Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

Does Nonsuicidal Self-Injury Predict Later Suicidal Attempts? A Review of Studies.

Co-occurrence of nonsuicidal self-injury (NSSI) and suicide attempts (SA) might occur because they share common risk factors, or alternatively because one leads to the other. Using search terms salient to NSSI and SA, we screened 555 studies to identify 17 that presented temporal data about NSSI and SA. Much of the evidence indicates that NSSI predates SA, especially among females and individuals with depressive symptoms, or diagnosed with borderline personality disorder or mood disorders. However, in some studies, associated risk factors likely accounted for the effect. Greater NSSI frequency to a threshold increases risk for later SA. Findings suggest that the behaviors have common predisposing factors, but that there is also a potent gateway effect whereby NSSI precedes SA.

The Care of Patients With Complex Mood Disorders.

This article focuses on some common dilemmas facing clinicians, patients, and families in managing the treatment of complicated mood disorders. Specifically, this article reviews the interaction of depressive states, including unipolar, bipolar, and mixed, with other adversities, including comorbid physical and psychological disorders, personality vulnerabilities, misuse of drugs and alcohol, and social and family problems. These issues are not always clearly differentiated from the depressive illness. Each of these adversities can worsen an existing mood disorder and influence the patient's resolve to persist with a treatment plan. Although this article is not focused strictly on treatment-resistant depression, these coexisting issues make depressive states harder to manage therapeutically. For brevity, the aim of this article has been limited to discussion of some complex situations that psychiatrists in general practice may encounter.

Posttraumatic stress disorder increases risk for suicide attempt in adults with recurrent major depression.

BACKGROUND: Genetics of Recurrent Early-Onset Depression study (GenRED II) data were used to examine the relationship between posttraumatic stress disorder (PTSD) and attempted suicide in a population of 1,433 individuals with recurrent early-onset major depressive disorder (MDD). We tested the hypothesis that PTSD resulting from assaultive trauma increases risk for attempted suicide among individuals with recurrent MDD. METHODS: Data on lifetime trauma exposures and clinical symptoms were collected using the Diagnostic Interview for Genetic Studies version 3.0 and best estimate diagnoses of MDD, PTSD, and other DSM-IV Axis I disorders were reported with best estimated age of onset. RESULTS: The lifetime prevalence of suicide attempt in this sample was 28%. Lifetime PTSD was diagnosed in 205 (14.3%) participants. We used discrete time-survival analyses to take into account timing in the PTSD-suicide attempt relationship while adjusting for demographic variables (gender, race, age, and education level) and comorbid diagnoses prior to trauma exposure. PTSD was an independent predictor of subsequent suicide attempt (HR = 2.5, 95% CI: 1.6, 3.8; P < .0001). Neither assaultive nor nonassaultive trauma without PTSD significantly predicted subsequent suicide attempt after Bonferroni correction. The association between PTSD and subsequent suicide attempt was driven by traumatic events involving assaultive violence (HR = 1.7, 95% CI: 1.3, 2.2; P< .0001). CONCLUSIONS: Among those with recurrent MDD, PTSD appears to be a vulnerability marker of maladaptive responses to traumatic events and an independent risk factor for attempted suicide. Additional studies examining differences between those with and without PTSD on biological measures might shed light on this potential vulnerability.

A collaborative approach to teaching medical students how to screen, intervene, and treat substance use disorders.

Few medical schools require a stand-alone course to develop knowledge and skills relevant to substance use disorders (SUDs). The authors successfully initiated a new course for second-year medical students that used screening, brief intervention, and referral to treatment (SBIRT) as the course foundation. The 15-hour course (39 faculty teaching hours) arose from collaboration between faculty in Departments of Medicine and Psychiatry and included 5 hours of direct patient interaction during clinical demonstrations and in small-group skills development. Pre- and post-exam results suggest that the course had a significant impact on knowledge about SUDs. The authors' experience demonstrates that collaboration between 2 clinical departments can produce a successful second-year medical student course based in SBIRT principles.

Association study of serotonin pathway genes in attempted suicide.

