibility gene for BPD per se, but not for the early-onset sub-type. The optimal strategy to identify gene for the early-onset BPD is to include the non-early-onset BPD group for comparison. In this paper, we reported findings from a GWAS with high-density SNP chips on early-onset, defined as ≤20 years of age, BPI patients of Han Taiwanese descent.
The clinical phenotype assessment of manic and depressive episodes was performed by well-trained psychiatric nurses and psychiatrists using a cross culturally validated and reliable Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry, supplemented by available medical records. All of them were diagnosed according to the DSM-IV criteria for BPI disorder with recurrent episodes of mania with or without depressive episode. The assessment of onset age was based on a life chart prepared with graphic depiction of lifetime clinical course for each of the BPI patient recruited. This life chart included largely all the mood episodes with date of onset , duration, and severity . The construction of this life chart was based on integrated information gathered from direct interview with patients and their family members, interviews with in-charge psychiatrists, and a thorough medical chart review. Different definitions for early onset of BPI have been proposed in previous work. Our selection of 20 as the age threshold was based on a systematic review for pediatric BPD. The age at onset was defined by the first mood episode . Of all patients, 1306 with genotyping data available were included in the discovery group for GWAS and the rest 473 without genotyping data were included in the replication group.In this paper, we have reported one of the largest GWASs to investigate genetic susceptibility to early-onset BPI with the first mood episode occurring ≤20 years of age. We employed standardized psychiatric interview and constructed a life chart with detailed clinical history to ensure the accuracy and homogeneity of phenotype for genotyping. Our GWAS with high-density SNP chips identified the SNP rs11127876 in CADM2 gene to be associated with early-onset BPI in both discovery and replication groups, and meta-analysis for the association was close to genome-wide significance .
The gene CADM2 on chromosome 3 encodes a synaptic cell adhesion molecule that is prominently expressed in neurons, and plays key roles in the development, differentiation, and maintaining synaptic circuitry of the central nervous system. In previous GWASs, CADM2 has been found to be associated with a number of mental health related traits, including alcohol consumption, cannabis use, reduced anxiety, neuroticism and conscientiousness, and increased risk-taking behavior. CADM2 was also reported to be associated with executive functioning and processing speed, general cognitive function, and educational attainment. Though there have been no investigations examining the risk-taking phenotype in early-onset relative to non early-onset BPD, Homes et al. showed that BPD patients with a past history of alcohol abuse or dependence had a higher risk-taking propensity, suggesting a relationship between early-onset BPD and risk-taking propensity. Of note, Morris et al. suggested that CADM2 variants may not only link with psychological traits, but also influence metabolic-related traits, such as body mass index, blood pressure, and C-reactive protein. In addition, they found that CADM2 variants had genotype specific effects on CADM2 expression levels in adult brain and adipose tissues. The finding highlights the potential pleiotropy of CADM2 gene, i.e., the genetic variants may influence multiple traits, and shared biological mechanisms across brain and adipose tissues through the regulation of CADM2 expression. Given that the metabolic comorbidities are prevalent in patients with early-onset BPD, it is conceivable that CADM2 variants may influence both psychological and physical traits, further contributing to a more severe clinical subtype of BPD with accompanying risk of metabolic adversities. In addition, an association between risk-taking and obesity has also been implicated in previous research, which suggests that risk takers tend to overlook health-related outcomes and are prone to aberrant reward circuitry predisposing them to poor dietary choices and excessive intake. Collectively,vertical grow rack in line with the characteristics found to be associated with CADM2 variants, it is likely that CADM2 may exert an effect on the constellation of clinical features related to early-onset BPD with greater symptom severity . Therefore, our findings suggest that CADM2 genetic variants may have significant effects on a subtype of BPD with early-onset. Two previous GWASs comparing early-onset BPD patients with healthy controls did not find any genetic variants reaching genome-wide significance. Our study included a larger sample of early-onset BPI patients to conduct GWAS using high-density genotyping . The statistical power was calculated using Post-hoc Power Calculator , combining the allelic frequencies of both discovery and replication groups. In this study of two independent samples of BPI with dichotomous endpoint, the power reached 99.4% and 18.2% under type I error = 0.05 and = 5 × 10−8 , respectively. Results of our study are also likely to be under powered under the stringency setting of type I error. However, the frequency of risk allele T was higher in patients with onset ≤20 than in patients with onset >20 in both discovery and replication groups. We believe all these have provided strong evidence to confirm the association of this SNP with earlyonset BPD. In Table 2, the minor allele frequencies differ quite a bit between the discovery and replication cohorts. In the NCBI SNP database, minor allele frequency of rs11127876 is 0.08 in Han Chinese in Beijing, close to our results and suggest that the different allele frequencies observed in Table 2 may mainly result from our sampling. The over-representative minor allele frequency in replication group may have come from random sampling or effects of hidden characters of our patients recruited. Genetic variant of CADM2 has been reported to be associated with behavioral and metabolic traits, which were not assessed in this study.
