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Medical comorbidity and healthcare utilization in patients with treatment resistant depression (TRD) is usually reported in convenience samples, making estimates unreliable. There is only limited large-scale clinical research on comorbidities and healthcare utilization in TRD patients.Electronic Health Record data from over 3.3 million patients from the INSIGHT Clinical Research Network in New York City was used to define TRD as initiation of a third antidepressant regimen in a 12-month period among patients diagnosed with major depressive disorder (MDD). Age and sex matched TRD and non-TRD MDD patients were compared for anxiety disorder, 27 comorbid medical conditions, and healthcare utilization.Out of 30,218 individuals diagnosed with MDD, 15.2 % of patients met the criteria for TRD (n = 4605). Compared to MDD patients without TRD, the TRD patients had higher rates of anxiety disorder and physical comorbidities. They also had higher odds of ischemic heart disease (OR = 1.38), stroke/transient ischemic attack (OR = 1.57), chronic kidney diseases (OR = 1.53), arthritis (OR = 1.52), hip/pelvic fractures (OR = 2.14), and cancers (OR = 1.41). As compared to non-TRD MDD, TRD patients had higher rates of emergency room visits, and inpatient stays. In relation to patients without MDD, both TRD and non-TRD MDD patients had significantly higher levels of anxiety disorder and physical comorbidities.The INSIGHT-CRN data lack information on depression severity and medication adherence.TRD patients compared to non-TRD MDD patients have a substantially higher prevalence of various psychiatric and medical comorbidities and higher health care utilization. These findings highlight the challenges of developing interventions and care coordination strategies to meet the complex clinical needs of TRD patients.

To evaluate the prevalence and clinical correlates of lifetime migraine among patients with bipolar disorder (BD).In a cross-sectional study, we evaluated 721 adults with BD from the Mayo Clinic Bipolar Disorder Biobank and compared clinical correlates of those with and without a lifetime history of migraine. A structured clinical interview (DSM-IV) and a clinician-assessed questionnaire were utilized to establish a BD diagnosis, lifetime history of migraine, and clinical correlates.Two hundred and seven (29%) BD patients had a lifetime history of migraine. BD patients with migraine were younger and more likely to be female as compared to those without migraine (p values0.01). In a multivariate logistic regression model, younger age (OR=0.98, p0.01), female sex (OR=2.02, p0.01), higher shape/weight concern (OR=1.04, p=0.02), greater anxiety disorder comorbidities (OR=1.24, p0.01), and evening chronotype (OR=1.65, p=0.03) were associated with migraine. In separate regression models for each general medical comorbidity (controlled for age, sex, and site), migraines were significantly associated with fibromyalgia (OR=3.17, p0.01), psoriasis (OR=2.65, p=0.03), and asthma (OR=2.0, p0.01). Participants with migraine were receiving ADHD medication (OR=1.53, p=0.05) or compounds associated with weight loss (OR=1.53, p=0.02) at higher rates compared to those without migraine.Study design precludes determination of causality. Migraine subtypes and features were not assessed.Migraine prevalence is high in BD and is associated with a more severe clinical burden that includes increased comorbidity with pain and inflammatory conditions. Further study of the BD-migraine phenotype may provide insight into common underlying neurobiological mechanisms.

OBJECTIVES: Recognizing bipolar disorder as a multi-system metabolic condition driven, in part, by binge eating behavior and atypical depressive symptoms, this study aimed to quantify diet quality and evaluate clinical correlates in a bipolar disorder cohort. METHODS: Participants from the Mayo Clinic Bipolar Disorder Biobank (n = 734) completed the Rapid Eating Assessment for Participants – Shortened version (REAP-S) to determine diet quality. The average REAP-S score for a U.S. omnivorous diet is 32 (range 13 to 39) with higher scores indicating healthier diet. Demographic variables were collected in a standardized clinical questionnaire. Depressive symptoms were assessed by the Bipolar Inventory of Symptoms Scale. Cardiometabolic variables were retrieved from the electronic health record. Associations between continuous variables and REAP-S scores (total, ‘healthy foods’ and ‘avoidance of unhealthy foods’) were assessed using linear regression. RESULTS: Overall, our sample had a mean REAP-S score of 27.6 (4.9), suggestive of a lower diet quality than the average general population in the US. There was a significant inverse relationship between mean REAP-S lower scores with increased BMI, waist circumference, disordered eating and depression. All these associations were significantly stronger in female participants. LIMITATIONS: EHR cross-sectional data. CONCLUSIONS: Our data suggest unhealthy diet quality in bipolar disorder is associated with depression, obesity and cardiometabolic abnormalities. Additional work is encouraged to prospectively track mood and diet quality to further understand the bidirectional relationship and clarify if dietary interventions can positively impact mood. Further delineating potential sex differences in diet quality and depression may provide greater appreciation of modifiable risk factors for future cardiometabolic burden.

Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic disorders. Genomic studies may help define if they share genetic liability. This selective review of BD with obesity and T2D will focus on genomic studies, stress their current limitations and guide future steps in developing the field.We searched electronic databases (PubMed, Scopus) until December 2021 to identify genome-wide association studies, polygenic risk score analyses, and functional genomics of BD accounting for body mass index (BMI), obesity, or T2D.The first genome-wide association studies (GWAS) of BD accounting for obesity found a promising genome-wide association in an intronic gene variant of TCF7L2 that was further replicated. Polygenic risk scores of obesity and T2D have also been associated with BD, yet, no genetic correlations have been demonstrated. Finally, human-induced stem cell studies of the intronic variant in TCF7L2 show a potential biological impact of the products of this genetic variant in BD risk.The narrative nature of this review.Findings from BD GWAS accounting for obesity and their functional testing, have prompted potential biological insights. Yet, BD, obesity, and T2D display high phenotypic, genetic, and population-related heterogeneity, limiting our ability to detect genetic associations. Further studies should refine cardiometabolic phenotypes, test gene-environmental interactions and add population diversity.

Misdiagnosis is common in bipolar disorder and disproportionally affects racial and ethnic minorities. There is interest in better understanding the contribution of differential symptomatic illness presentation to misdiagnosis.Utilizing the Genetic Association Information Network (GAIN) public database, this study compared clinical phenomenology between bipolar patients of African vs European ancestry (AA = 415 vs EA = 480). The Diagnostic Interview for Genetic Studies (DIGS) was utilized to evaluate symptom endorsement contributing to diagnostic confirmation of bipolar I disorder (BPI) and lifetime medication use.Elevated/euphoric mood was less endorsed in AA vs EA participants (p = 0.03). During the most severe episode of mania, AA participants, in comparison to EA participants, had a lower sum of manic symptoms (p = 0.006) and a higher rate of hallucinations (p = 0.01). During lifetime psychosis, AA participants, in comparison to EA participants, had a higher lifetime sum of delusions (p = 0.01) and hallucinations (p 0.0001). AA participants reported lower use of lithium (p 0.0001) and mood stabilizing anticonvulsants (p = 0.0003).The differential rate of manic and psychotic symptom endorsement from a semi-structured diagnostic interview may represent differential illness presentation based on biological differences or racial or study biases (e.g. ascertainment). Increased minority recruitment in bipolar research is therefore a necessary future direction.Recall and interviewer bias may affect study results, but are likely diminished by the alignment of symptom endorsement and medication use.

Objectives To compare the relative influence (RI) of individual predictors for lifetime attempted suicide between adults with bipolar I (BDBD-I) and bipolar II disorder (BDBD-II). Methods We conducted an analysis of data from 1465 enrollees in the Mayo Clinic Bipolar Disorder Biobank. Demographic and clinical variables and history of attempted suicide were ascertained using standardized questionnaires. Height and weight were assessed to determine body mass index (BMI); obesity was defined as BMI ≥30 kg/m 2 . The frequencies of these variables were compared between persons with and without self-reported lifetime suicide attempts both overall, and within BD-I and BD-II subgroups. Gradient boosting machine (GBM) models were used to quantify the RI of study variables on the risk of lifetime attempted suicide. Results Nearly one-third of patients reported having a lifetime suicide attempt. Attempted suicide rates were higher in patients with BD-I than BD-II, but absolute differences were small. Lifetime attempted suicide was associated with female sex, BD-I subtype, psychiatric and substance use comorbidities, binge eating behavior, lifetime history of rapid cycling, other indicators of adverse illness course, and early age of bipolar illness onset in the entire cohort. Differences in the rank-ordering of RI for predictors of attempted suicide between BD-I and BD-II patients were modest. Rapid cycling was a strong risk factor for attempted suicide, particularly in men with BD-I. Limitations Actively psychotic or suicidal patients needing psychiatric hospitalization were initially excluded, but were approached after these acute psychiatric problems resolved. Conclusions The prevalence of lifetime attempted suicide was significantly higher in BD-I than BD-II in this large, cross-sectional cohort. Predictors of attempted suicide were similar in BD-I and BD-II subgroups.

