Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry.

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects approximately 1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 x 10(-6). We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P approximately 10(-7): 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10(-7)) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

Epigenetic age dysregulation in individuals with bipolar disorder and schizophrenia.

Bipolar disorder (BD) and schizophrenia (SCZ) are debilitating disorders that are associated with significant burden and reduced quality of life. In this study, we leveraged microarray data derived from both the Illumina HumanMethylation450 platform to investigate the epigenetic age of individuals with SCZ (n = 40), BD (n = 40), and healthy controls (n = 38), across five epigenetic clocks. Various statistical metrics were used to identify discrepancies between epigenetic and chronological age across the three groups. We observed a significant increase in epigenetic age compared to chronological age in the BD group. Mean epigenetic age acceleration was also higher in individuals with bipolar disorder compared to healthy controls across four different epigenetic clocks (p<0.05). Despite the study's relatively small sample size, these findings suggest that both individuals with bipolar disorder and schizophrenia may have epigenetic markers associated with a premature aging phenotype, which could be suggestive of negative outcomes associated with the disease. In our future studies, we hope to elucidate this finding further by elucidating the precise link between epigenetic age, symptomatology and disease progression.

Guidelines of care for acne vulgaris management.

DISCLAIMER: Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient.

Beyond parallel play: Science befriending the art of method acting to advance healing relationships.

Research underscores the central role of factors in healing that appear to relate to the therapeutic relationship. These nonspecific or common factors and placebo effects are often overshadowed by an emphasis in the field on particular empirically supported therapies. Yet relationship variables account for a greater proportion of the variance in treatment outcomes than the technical intervention employed, representing a notable blind spot in our science and, by extension, our practice. As a consequence, clinical instruction in psychology and in the health professions more broadly generally lacks adequate specificity with respect to how to cultivate a healing relationship. Through the elaboration of several techniques derived from theatrical traditions, the authors propose that method acting and similar schools of drama provide a method for honing clinical skills in these areas that is amenable to empirical scrutiny. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Uncertainty Theory: A Powerful Approach to Understanding Psychiatric Disorder.

OBJECTIVE: The tendency over the years in the mental health field has been to cling in circular fashion to one single domain after another, biological, psychological, or social, to explain severe disorder and not even to consider the data from the domain of focus that came before. This report notes that attempts to explore more complex biopsychosocial explanations that integrate the diverse domains have been generally ignored or foundered on the problems posed by the complexities involved and suggests an approach for moving beyond these problems. METHOD: A case history using two different formats highlights the degree to which the single domain models ignore one or another area of data. RESULTS: Uncertainty theory is suggested as providing an important basis for exploring the complexities of a biopsychosocial understanding of mental health problems. CONCLUSIONS: This approach can provide a possible orientation to promote improved research, training, and treatment.

Childhood emotional and sexual maltreatment moderate the relation of the serotonin transporter gene to stress generation.

Emerging evidence suggests that the tendency to generate stressful life events may be, at least in part, genetically determined. However, the role of the early environment in shaping responses to later stressors is crucial to fully specifying biogenetic models of stress generation. The current study examined the moderating role of childhood emotional, physical, and sexual maltreatment on the relation of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene to proximal independent, dependent, and dependent-interpersonal life events. This question was tested in a cross-sectional community sample of 297 adolescents and young adults. Childhood maltreatment history and proximal life events were assessed with state-of-the-art interviews that provide independent and standardized ratings of the environmental context. Consistent with the stress generation hypothesis, individuals with the risk s-allele of the serotonin transporter gene reported significantly higher rates of dependent and dependent-interpersonal life events than those homozygous for the l-allele, but only in the context of a history of maternal emotional maltreatment or sexual maltreatment. Neither serotonin transporter gene polymorphisms or childhood maltreatment, or their interaction, were associated with reports of independent life events. The current results demonstrate the importance of considering specificity in the early environmental context when examining the relation of genetic factors to the generation of proximal stress.

Improvement of acanthosis nigricans on isotretinoin and metformin.

Acanthosis nigricans (AN) is an eruption of hyperpigmented, velvety thickened patches, often with papillomatosis, that occurs symmetrically on any body site but most commonly at the axillae, neck, groin, and flexural surfaces. We report a case of a 55-year-old obese male who developed acanthosis nigricans with striking papillomatosis and tripe palms who experienced improvement on a long-term tapering dosage of isotretinoin, with additional benefit with the addition of metformin. While oral retinoids have been reported to positively impact AN, improvement of AN with metformin has been reported in only two prior cases. Combined therapy with isotretinoin and metformin for AN has not been reported previously.