Epidemiological studies, such as family, twin, and adoption studies, demonstrate the presence of a heritable component to both attempted and completed suicide. Some of this heritability is accounted for by the presence of comorbid psychiatric disorders, but the evidence also indicates that a portion of this heritability is specific to suicidality. The serotonergic system has been studied extensively in this phenotype, but findings have been inconsistent, possibly due to the presence of multiple susceptibility variants and/or gene-gene interactions. In this study, we genotyped 174 tag and coding single nucleotide polymorphisms (SNPs) from 17 genes within the serotonin pathway on 516 subjects with a major mood disorder and a history of a suicide attempt (cases) and 515 healthy controls, with the goal of capturing the common genetic variation across each of these candidate genes. We tested the 174 markers in single-SNP, haplotype, gene-based, and epistasis analyses. While these association analyses identified multiple marginally significant SNPs, haplotypes, genes, and interactions, none of them survived correction for multiple testing. Additional studies, including assessment in larger sample sets and deep resequencing to identify rare causal variants, may be required to fully understand the role that the serotonin pathway plays in suicidal behavior.

Genome-wide linkage and follow-up association study of postpartum mood symptoms.

OBJECTIVE: Family studies have suggested that postpartum mood symptoms might have a partly genetic etiology. The authors used a genome-wide linkage analysis to search for chromosomal regions that harbor genetic variants conferring susceptibility for such symptoms. The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms. METHOD: Subjects were ascertained from two studies: the NIMH Genetics Initiative Bipolar Disorder project and the Genetics of Recurrent Early-Onset Depression. Subjects included women with a history of pregnancy, any mood disorder, and information about postpartum symptoms. In the linkage study, 1,210 women met criteria (23% with postpartum symptoms), and 417 microsatellite markers were analyzed in multipoint allele sharing analyses. For the association study, 759 women met criteria (25% with postpartum symptoms), and 16,916 SNPs in the regions of the best linkage peaks were assessed for association with postpartum symptoms. RESULTS: The maximum linkage peak for postpartum symptoms occurred on chromosome 1q21.3-q32.1, with a chromosome-wide significant likelihood ratio Z score (Z(LR)) of 2.93 (permutation p=0.02). This was a significant increase over the baseline Z(LR) of 0.32 observed at this locus among all women with a mood disorder (permutation p=0.004). Suggestive linkage was also found on 9p24.3-p22.3 (Z(LR)=2.91). In the fine-mapping study, the strongest implicated gene was HMCN1 (nominal p=0.00017), containing four estrogen receptor binding sites, although this was not region-wide significant. CONCLUSIONS: This is the first study to examine the genetic etiology of postpartum mood symptoms using genome-wide data. The results suggest that genetic variations on chromosomes 1q21.3-q32.1 and 9p24.3-p22.3 may increase susceptibility to postpartum mood symptoms.

Premenstrual mood symptoms: study of familiality and personality correlates in mood disorder pedigrees.

We sought to determine whether premenstrual mood symptoms exhibit familial aggregation in bipolar disorder or major depression pedigrees. Two thousand eight hundred seventy-six women were interviewed with the Diagnostic Interview for Genetic Studies as part of either the NIMH Genetics Initiative Bipolar Disorder Collaborative study or the Genetics of Early Onset Major Depression (GenRED) study and asked whether they had experienced severe mood symptoms premenstrually. In families with two or more female siblings with bipolar disorder (BP) or major depressive disorder (MDD), we examined the odds of having premenstrual mood symptoms given one or more siblings with these symptoms. For the GenRED MDD sample we also assessed the impact of personality as measured by the NEO-FFI. Premenstrual mood symptoms did not exhibit familial aggregation in families with BP or MDD. We unexpectedly found an association between high NEO openness scores and premenstrual mood symptoms, but neither this factor, nor NEO neuroticism influenced evidence for familial aggregation of symptoms. Limitations include the retrospective interview, the lack of data on premenstrual dysphoric disorder, and the inability to control for factors such as medication use.

Family-based association study of Neuregulin 1 with psychotic bipolar disorder.

