Neurocognitive correlates of polygenic risk for bipolar disorder among youth with and without bipolar disorder.

INTRODUCTION: There is well-established evidence of reduced neurocognitive performance in adults and youth with bipolar disorder (BD). However, little is known about the polygenic underpinnings of neurocognition in individuals with BD, particularly in youth. The current study aimed to examine the association between polygenic risk score for BD (BD-PRS) and neurocognition among youth with BD and healthy controls (HC). METHODS: 129 youth of European ancestry (72 BD, 57 HC), ages 13-20 years, were included. Six neurocognitive tasks within the Cambridge Neuropsychological Test Automated Battery were assessed. General linear models were used to examine the association between BD-PRS and neurocognitive composite scores, controlling for age, sex, IQ, and two genetic principal components. RESULTS: In the overall sample, higher BD-PRS was associated with significantly poorer affective processing (ß = -0.25, p = 0.01), decision-making (ß = -0.23, p = 0.02), and sustained attention (ß = -0.28, p = 0.002). Secondary analyses revealed that higher BD-PRS was associated with significantly poorer sustained attention within the BD group (ß = -0.27, p = 0.04), and with significantly poorer affective processing within the HC group (ß = -0.29, p = 0.04). LIMITATIONS: Cross-sectional design. Modest sample size may have reduced power to detect smaller effect sizes. CONCLUSION: The current study found that higher BD-PRS generated based on adult GWAS was associated with poorer neurocognitive performance in youth with BD and HC. Future longitudinal studies incorporating repeated neurocognitive assessments would further inform whether the associations of BD-PRS with neurocognition vary from youth to adulthood, and whether BD-PRS is associated with differential neurodevelopmental trajectories in individuals with and without BD.

Pilot study of circulating cell-free mitochondrial DNA in relation to brain structure in youth bipolar disorder.

BACKGROUND: Mitochondrial dysfunction is implicated in the neuropathology of bipolar disorder (BD). Higher circulating cell-free mitochondrial DNA (ccf-mtDNA), generally reflecting poorer mitochondrial health, has been associated with greater symptoms severity in BD. The current study examines the association of serum ccf-mtDNA and brain structure in relation to youth BD. We hypothesized that higher ccf-mtDNA will be associated with measures of lower brain structure, particularly in the BD group. METHODS: Participants included 40 youth (BD, n = 19; Control group [CG], n = 21; aged 13-20 years). Serum ccf-mtDNA levels were assayed. T1-weighted brain images were acquired using 3T-MRI. Region of interest (ROI) analyses examined prefrontal cortex (PFC) and whole brain gray matter, alongside exploratory vertex-wise analyses. Analyses examined ccf-mtDNA main-effects and ccf-mtDNA-by-diagnosis interaction effects controlling for age, sex, and intracranial volume. RESULTS: There was no significant difference in ccf-mtDNA levels between BD and CG. In ROI analyses, higher ccf-mtDNA was associated with higher PFC surface area (SA) (ß = 0.32 p < 0.001) and PFC volume (ß = 0.32 p = 0.002) in the overall sample. In stratified analyses, higher ccf-mtDNA was associated with higher PFC SA within both subgroups (BD: ß = 0.39 p = 0.02; CG: ß = 0.24 p = 0.045). Higher ccf-mtDNA was associated with higher PFC volume within the BD group (ß = 0.39 p = 0.046). In vertex-wise analyses, higher ccf-mtDNA was associated with higher SA and volume in frontal clusters within the overall sample and within the BD group. There were significant ccf-mtDNA-by-diagnosis interactions in three frontal and parietal clusters, whereby higher ccf-mtDNA was associated with higher neurostructural metrics in the BD group but lower neurostructural metrics in CG. CONCLUSIONS: Contrasting our hypothesis, higher ccf-mtDNA was consistently associated with higher, rather than lower, regional neuralstructural metrics among youth with BD. While this finding may reflect a compensatory mechanism, future repeated-measures prospective studies evaluating the inter-relationship among ccf-mtDNA, mood, and brain structure across developmental epochs and illness stages are warranted.

Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder, Youth at High Risk for Bipolar Disorder, and Controls.

OBJECTIVE: There is a pronounced gap in knowledge regarding polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk scores (PRSs) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls. METHOD: Participants were 344 youths of European ancestry (13-20 years old), including 136 youths with BD, 121 HR youths, and 87 controls. PRSs for BD, schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs HR vs controls). All genetic analyses controlled for age, sex, and 2 genetic principal components. RESULTS: The BD group showed significantly higher BD-PRS than the control group (odds ratio = 1.54, 95% CI = 1.13-2.10, p = .006), with the HR group numerically intermediate. BD-PRS explained 7.9% of phenotypic variance. PRSs for schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were not significantly different among groups. In the BD group, BD-PRS did not significantly differ in relation to BD subtype, age of onset, psychosis, or family history of BD. CONCLUSION: BD-PRS derived from adult genome-wide summary statistics is elevated in youth with BD. Absence of significant between-group differences in PRSs for other psychiatric disorders supports the specificity of BD-PRS in youth. These findings add to the biological validation of BD in youth and could have implications for early identification and diagnosis. To enhance clinical utility, future genome-wide association studies that focus specifically on early-onset BD are warranted, as are studies integrating additional genetic and environmental factors. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Improving physician wellness through the Applied Mindfulness Program for Medical Personnel: findings from a prospective qualitative study.

BACKGROUND: Physicians play a critical role across health care delivery systems, yet their own well-being is often overlooked; mindfulness has been widely recommended as a promising modality to support physician wellness. We sought to explore how physicians experience and engage with a 5-week applied mindfulness program and how they perceive its impact on their personal well-being in the context of their daily lives. METHOD: We delivered the Applied Mindfulness Program for Medical Personnel (AMP-MP) at a tertiary care hospital in downtown Toronto, Canada. This prospective qualitative study consists of a thematic analysis of post-program interviews with physicians, from across different specialties, who participated in the AMP-MP. The program includes 2-hour sessions, delivered once a week over 5 weeks, and is based on the teachings of Thích Nhat Hanh. RESULTS: We interviewed 28 physicians after they completed the AMP-MP. Our data show that a 5-week training was sufficient for physicians to develop a foundational level of mindfulness that integrated into their daily life. Two themes were identified: mindfulness encourages behavioural and cognitive changes that facilitate well-being, and mindfulness improves communication with patients and colleagues. INTERPRETATION: Our results show applied mindfulness to be well received by physicians as an effective modality to increase their perceived sense of wellness and enhance communication with their patients and colleagues. Further research is necessary to better understand the individual and systemic implications of mindfulness training, and how this modality can complement other efforts being made to address and maintain physician wellness.

Association of polygenic risk for bipolar disorder with grey matter structure and white matter integrity in youth.

There is a gap in knowledge regarding the polygenic underpinnings of brain anomalies observed in youth bipolar disorder (BD). This study examined the association of a polygenic risk score for BD (BD-PRS) with grey matter structure and white matter integrity in youth with and without BD. 113 participants were included in the analyses, including 78 participants with both T1-weighted and diffusion-weighted MRI images, 32 participants with T1-weighted images only, and 3 participants with diffusion-weighted images only. BD-PRS was calculated using PRS-CS-auto and was based on independent adult genome-wide summary statistics. Vertex- and voxel-wise analyses examined the associations of BD-PRS with grey matter metrics (cortical volume [CV], cortical surface area [CSA], cortical thickness [CTh]) and fractional anisotropy [FA] in the combined sample, and separately in BD and HC. In the combined sample of participants with T1-weighted images (n = 110, 66 BD, 44 HC), higher BD-PRS was associated with smaller grey matter metrics in frontal and temporal regions. In within-group analyses, higher BD-PRS was associated with lower CTh of frontal, temporal, and fusiform gyrus in BD, and with lower CV and CSA of superior frontal gyrus in HC. In the combined sample of participants with diffusion-weighted images (n = 81, 49 BD, 32 HC), higher BD-PRS was associated with lower FA in widespread white matter regions. In summary, BD-PRS calculated based on adult genetic data was negatively associated with grey matter structure and FA in youth in regions implicated in BD, which may suggest neuroimaging markers of vulnerability to BD. Future longitudinal studies are needed to examine whether BD-PRS predicts neurodevelopmental changes in BD vs. HC and its interaction with course of illness and long-term medication use.