Background The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD. Methods Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed. Results Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2). Limitation Relatively small sample size. Conclusion Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.

Our aim was to investigate evening chronotype, a proxy marker of circadian system dysfunction, as a clinical subphenotype in bipolar disorder (BD).In this cross-sectional study, 773 BD participants and 146 control subjects were evaluated using the Structured Clinical Interview for DSM-IV and a set of questionnaires. Chronotype was determined using item-5 from the reduced Morningness-Eveningness Questionnaire. Univariate analyses and regression models were used to compare evening and non-evening chronotype in BD and chronotype association with clinical variables.Overall, 205 (27%) of BD patients reported an evening chronotype. Evening chronotype was higher in a matched sub-sample of BD patients (n = 150) than in controls (24% and 5% respectively, OR=5.4, p0.01). Compared to those with non-evening chronotypes, BD patients with an evening chronotype were younger, had an earlier age of onset of BD, and had more prior depressive and manic episodes, higher rates of rapid cycling, past suicide attempts, more comorbid anxiety and substance use disorders. Multivariate regression showed age, prior suicide attempts, and co-occurring substance use disorder were associated with evening chronotype (OR range of 0.97 to1.59). Hypertension, migraine, asthma, and obstructive sleep apnea were significantly associated with evening chronotype (OR range of 1.56 to 2.0).Limitations include a cross-sectional study design that precludes establishing causality. Analyses did not control for medication use. Younger participant age may prevent evaluation of associations with late-life illnesses.Evening chronotype may be a discrete clinical subphenotype in BD and circadian dysfunction a shared pathophysiological mechanism between psychopathology and medical morbidity.

Background Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity. Methods We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls. Results No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E−06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression. Limitations The sample sizes of the early-onset BD subgroups were relatively small. Conclusions Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model.

Background Prior work suggests that adult bipolar disorder (BD) is associated with increased oxidative stress and inflammation. This exploratory study examined markers of lipid and protein oxidation and inflammation in adolescents with and at varying risk for BD type I (BD-I). Methods Blood was obtained from four groups of adolescents (9–20 years of age): (1) healthy comparison subjects with no personal or family history of psychiatric disorders (n=13), (2) subjects with no psychiatric diagnosis and at least one parent with BD-I (‘high-risk’, n=15), (3) subjects with at least one parent with BD-I and a diagnosis of depressive disorder not-otherwise-specified (‘ultra-high-risk’, n=20), and (4) first-episode patients exhibiting mixed or manic symptoms that received a diagnosis of BD-I (n=16). Plasma levels of lipid peroxidation (LPH, 4-HNE, 8-ISO), protein carbonyl, and inflammation (IL-1α-β, IL-6, IL-10, IFNγ, TNFα) were assessed using analysis of variance and covariance models. Results LPH was lower in adolescents with fully syndromal BD than controls, while LPH levels in the at-risk groups were between healthy controls and fully syndromal BD. Post-hoc analysis showed a non-significant increase in the (4-HNE+8-ISO)/LPH ratio suggesting a potential conversion of LPH into late-stage markers of lipid peroxidation. There were no significant differences among protein carbonyl content and inflammatory markers. Conclusions In adolescents, fully syndromal BD is associated with significant reductions in LPH levels, and LPH levels decrease along the spectrum of risk for BD-I. Quantifying lipid peroxidation in longitudinal studies may help clarify the role of LPH in BD risk progression.

Background Patients with bipolar disorder demonstrate sex differences in clinical presentation, particularly in the sub-phenotypes related to periodicity of mood episodes, such as rapid cycling. Additionally, recent studies have linked P2RX7 gene variants with the risk of rapid cycling in clinical cohorts of patients with bipolar disorder, as well as other mood disorders. However, little is known about potential sex differences in the relationship between variants in P2RX7 and bipolar disorder. Methods We investigated sex-specific genetic associations between variants of P2RX7 (rs1621388 and rs2230912) in 756 patients with bipolar disorder and 787 control patients matched on age, sex, and ancestry. We examined sex-specific genetic associations with bipolar disorder by comparing cases and controls, as well as rapid cycling of mood episodes in cases. Findings were replicated in an independent dataset. Results P2RX7 variants implying an increased pore activity were more common in bipolar disorder, in females but not in males. Neither P2RX7 variants associated with rapid cycling among bipolar patients. Limitations Low sample size limited power for tests of SNP by sex interaction, and data about the onset of rapid cycling and the timing of medication use were not available. Conclusion The effects of P2RX7 variants on bipolar disorder may be sex-specific, with increased P2X7 activity potentially elevating risk for bipolar disorder in females. Future research to examine the effect of P2RX7 on bipolar disorder should consider sex-specific effects.