The Neuregulin 1 gene (NRG1) has been associated with schizophrenia, and, to a lesser extent, with bipolar disorder (BP). We investigated the association of NRG1 with BP in a large family sample, and then performed analyses according to the presence of psychotic features or mood-incongruent psychotic features. We genotyped 116 tagSNPs and four Icelandic "core" SNPs in 1,199 subjects from 314 nuclear families. Of 515 BP offspring, 341 had psychotic features, and 103 had mood-incongruent psychotic features. In single-marker and sliding window haplotype analyses using FBAT, there was little association using the standard BP or mood-incongruent psychotic BP phenotypes, but stronger signals were seen in the psychotic BP phenotype. The most significant associations with psychotic BP were in haplotypes within the 5' "core" region. The strongest global P-value was across three SNPs: NRG241930-NRG243177-rs7819063 (P = 0.0016), with an undertransmitted haplotype showing an individual P = 0.0007. The most significant individual haplotype was an undertransmitted two-allele subset of the above (NRG243177-rs7819063, P = 0.0004). Additional associations with psychotic BP were found across six SNPs in a 270 kb central region of the gene. The most 3' of these, rs7005606 (P = 0.0029), is located approximately 4 kb from the type I NRG1 isoform promoter. In sum, our study suggests that NRG1 may be specifically associated with the psychotic subset of BP; however, our results should be interpreted cautiously since they do not meet correction for multiple testing and await independent replication.

Carbon dioxide induces erratic respiratory responses in bipolar disorder.

BACKGROUND: CO(2) respiration stimulates both anxiety and dyspnea ("air hunger") and has long been used to study panic vulnerability and respiratory control. High comorbidity with panic attacks suggests individuals with bipolar disorder may also mount a heightened anxiety response to CO(2). Moreover, problems in the arousal and modulation of appetites are central to the clinical syndromes of mania and depression; hence CO(2) may arouse an abnormal respiratory response to "air hunger". METHODS: 72 individuals (34 bipolar I, 25 depressive and bipolar spectrum, 13 with no major affective diagnosis) breathed air and air with 5% CO(2) via facemask for up to 15 min each; subjective and respiratory responses were recorded. RESULTS: Nearly half the subjects diverged from the typical response to a fixed, mildly hypercapneic environment, which is to increase breathing acutely, and then maintain a hyperpneic plateau. The best predictors of an abnormal pattern were bipolar diagnosis and anxiety from air alone. 25 individuals had a panic response; panic responses from CO(2) were more likely in subjects with bipolar I compared to other subjects, however the best predictors of a panic response overall were anxiety from air alone and prior history of panic attacks. LIMITATIONS: Heterogeneous sample, liberal definition of panic attack. CONCLUSION: Carbon dioxide produces abnormal respiratory and heightened anxiety responses among individuals with bipolar and depressive disorders. These may be due to deficits in emotional conditioning related to fear and appetite. Although preliminary, this work suggests a potentially useful test of a specific functional deficit in bipolar disorder.

Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays an important role in the survival, differentiation, and outgrowth of select peripheral and central neurons throughout adulthood. Growing evidence suggests that BDNF is involved in the pathophysiology of mood disorders. METHODS: Ten single nucleotide polymorphisms (SNPs) across the BDNF gene were genotyped in a sample of 1749 Caucasian Americans from 250 multiplex bipolar families. Family-based association analysis was used with three hierarchical bipolar disorder models to test for an association between SNPs in BDNF and the risk of bipolar disorder. In addition, an exploratory analysis was performed to test for an association of the SNPs in BDNF and the phenotypes of rapid cycling and episode frequency. RESULTS: Evidence of association (P<0.05) was found with several of the SNPs using multiple models of bipolar disorder; one of these SNPs also showed evidence of association (P<0.05) with rapid cycling. CONCLUSION: These results provide further evidence that variation in BDNF affects the risk for bipolar disorder.

Rapid switching of mood in families with familial bipolar disorder.