Association of polygenic risk for bipolar disorder with resting-state network functional connectivity in youth with and without bipolar disorder.

Little is known regarding the polygenic underpinnings of anomalous resting-state functional connectivity (rsFC) in youth bipolar disorder (BD). The current study examined the association of polygenic risk for BD (BD-PRS) with whole-brain rsFC at the large-scale network level in youth with and without BD. 99 youth of European ancestry (56 BD, 43 healthy controls [HC]), ages 13-20 years, completed resting-state fMRI scans. BD-PRS was calculated using summary statistics from the latest adult BD genome-wide association study. Data-driven independent component analyses of the resting-state fMRI data were implemented to examine the association of BD-PRS with rsFC in the overall sample, and separately in BD and HC. In the overall sample, higher BD-PRS was associated with lower rsFC of the salience network and higher rsFC of the frontoparietal network with frontal and parietal regions. Within the BD group, higher BD-PRS was associated with higher rsFC of the default mode network with orbitofrontal cortex, and altered rsFC of the visual network with frontal and occipital regions. Within the HC group, higher BD-PRS was associated with altered rsFC of the frontoparietal network with frontal, temporal and occipital regions. In conclusion, the current study found that BD-PRS generated based on adult genetic data was associated with altered rsFC patterns of brain networks in youth. Our findings support the usefulness of BD-PRS to investigate genetically influenced neuroimaging markers of vulnerability to BD, which can be observed in youth with BD early in their course of illness as well as in healthy youth.

Prevalence and health care costs of mitochondrial disease in Ontario, Canada: A population-based cohort study.

BACKGROUND: Mitochondrial disease prevalence has been estimated at 1 in 4000 in the United States, and 1 in 5000 worldwide. Prevalence in Canada has not been established, though multi-linked health administrative data resources present a unique opportunity to establish robust population-based estimates in a single-payer health system. This study used administrative data for the Ontario, Canada population between April 1988 and March 2019 to measure mitochondrial disease prevalence and describe patient characteristics and health care costs. RESULTS: 3069 unique individuals were hospitalized with mitochondrial disease in Ontario and eligible for the study cohort, representing a period prevalence of 2.51 per 10,000 or 1 in 3989. First hospitalization was most common between ages 0-9 or 50-69. The mitochondrial disease population experiences a high need for health care and incurred high costs (mean = CAD$24,023 in 12 months before first hospitalization) within the single-payer Ontario health care system. CONCLUSIONS: This study provides needed insight into mitochondrial disease in Canada, and demonstrates the high health burden on patients. The methodology used can be adapted across jurisdictions with similar routine collection of health data, such as in other Canadian provinces. Future work should seek to validate this approach via record linkage of existing disease cohorts in Ontario, and identify specific comorbidities with mitochondrial disease that may contribute to high health resource utilization.

Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study.

BACKGROUND: Numerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. METHODS: 79 adolescents, ages 13-19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. RESULTS: Adolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p = 0.01) and pro- to anti-inflammatory ratios (CRP/IL-10; p < 0.001 and IL-6/IL-10; p = 0.046) were significantly greater, and IL-10 levels (p = 0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p = 0.01) and IL-10 levels (p = 0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode. CONCLUSIONS: In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.

Transgender health in medical education.