Teaching clinical research: what clinicians need to know.

Clinicians are well suited in many ways to conducting research, but appropriate training and support must be provided. A series of multidisciplinary workshops designed to facilitate clinical research are used as a focus for describing common problems and their solutions. Practical means for initiating and assisting clinical research are proposed.

Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD. METHODS: Fifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG 'units' across three amplicons of BDNF promoters 3 and 5. RESULTS AND DISCUSSION: Methylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values ≤ 0.004) with medium to large effect sizes (Cohen's d ≥ 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 ×10(-5)) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD.

Considering DSM-5: the personal experience of schizophrenia in relation to the DSM-IV-TR criteria.

Previous analyses have suggested that the personal experience of schizophrenia might be different from its depiction in the DSM-IV-TR. In this study, 17 people with schizophrenia or schizoaffective disorder were interviewed about their experiences of the DSM-IV-TR diagnostic criteria for schizophrenia. Descriptive phenomenological analysis was used to analyze the ways in which the personal experiences of the people in this study were similar to or different from the depiction of schizophrenia in the DSM-IV-TR. The personal experience of schizophrenia was similar in some way to each of the five diagnostic criteria for schizophrenia. Participants' personal experiences also went beyond the DSM-IV-TR criteria. Specifically, participants described strong emotional reactions to their symptoms, including fear, sadness, embarrassment, and alienation. Also, participants described intense interest but severe disruptions in goal-directed behavior due to their hallucinations being engrossing, confusing, and distracting. Further, participants described not sharing their experiences in order to avoid social stigma. These findings suggest that the description of schizophrenia in DSM-5 may benefit from a change to DSM-IV-TR criteria to incorporate more of the personal experience of schizophrenia. Further research is needed to establish the representativeness, reliability, and validity of the qualitative findings described here.

The Need for Patient-Subjective Data in the DSM and the ICD.

One improvement from the second to the third edition of the Diagnostic and Statistical Manual of Mental Disorders was to replace clinicians' subjective interpretations of mental disorders with objective descriptions of signs and symptoms that could be rated reliably across investigators. Along with clinicians' subjective impressions, however, the subjective experiences of the person with the mental disorder were minimized. This information could be valuable, as people's subjective experiences of disorders may indicate major underlying processes and be different from how characteristics of disorders appear objectively to outside observers. The authors suggest that empirically derived, patient-subjective characteristics of mental disorders be incorporated into future editions of the DSM and the ICD. Not only will these data offer important information that will help to enhance the accuracy of the diagnostic categories of the DSM and ICD, but such data also may serve to enhance clinicians' abilities to conceptualize accurately and empathically treat these disorders in their patients. Examples of patient-subjective criteria and their relationship to current DSM criteria are examined for borderline personality disorder and schizophrenia and suggestions for DSM-V and ICD-11 are offered. Diagnostic criteria that accurately reflect patients' subjective experience could also increase clinicians' ability to empathize with patients, one of the most important variables in treatment alliances.

No association between oxytocin or prolactin gene variants and childhood-onset mood disorders.

BACKGROUND: Oxytocin (OXT) and prolactin (PRL) are neuropeptide hormones that interact with the serotonin system and are involved in the stress response and social affiliation. In human studies, serum OXT and PRL levels have been associated with depression and related phenotypes. Our purpose was to determine if single nucleotide polymorphisms (SNPs) at the loci for OXT, PRL and their receptors, OXTR and PRLR, were associated with childhood-onset mood disorders (COMD). METHODS: Using 678 families in a family-based association design, we genotyped 16 SNPs at OXT, PRL, OXTR and PRLR to test for association with COMD. RESULTS: No significant associations were found for SNPs in the OXTR, PRL, or PRLR genes. Two of three SNPs 3' of the OXT gene were associated with COMD (p≤0.02), significant after spectral decomposition, but were not significant after additionally correcting for the number of genes tested. Supplementary analyses of parent-of-origin and proband sex effects for OXT SNPs by Fisher's Exact test were not significant after Bonferroni correction. CONCLUSIONS: We have examined 16 OXT and PRL system gene variants, with no evidence of statistically significant association after correction for multiple tests.