OBJECTIVE: Rapid switching of moods in bipolar disorder has been associated with early age at onset, panic comorbidity, and suicidality. This study aims to confirm these associations and investigate other potential correlates of rapid switching of mood using families from a multisite bipolar linkage study. METHODS: The subjects were comprised of 1,143 probands and relatives with diagnosis of bipolar disorder. All subjects were interviewed directly with a standard diagnostic instrument, and all subjects who met criteria for bipolar disorder were asked if their moods had ever switched rapidly. RESULTS: Individuals with rapid mood switching had significantly earlier age at onset (18 versus 21 years, p < 0.00001), higher comorbid anxiety (47% versus 26%, p < 0.00001) and substance use disorders (52% versus 42%, p = 0.0006), higher rate of violent behavior (6% versus 3%, p < 0.004), suicidal behavior (46% versus 31%, p < 0.00001), and nonsuicidal self-harm (13% versus 6%, p < 0.0002). Multiple logistic regression analysis found significant net effects on rapid mood switching for early emergence of symptoms [odds ratio (OR) = 0.62; 95% confidence interval (CI): 0.45-0.85]; anxiety comorbidity (OR = 2.31; 95% CI: 1.34-3.98); and hypersensitivity to antidepressants (OR = 2.05; 95% CI: 1.49-2.83) as the strongest predictors. CONCLUSIONS: This confirms earlier reports associating rapid switching with a more complex clinical course, in particular early emergence of bipolar symptomatology, antidepressant activation, and anxiety comorbidity. These results support a clinical differentiation of bipolar disorder into subtypes based on symptom stability.

Bipolar disorder as maladaptive arousal: a behavioral model and evidence.

Bipolar disorder can be understood as a disorder of behavioral regulation. Manic and depressed individuals are impaired in the titration of appetitive arousal, possibly at the level of neuronal plasticity. An experiment in which fixed 5% CO2 stimulates respiration and blocks satiety tests the regulation of appetitive arousal. In preliminary analysis of data from 35 individuals (24 with bipolar disorder) individuals with bipolar disorder were more likely to fail to find a stable state of respiratory adjustment to CO2. If confirmed, the unstable respiratory response to CO2 may prove useful as a bipolar-disorder endophenotype.

Familial aggregation of postpartum mood symptoms in bipolar disorder pedigrees.

OBJECTIVES: We sought to determine if postpartum mood symptoms and depressive episodes exhibit familial aggregation in bipolar I pedigrees. METHODS: A total of 1,130 women were interviewed with the Diagnostic Interview for Genetic Studies as part of the National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative Study and were asked whether they had ever experienced mood symptoms within four weeks postpartum. Women were also asked whether either of two major depressive episodes described in detail occurred postpartum. We examined the odds of postpartum mood symptoms in female siblings, who had previously been pregnant and had a diagnosis of bipolar I, bipolar II, or schizoaffective (bipolar type) disorders (n = 303), given one or more relatives with postpartum mood symptoms. RESULTS: The odds ratio for familial aggregation of postpartum mood symptoms was 2.31 (p = 0.011) in an Any Mood Symptoms analysis (n = 304) and increased to 2.71 (p = 0.005) when manic symptoms were excluded, though this was not significantly different from the Any Mood Symptoms analysis. We also examined familial aggregation of postpartum major depressive episodes; however, the number of subjects was small. CONCLUSIONS: Limitations of the study include the retrospective interview, the fact that the data were collected for other purposes and the inability to control for such factors as medication use. Taken together with previous studies, these data provide support for the hypothesis that there may be a genetic basis for the trait of postpartum mood symptoms generally and postpartum depressive symptoms in particular in women with bipolar disorder. Genetic linkage and association studies incorporating this trait are warranted.

Psychotic features in bipolar and unipolar depression.