Transforming our world the 2030 agenda for sustainable development is working towards a world that reflects equity, with universal respect for human dignity, pledging to leave no one behind. However, transgender and gender-diverse individuals experience significant health inequities, including negative health outcomes and multiple barriers to accessing care. In this article, we first highlight the health inequities that transgender and gender-diverse people face globally. We describe important aspects of transgender and gender-diverse health care, including the design and provision of health services, epidemiological considerations, transition-related care, changes in transition-related goals, cultural considerations, and political and legal issues. We then review the existing global literature on incorporating transgender health into medical curricula. We make a case for prioritizing improved education in medical schools on the specific health needs of transgender and gender-diverse people as part of addressing global health inequities in care. Our recommendations for comprehensive education on transgender health include cultural humility and anti-oppression training; involvement of transgender and gender-diverse community members; integration of transgender and gender-diverse health into curricula; practice-focused and in situ training; staff development in medical schools; and improving access to careers in medicine for transgender and gender-diverse people.

Transformer notre monde: le Programme de développement durable à l'horizon 2030 aspire à un monde où règne l'équité, le respect universel de la dignité humaine, et s'engage à ce que personne ne soit oublié. Pourtant, les individus transgenres et de genre variant subissent de profondes inégalités sur le plan sanitaire, qui affectent leur état de santé et compliquent grandement l'accès aux soins. Dans cet article, nous commençons par souligner les inégalités sanitaires auxquelles sont confrontés les individus transgenres et de genre variant à travers le monde. Nous évoquons d'importants aspects à prendre en compte pour les soins de santé aux personnes transgenres et de genre variant, parmi lesquels la conception et la fourniture de services de santé, les considérations d'ordre épidémiologique, les soins liés à la transition, l'évolution des objectifs liés à la transition, les facteurs culturels, ainsi que les enjeux politiques et juridiques. Nous examinons ensuite la littérature internationale consacrée à l'intégration de la santé transgenre dans les programmes d'enseignement médical. Nous soutenons que, dans le cadre de la lutte contre les inégalités sanitaires au niveau mondial, il faut privilégier une amélioration de l'enseignement dans les écoles de médecine afin de sensibiliser aux besoins spécifiques des individus transgenres et de genre variant en matière de santé. Nous avons formulé plusieurs recommandations en vue d'instaurer un enseignement qui tient compte de la santé des personnes transgenres: apprentissage anti-oppressif intégrant la notion d'humilité culturelle; implication de membres de la communauté transgenre et de genre variant; ajout de la santé transgenre et de genre variant dans les programmes de cours; formation centrée sur la pratique, dispensée sur le terrain; développement du personnel des écoles de médecine; et enfin, amélioration de l'accès aux carrières médicales pour les individus transgenres et de genre variant.

Transforming our world: the 2030 agenda for sustainable development (Transformar de nuestro mundo: la Agenda 2030 para el desarrollo sostenible) trabaja por un mundo que refleje la igualdad, con respeto universal por la dignidad humana, comprometiéndose a no dejar a nadie atrás. Sin embargo, las personas transgénero y con género diverso experimentan importantes desigualdades en materia de salud, incluidos resultados sanitarios negativos y múltiples obstáculos para acceder a la atención sanitaria. En este artículo, destacamos, en primer lugar, las desigualdades sanitarias a las que se enfrentan las personas transgénero y de género diverso en todo el mundo. Describimos aspectos importantes de la atención sanitaria a las personas transgénero y con género diverso, como el diseño y la prestación de servicios sanitarios, las consideraciones epidemiológicas, la atención relacionada con la transición, los cambios en los objetivos relacionados con la transición, las consideraciones culturales y las cuestiones políticas y jurídicas. A continuación, revisamos la documentación global existente sobre la incorporación de la salud transgénero en los planes de estudio de medicina. Defendemos la necesidad de dar prioridad a la mejora de la formación en las facultades de medicina sobre las necesidades sanitarias específicas de las personas transgénero y con género diverso como parte del tratamiento de las desigualdades sanitarias globales en la atención sanitaria. Nuestras recomendaciones para una educación integral sobre la salud de las personas transgénero incluyen la formación en humildad cultural y lucha contra la opresión; la participación de los miembros de la comunidad transgénero y con género diverso; la integración de la salud de las personas transgénero y con género diverso en los planes de estudio; la formación centrada en la práctica e in situ; el desarrollo del personal en las facultades de medicina; y la mejora del acceso a las carreras de medicina para las personas transgénero y con género diverso.