Though the minor allele frequencies of rs11127876 were different in discovery and replication groups, the same direction of ORs of rs11127876 minor allele supports the reliability of our findings. The SNP rs75928006 located in the upstream of MIR522 reached genome-wide significance in discovery group but failed to show statistical significance in replication group. MIR522 promotes glioblastoma cell proliferation, but there was no evidence to suggest its association with any psychiatric disorders. One major limitation of this study is the possibility of recall bias about the exact onset age of the first mood episode of BPI, particular when there was a long history of the illness. Previous studies have however suggested that age at onset can be assessed reliably. The preparation of life chart containing detailed clinical course and treatment based on a semi-structured clinical interview plus a thorough medical chart review for individual patients should have overcome this potential limitation satisfactorily. In summary, we have identified a genetic locus rs11127876 in CADM2 gene to be associated with earlyonset BPI. The finding has reflected the co-sharing genetic features of psychiatric disorders and behavioral traits. Further investigations of the CADM2 biological function in BPI are warranted.The misuse of opiates is a serious problem worldwide, is increasing in young adults, and has substantial individual and societal consequences. In 2014 in the United States alone, approximately 1.9 million people had an opiate use disorder, including 586,000 heroin users. Neuroimaging in opiate dependence indicates both altered brain structure, particularly in the anterior cingulate cortex , and brain function involving dorsolateral prefrontal cortex and ACC. Magnetic resonance spectroscopy allows the non-invasive quantitation of brain metabolites that provide information on the neurophysiologic integrity of brain tissue. The few 1H MRS studies in opiate dependence to date revealed lower concentration of N-acetylaspartate , a marker of neuronal integrity, in the medial frontal cortex, including the ACC, as well as lower glutamate , a primary excitatory neurotransmitter, or glutamate+glutamine concentration in some but not all studies. The discrepant MRS findings may relate to differences among study participants regarding the prevalence and severity of comorbid substance use , the type, dose and duration of replacement therapy for heroin users , and/or participant age. The ACC, DLPFC and orbitofrontal cortex are important components of the brain reward/executive oversight system, a neural network critically involved in the development and maintenance of addictive disorders. Structural brain imaging in opiate dependence revealed generally lower gray matter volume or density in frontal regions, including the DLPFC, with thinner frontal cortices related to longer duration of opiate misuse. Functional MR imaging showed that the DLPFC, OFC and ACC are involved in decision making, and in opiate dependent individuals, lower task-based fMRI activity in the ACC related to compromised behavioural control of cognitive interference. Furthermore, smaller frontal gray matter volume in opiate dependence related to higher impulsivity on the Barratt Impulsivity Scale . Correspondingly, opiate dependence is associated with cognitive deficits, primarily in executive functioning and self-regulation . Thus, the neuroimaging literature in opiate dependence suggests altered frontal brain structure as well as compromised neuronal integrity and glutamatergic metabolism. Few if any studies however investigated their relationships to opioid and other substance use behaviour or cognition. Further research into specific regional brain effects and their potential cognitive and behavioural correlates may inform better targeted treatment of individuals with opioid use disorders.