Objective To determine prevalence rates and clinical correlates of current DSM-5 eating disorders in patients with bipolar disorder (BP). Methods Prevalence rates of current DSM-5- and DSM-IV-defined binge eating disorder (BED), bulimia nervosa (BN), and anorexia nervosa (AN) were assessed with the Eating Disorder Diagnostic Scale (EDDS) in 1092 patients with BP. Psychiatric illness burden was evaluated with five proxy measures of BP illness severity. Medical illness burden was evaluated with the Cumulative Index Rating Scale (CIRS). Results Twenty-seven percent of patients had a current DSM-5 eating disorder: 12% had BED, 15% had BN, and 0.2% had AN. Rates of DSM-5-defined BED and BN were higher than clinical diagnosis rates and rates of DSM-IV-defined BED and BN. Compared with BP patients without an eating disorder, BP patients with a DSM-5 eating disorder were younger and more likely to be women; had an earlier age of onset of BP; had higher EDDS composite scores and higher degrees of suicidality, mood instability, and anxiety disorder comorbidity; and had a higher mean BMI, higher rate of obesity, and higher CIRS total scores. In a logistic regression model controlling for previously identified correlates of an eating disorder, younger age, female gender, and higher BMI remained significantly associated with an eating disorder. Limitations The EDDS has not been validated in BP patients. Conclusion DSM-5-defined BED and BN are common in BP patients, possibly more common than DSM-IV-defined BED and BN, and associated with greater psychiatric and general medical illness burden. Further studies assessing DSM-5 eating disorders in people with BP are greatly needed.

Background Substantial research progress can be achieved if available clinical datasets can be mapped to the National Institute of Mental Health Research-Domain-Criteria (RDoC) constructs. This mapping would allow investigators to both explore more narrowly defined clinical phenotypes and the relationship of these phenotypes to biological markers and clinical outcomes approximating RDoC criteria. Methods Using expert review and consensus, we defined four major depression phenotypes based on specific RDoC constructs. Having matched these constructs to individual items from the Hamilton Depression Rating Scale and Quick Inventory of Depressive Symptomatology, we identified subjects meeting criteria for each of these phenotypes from two large clinical trials of patients treated for major depression. In a post hoc analysis, we evaluated the overall treatment response based on the phenotypes: Core Depression (CD), Anxiety (ANX), and Neurovegetative Symptoms of Melancholia (NVSM) and Atypical Depression (NVSAD). Results The phenotypes were prevalent (range 10.5–52.4%, 50% reduction range 51.9–82.9%) and tracked with overall treatment response. Although the CD phenotype was associated with lower rates of remission in both cohorts, this was mainly driven by baseline symptom severity. However, when controlling for baseline severity, patients with the ANX phenotype had a significantly lower rate of remission. Limitations The lack of replication between the studies of the phenotypes’ treatment prediction value reflects important variability across studies that may limit generalizability. Conclusion Further work evaluating biological markers associated with these phenotypes is needed for further RDoC concept development.

Objective To determine whether bipolar spectrum disorder with binge eating behavior (BE) is an important clinical sub-phenotype. Methods Prevalence rates and correlates of different levels of BE were assessed in 1114 bipolar spectrum patients participating in a genetic biobank. BE and eating disorders (EDs) were assessed with the Eating Disorder Diagnostic Scale (EDDS). Psychiatric illness burden was evaluated with measures of suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. Medical illness burden was evaluated with body mass index (BMI) and the Cumulative Index Rating Scale (CIRS). Results Thirty percent of patients had any BE and 27% had BE plus an ED diagnosis. Compared with bipolar spectrum patients without BE, bipolar spectrum patients with BE were younger and more likely to be female; had significantly higher levels of eating psychopathology, suicidality, mood instability, and anxiety disorder comorbidity; had a significantly higher mean BMI and a significantly higher rate of obesity; and had a significantly higher medical illness burden. Bipolar spectrum patients with BE but no ED diagnosis were more similar to bipolar spectrum patients without BE than to those with an ED. Nonetheless, the positive predictive value and specificity of BE predicting an ED was 0.90 and 0.96, respectively. Limitations As only two patients had co-occurring anorexia nervosa, these results may not generalize to bipolar spectrum patients with restricting EDs. Conclusion Bipolar spectrum disorder with broadly-defined BE may not be as clinically relevant a sub-phenotype as bipolar spectrum disorder with an ED but may be an adequate proxy for the latter when phenotyping large samples of individuals.