Three visions of doctoring: a Gadamerian dialogue.

Medicine in the twenty-first century faces an 'identity crisis,' as it grapples with the emergence of various 'ways of knowing,' from evidence-based and translational medicine, to narrative-based and personalized medicine. While each of these approaches has uniquely contributed to the advancement of patient care, this pluralism is not without tension. Evidence-based medicine is not necessary individualized; personalized medicine may be individualized but is not necessarily person-centered. As novel technologies and big data continue to proliferate today, the focus of medical practice is shifting away from the dialogic encounter between doctor and patient, threatening the loss of humanism that many view as integral to medicine's identity. As medical trainees, we struggle to synthesize medicine's diverse and evolving 'ways of knowing' and to create a vision of doctoring that integrates new forms of medical knowledge into the provision of person-centered care. In search of answers, we turned to twentieth-century philosopher Hans-Georg Gadamer, whose unique outlook on "health" and "healing," we believe, offers a way forward in navigating medicine's 'messy pluralism.' Drawing inspiration from Gadamer's emphasis on dialogue and 'practical wisdom' (phronesis), we initiated a dialogue with the dean of our medical school to address the question of how medical trainees and practicing clinicians alike can work to create a more harmonious pluralism in medicine today. We propose that implementing a pluralistic approach ultimately entails 'bridging' the current divide between scientific theory and the practical art of healing, and involves an iterative and dialogic process of asking questions and seeking answers.

DNA redox modulations and global DNA methylation in bipolar disorder: Effects of sex, smoking and illness state.

DNA redox modulations and methylation have been associated with bipolar disorder (BD) pathophysiology. We aimed to investigate DNA redox modulation and global DNA methylation and demethylation levels in patients with BD during euthymia, mania or depression in comparison to non-psychiatric controls. The roles of sex and smoking as susceptibility factors for DNA redox modulations and global DNA methylation and demethylation were also explored. Levels of 5-methylcytosine (5-mC), 5-hydroxymethylcytosine (5-hmC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were assessed in DNA samples of 75 patients with DSM-IV BD type I (37 euthymic, 18 manic, 20 depressive) in comparison to 60 non-psychiatric controls. Levels of 5-mC and 5-hmC were assessed using Dot Blot as a screening process, and verified using ELISA. Levels of 8-OHdG were assessed using ELISA. The levels of 8-OHdG significantly differed among non-psychiatric control, euthymia, mania and depression groups [F (3,110) = 2.771, p = 0.046], whereas there were no alterations in the levels of 5-hmC and 5-mC. Linear regression analyses revealed the significant effects of smoking (p = 0.031) and sex (p = 0.012) as well as state of illness on the levels of 8-OHdG (p = 0.025) in patients with BD. Our results suggest that levels of 8-OHdG may be affected by sex, illness states and smoking in BD.

A Longitudinal Study of the Relationships Between Mood Symptoms, Body Mass Index, and Serum Adipokines in Bipolar Disorder.

OBJECTIVE: There is a bidirectional relationship between obesity and mood disorders, with each increasing the risk of developing the other. This relationship suggests that they have overlapping pathophysiologic mechanisms. Adipose tissue-derived hormones, or adipokines, regulate appetite and metabolism and have activity in limbic brain regions, making them potential shared etiologic factors between elevated body mass index (BMI) and mood disorders. However, the precise relationships between BMI, mood, and adipokines are unknown. METHODS: We measured the serum levels of adiponectin, lipocalin-2, resistin, adipsin, and leptin in 53 people with early-stage DSM-IV-defined bipolar disorder, diagnosed with the Mini-International Neuropsychiatric Interview, and 22 healthy comparison subjects. Participants were followed at the University of British Columbia Mood Disorders Centre between June 2004 and June 2012. We were primarily interested in determining, in patients, (1) whether BMI and recent mood episodes predicted adipokine levels and (2) whether adipokine levels in turn predicted subsequent mood relapses and change in BMI. RESULTS: Using linear regression, we found that (1) past-6-month mood episodes predicted lower adiponectin (ß = -0.385, P = .04) and adipsin (ß = -0.376, P = .03) levels and higher lipocalin-2 levels (ß = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (ß = 0.482, P < .01). Furthermore, lower adiponectin (ß = -0.353, P = .01) and leptin (ß = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (ß = 0.496, P < .01) and leptin (ß = 0.421, P < .01) levels predicted BMI gain. CONCLUSIONS: Our results suggest that mood episodes and medication treatment contribute to adipokine abnormalities in bipolar disorder and that adipokines influence psychiatric illness course and BMI change. Adipokines may represent a novel pathophysiologic mechanism linking elevated BMI and mood disorders and deserve further study as potential mood-regulating molecules.