BACKGROUND: While some prior studies have found higher rates of psychotic depression in those with bipolar disorder or a bipolar relative, others have failed to confirm these observations. We examined the relationship of psychotic depression to polarity in several large familial samples of mood disorder. METHODS: A total of 4,724 subjects with major mood disorder in three family studies on the genetics of bipolar I disorder (BPI) or recurrent major depressive disorder (MDDR) were administered semi-structured interviews by clinicians. Determination of psychotic features was based on a report of hallucinations and/or delusions during the most severe depressive episode in the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or the Diagnostic Interview for Genetic Studies interview. Rates of psychotic depression were calculated by diagnostic category and comparisons were made between diagnoses within and across studies using the generalized estimating equation. RESULTS: A diagnosis of BPI disorder was strongly predictive of psychotic features during depression compared to MDDR [odds ratio (OR) = 4.61, p < 0.0005]. Having bipolar II compared to MDDR was not predictive of psychosis (OR = 1.05, p = 0.260), nor was having a family history of BPI in MDDR subjects (OR = 1.20, p = 0.840). CONCLUSIONS: Psychotic features during a depressive episode increased the likelihood of a BPI diagnosis. Prospective studies are needed to confirm these findings. The potential genetic underpinnings of psychotic depression warrant further study.

Genome-wide scan of bipolar II disorder.

OBJECTIVE: Bipolar disorder (BD) II is characterized by recurrent hypomanic and depressive episodes and has been somewhat of a controversial diagnosis since its description in the 1970s. Clinical opinions notwithstanding, the biological validity of BD II was supported in a genetic study of 58 multiplex bipolar families wherein the statistical evidence for linkage derived from BD II sibling-pairs sharing marker alleles on chromosome 18q. The BD II phenotype alone has never been studied in a genome-wide scan analysis in the current or other bipolar family samples. We have performed genome-wide non-parametric analysis on 74 bipolar pedigrees using only the BD II phenotype as affection model. METHODS: This sample consists of the 65 pedigrees previously reported and 9 additional novel pedigrees that had BD II exclusively, as the affected phenotype. In the entire sample, there were 146 all possible relative-pairs. Analysis was performed using the non-parametric method in GENEHUNTER, with the 'ALL' option that computes linkage scores in all individuals in a pedigree simultaneously. RESULTS: The current analyses supported the previous finding on chromosome 18q21. In addition a peak with a non-parametric LOD (NPL) of 2.07 occurred between D9S915 and D9S2157, located on 9q34. Analysis of the nine BD II families alone identified peaks on 9p13 and 9q33, with NPL scores of 3.20 and 2.09, respectively. There was no evidence at 18q21 in these nine families. CONCLUSIONS: This suggests that there may be substantial differences in the etiology of BD in families that have BD II exclusively as the diagnosis.

The bipolar disorder phenome database: a resource for genetic studies.

OBJECTIVE: The purpose of this study was to assemble and validate a database of phenotypic variables that were collected from families with bipolar disorder as a resource for genetic and other biological studies. METHOD: Participants were ascertained for two bipolar disorder genetic linkage studies: the University of Chicago, Johns Hopkins, and National Institute of Mental Health (NIMH) Intramural Program (CHIP) Collaboration and the NIMH Genetics Initiative project. All participants underwent detailed, phenotypic assessment with either the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or one of four versions of the Diagnostic Interview for Genetic Studies. Clinicians reviewed the interview items and derived variable definitions that were used to extract data from the original datasets. The combined data were subjected to range and logic assessments, and a subset was re-verified against the original data. Inconsistent data and variables that were deemed unreliable were excluded. Several of the resulting variables were characterized in the total cohort and tested for familial clustering, heritability, and statistical power in genetic linkage and association studies. RESULTS: The combined database of phenotypic variables contained 197 variables on 5,721 subjects in 1,177 families. Deoxyribonucleic acid (DNA) samples are available for 5,373 of these subjects. The clinical presentation of bipolar disorder varied markedly. Most subjects suffered from serious and often disabling illness. Many phenotypic variables are strongly familial, and some quantitative variables are highly heritable. The cohort assembled in this study offers substantial power to carry out genetic linkage and association studies that use specific clinical features as covariates or as primary phenotypes. CONCLUSIONS: This is the largest database of phenotypic variables yet assembled for bipolar disorder, and it is now available to the research community. Researchers and clinicians can use this database to explore the connections between phenomenology and genetics in a cohort that is adequately powered to detect even modest genetic effects in bipolar disorder.