Background Depression is the predominant pole of illness disability in bipolar disorder and, compared with acute mania, has less systematic research guiding treatment development. The aim of this review is to present the therapeutic options currently available for managing bipolar depression and to highlight areas of unmet need and future research. Methods Literature search of PubMed, PsycINFO, and Cochrane databases and bibliographies from 2000 to August 2013 for treatments that have regulatory approval for bipolar depression or early controlled preliminary data on efficacy. Results Treatment options for bipolar depression have increased over the last decade, most notably with regulatory approval for olanzapine/fluoxetine combination, quetiapine, and lurasidone. Conventional mood stabilizers lamotrigine and divalproex have meta-analyses suggesting acute antidepressant response. Manual-based psychotherapies also appear to be effective in treating bipolar depression. The therapeutic utility of unimodal antidepressants, as a class, for the treatment of patients with bipolar depression, as a group, remains to be confirmed. There is a substantially unmet need to develop new interventions that are efficacious, effective, and have low side effect burden. Limitations Additional compounds are currently being developed that may ultimately be applicable to the treatment of bipolar depression and early open-trial data encourage further studies, but both of these topics are beyond the scope of this review. Conclusion Future registrational trials will need to establish initial efficacy, but increasing interest for personalized or individualized medicine will encourage further studies on individual predictors or biomarkers of response.

To explore the relationship between binge eating disorder (BED) and obesity in patients with bipolar disorder (BP).717 patients participating in the Mayo Clinic Bipolar Biobank completed structured diagnostic interviews and questionnaires for demographic and illness-related variables. They also had weight and height measured to determine body mass index (BMI). The effects of BED and obesity (BMI≥30 kg/m(2)), as well as their interaction, were assessed on one measure of general medical burden and six proxies of psychiatric illness burden.9.5% of patients received a clinical diagnosis of BED and 42.8% were obese. BED was associated with a significantly elevated BMI. Both BED and obesity were associated with greater psychiatric and general illness burden, but illness burden profiles differed. After controlling for obesity, BED was associated with suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. After controlling for BED status, obesity was associated with greater general medical comorbidity, but lower substance abuse comorbidity. There were no significant interaction effects between obesity and BED, or BMI and BED, on any illness burden outcome.There may have been insufficient power to detect interactions between BED and obesity.Among patients with BP, BED and obesity are highly prevalent and correlated, but associated with different profiles of enhanced illness burden. As the association of BED with greater psychiatric illness burden remained significant even after accounting for the effect of obesity, BP with BED may represent a clinically important sub-phenotype.

Background Antidepressants can trigger a rapid mood switch from depression to mania. Identifying genetic risk factors associated with antidepressant induced mania (AIM) may enable individualized treatment strategies for bipolar depression. This review and meta-analysis evaluates the evidence for association between the serotonin transporter gene promoter polymorphism (5HTTLPR) and AIM. Methods Medline up to November 2009 was searched for key words bipolar, antidepressant, serotonin transporter, SLC6A4 , switch, and mania. Results Five studies have evaluated the SLC6A4 promoter polymorphism and AIM in adults (total N = 340 AIM+ cases, N = 543 AIM− controls). Although a random effects meta-analysis showed weak evidence of association of the S allele with AIM+ status, a test of heterogeneity indicated significant differences in estimated genetic effects between studies. A similar weak association was observed in a meta-analysis based on a subset of three studies that excluded patients on mood stabilizers; however the result was again not statistically significant. Limitations Few pharmacogenomic studies of antidepressant treatment of bipolar disorder have been published. The completed studies were underpowered and often lacked important phenotypic information regarding potential confounders such as concurrent use of mood stabilizers or rapid cycling. Conclusions There is insufficient published data to confirm an association between 5HTTLPR and antidepressant induced mania. Pharmacogenomic studies of antidepressant induced mania have high potential clinical impact provided future studies are of adequate sample size and include rigorously assessed patient characteristics (e.g. ancestry, rapid cycling, concurrent mood stabilization, and length of antidepressant exposure).