Dentate gyrus-cornu ammonis (CA) 4 volume is decreased and associated with depressive episodes and lipid peroxidation in bipolar II disorder: Longitudinal and cross-sectional analyses.

OBJECTIVES: Reduced dentate gyrus volume and increased oxidative stress have emerged as potential pathophysiological mechanisms in bipolar disorder. However, the relationship between dentate gyrus volume and peripheral oxidative stress markers remains unknown. Here, we examined dentate gyrus-cornu ammonis (CA) 4 volume longitudinally in patients with bipolar II disorder (BD-II) and healthy controls and investigated whether BD-II is associated with elevated peripheral levels of oxidative stress. METHODS: We acquired high-resolution structural 3T-magnetic resonance imaging (MRI) images and quantified hippocampal subfield volumes using an automated segmentation algorithm in individuals with BD-II (n=29) and controls (n=33). The participants were scanned twice, at study inclusion and on average 2.4 years later. In addition, we measured peripheral levels of two lipid peroxidation markers (4-hydroxy-2-nonenal [4-HNE] and lipid hydroperoxides [LPH]). RESULTS: First, we demonstrated that the automated hippocampal subfield segmentation technique employed in this work reliably measured dentate gyrus-CA4 volume. Second, we found a decreased left dentate gyrus-CA4 volume in patients and that a larger number of depressive episodes between T1 and T2 predicted greater volume decline. Finally, we showed that 4-HNE was elevated in BD-II and that 4-HNE was negatively associated with left and right dentate gyrus-CA4 volumes in patients. CONCLUSIONS: These results are consistent with a role for the dentate gyrus in the pathophysiology of bipolar disorder and suggest that depressive episodes and elevated oxidative stress might contribute to hippocampal volume decreases. In addition, these findings provide further support for the hypothesis that peripheral lipid peroxidation markers may reflect brain alterations in bipolar disorders.

Decreased Brain-Derived Neurotrophic Factor in Older Adults with Bipolar Disorder.

OBJECTIVES: Decreased levels of brain derived neurotrophic factor (BDNF) have been found in adult patients with bipolar disorder (BD) compared with a comparison group, yet there are no data specifically examining this in geriatric patients. The objective of this study was to examine whether euthymic late-life BD patients have lower BDNF levels than healthy comparators. DESIGN: Cross-sectional study. SETTING: Clinics at the University of Pittsburgh and the Centre for Addiction and Mental Health (Toronto). PARTICIPANTS: Older patients with BD (age ≥50 years, N = 118) and similarly aged healthy comparators (N = 76). There were both BD type I (N = 91) and type II (N = 27) patients. MEASUREMENTS: Serum BDNF levels were assessed in BD patients and healthy comparators. RESULTS: We found lower levels of BDNF in patients with BD than in healthy comparators (9.0 ± 6.2 versus 12.3 ± 8.9 pg/µg, t(192) = -3.01, p = 0.002), which remained even after controlling for age, sex, lithium use, and site (F(1,176) = 4.32, p = 0.039). This decrease was found specifically in patients with BD type I (8.0 ± 5.5 versus 12.3 ± 8.9 pg/µg, t(165) = 3.7, Bonferroni p < 0.001), but not type II (12.0 ± 7.5 versus 12.3 ± 8.9 pg/µg, t(101) = 0.14, Bonferroni p = 1.0). CONCLUSIONS: Older patients with BD have lower serum levels of BDNF compared with similarly aged comparators. These effects appear to be specific to patients with BD type I. Future studies are needed to investigate the impact of reduced BDNF levels on cognition, mood, and other aspects of BD throughout the life course.

Neuropathological relationship between major depression and dementia: A hypothetical model and review.

Major depression (MDD) is a chronic psychiatric condition in which patients often show increasing cognitive impairment with recurring episodes. Neurodegeneration may play an important component in the pathogenesis of MDD associated with cognitive complaints. In agreement with this, patients with MDD show decreased brain volumes in areas implicated in emotional regulation and cognition, neuronal and glial cell death as well as activation of various pathways that can contribute to cell death. Therefore, the aim of this review is to provide an integrative overview of potential contributing factors to neurodegeneration in MDD. Studies have reported increased neuronal and glial cell death in the frontal cortex, amygdala, and hippocampus of patients with MDD. This may be due to decreased neurogenesis from lower levels of brain-derived neurotrophic factor (BDNF), excitotoxicity from increased glutamate signaling, and lower levels of gamma-aminobutyric acid (GABA) signaling. In addition, mitochondrial dysfunction and oxidative stress are found in similar brain areas where evidence of excitotoxicity has been reported. Also, levels of antioxidant enzymes were reported to be increased in patients with MDD. Inflammation may also be a contributing factor, as levels of inflammatory cytokines were reported to be increased in the prefrontal cortex of patients with MDD. While preliminary, studies have also reported neuropathological alterations in patients with MDD. Together, these studies suggest that lower BDNF levels, mitochondrial dysfunction, oxidative stress, inflammation and excitotoxicity may be contributing to neuronal and glial cell death in MDD, leading to decreased brain volume and cognitive dysfunction with multiple recurrent episodes. This highlights the need to identify specific pathways involved in neurodegeneration in MDD, which may elucidate targets that can be treated to ameliorate the effects of disease progression in this disorder.

Association of peripheral inflammation with body mass index and depressive relapse in bipolar disorder.

Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse.

Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation.

Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflammasome, activating IL-1ß. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflammasome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F2,25 = 3.86, p < 0.05) and ASC (F2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F2,25 = 4.13, p < 0.05 for both), IL-1ß (F2,25 = 7.05, p < 0.01), IL-6 (F2,25 = 5.48, p < 0.05), TNFα (F2,25 = 7.14, p < 0.01) and IL-10 (F2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD.

Getting to wellness: The potential of the athletic model of marginal gains for the treatment of bipolar disorder.

OBJECTIVE: People with bipolar disorder frequently have persistent symptoms, continued problems functioning and comorbid medical conditions. We propose applying the athletic coaching concept of marginal gains to help patients address these challenges to achieve wellness. METHOD: We review the concept of marginal gains and potential interventions to improve long-term outcomes for bipolar patients. RESULTS: Evidence exists to help bipolar patients with diet and exercise, gradual behavioral change, mobile applications and peer support. CONCLUSION: Marginal gains, small and doable improvements across a broad range of areas, have great potential to improve the lives of people with bipolar disorder.

CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity.

Recently, multiple genome-wide association studies have identified a genetic polymorphism (CACNA1C rs1006737) that appears to confer susceptibility for BD. This article aims to summarize the existing literature regarding the impact of rs1006737 on functional and structural neuroimaging intermediate phenotypes. Twenty eight articles, representing 2486 healthy participants, 369 patients with BD and 104 healthy first-degree relatives of patients with BD, are incorporated. Multiple studies have demonstrated structural differences, functional differences associated with emotion-related and frontal-executive tasks, and/or differences in behavioral task performance in risk allele carriers (AA or AG). Results comparing participants with BD to health controls are generally less pronounced than within-group genetic comparisons. The review concludes with an integration of how cardiovascular comorbidity may be a relevant mediator of the observed findings, and proposes future directions toward optimized therapeutic use of calcium channel blockers in BD.