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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.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.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; p0.001 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.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.

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.تحويل عالمنا جدول أعمال عام 2030 للتنمية المستدامة: يسعى نحو عالم تتحقق فيه العدالة، مع الاحترام العالمي لكرامة الإنسان، والتعهد بعدم إهمال أي شخص. ومع ذلك، يعاني الأفراد المتحولون جنسياً وأصحاب التنوع الجنسي من تفاوتات صحية كبيرة، بما يشمل النتائج الصحية السلبية والعوائق المتعددة أمام الحصول على الرعاية. نقوم أولاً في هذه المقالة بالتركيز على التفاوتات الصحية التي يواجهها المتحولون جنسياً وأصحاب التنوع الجنسي على مستوى العالم. نحن نصف الجوانب المهمة للرعاية الصحية للمتحولين جنسياً وأصحاب التنوع الجنسي، بما في ذلك تصميم وتقديم الخدمات الصحية، والاعتبارات الوبائية، والرعاية المتعلقة بالتحول، والتغييرات في الأهداف المتعلقة بالتحول، والاعتبارات الثقافية، والمسائل السياسية والقانونية. ثم نراجع الثوابت العالمية الموجودة بخصوص دمج صحة المتحولين جنسيًا في المناهج الطبية. نحن نسعى لإعطاء الأولوية للتعليم المحسن في كليات الطب حول الاحتياجات الصحية المحددة للأشخاص المتحولين جنسياً وأصحاب التنوع الجنسي كجزء من التعامل مع التفاوتات الصحية العالمية في الرعاية. إن توصياتنا للتعليم الشامل حول صحة المتحولين جنسياً تشمل التدريب لمواجهة التحرش الثقافي ومكافحة الاضطهاد؛ وإشراك أعضاء المجتمع المتحولين جنسياً وأصحاب التنوع الجنسي؛ ودمج صحة المتحولين جنسياً وأصحاب التنوع الجنسي في المناهج الدراسية؛ والتدريب بالتركيز على الممارسة وفي الموقع؛ وتطوير فرق العمل في كليات الطب؛ وتحسين الحصول على وظائف طبية للأشخاص المتحولين جنسياً وأصحاب التنوع الجنسي.《改变我们的世界：2030 年可持续发展议程》致力于建立一个体现公平、普遍重视人类尊严的世界，保证不让任何一个人掉队。但是，跨性别者和性别多样化个体遭遇了严重的健康不平等问题，包括负面的健康结果以及在获得护理方面面临的多重障碍。在本文中，我们首先强调了全球跨性别者和性别多样化人群所面临的健康不平等问题。描述了跨性别者和性别多样化群体医疗保健服务的各个重要方面，包括卫生服务的设计和供应、流行病学考量、变性相关护理、变性相关目标变化、文化考量以及政治和法律问题。然后，我们回顾了有关将跨性别者健康问题纳入医学课程的全球现有文献。作为解决全球医疗卫生不平等问题的一部分，我们充分说明了优先要求医学院就跨性别者和性别多样化人群的特殊健康需求问题加强教育的原因。对于如何就跨性别者健康问题全面开展教育，我们的建议包括：提供宣扬谦逊精神和反压迫的培训；让跨性别者和性别多样化人群的社区成员参与；将跨性别者和性别多样化人群的健康问题纳入课程；提供注重实践的现场培训；在医学院加强医护人员的培训；以及为跨性别者和性别多样化人群提供更多进入医疗界的就业机会。.Документ Преобразование нашего мира: повестка дня в области устойчивого развития на период до 2030 годанаправлен на построение мира, который отражает равенство, всеобщее уважение человеческого достоинства и обязательство принятия во внимание интересов всех и каждого. Однако трансгендеры и люди с разнообразной гендерной самоидентификацией сталкиваются со значительным неравенством в отношении здоровья, включая негативные последствия для здоровья и множественные препятствия для доступа к медицинской помощи. В этой статье прежде всего подчеркивается несправедливость в отношении здоровья, с которой трансгендеры и люди с разнообразной гендерной самоидентификацией сталкиваются в глобальном масштабе. Авторы описывают важные аспекты медико-санитарной помощи трансгендерам и людям с разнообразной гендерной самоидентификацией, включая разработку и предоставление услуг здравоохранения, эпидемиологические соображения, медицинскую помощь в процессе смены пола, изменения в целях, связанных с процессом смены пола, культурные аспекты, а также политические и юридические вопросы. Затем следует обзор существующей мировой литературы по включению здоровья трансгендеров в медицинские учебные программы. Авторы приводят доводы в пользу придания приоритетной значимости повышению качества образования в медицинских институтах в отношении особых медицинских потребностей трансгендеров и людей с разнообразной гендерной самоидентификацией в рамках решения проблемы глобального неравенства в отношении здоровья при оказании медицинской помощи. Рекомендации по всестороннему обучению в вопросах здоровья трансгендеров включают: культурное принятие и обучение по принципам отсутствия притеснения; вовлечение в этот процесс трансгендеров и представителей групп людей с разнообразной гендерной самоидентификацией; включение вопросов здоровья трансгендеров и людей с разнообразной гендерной самоидентификацией в учебные программы; практическое обучение и обучение на месте; повышение квалификации сотрудников медицинских институтов; улучшение доступа к возможностям карьерного роста в медицинской сфере для трансгендеров и людей с разнообразной гендерной самоидентификацией.

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.

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 (β = -0.385, P = .04) and adipsin (β = -0.376, P = .03) levels and higher lipocalin-2 levels (β = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (β = 0.482, P < .01). Furthermore, lower adiponectin (β = -0.353, P = .01) and leptin (β = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (β = 0.496, P < .01) and leptin (β = 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.

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

Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK 7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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.

Background: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized. Methods: Using immunohistochemistry and acceptor photobleaching Forster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls. Results: We found increased oxidation of DAT-immunoreactive regions in patients with BD (F3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of THimmunoreactive regions in both patients with BD (F3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F3,46 = 1.75; p = 0.17). Limitations: Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem inter val and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis. Conclusion: These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.

Bipolar disorder (BD) is a chronic psychiatric illness described by severe changes in mood. Extensive research has been carried out to understand the aetiology and pathophysiology of BD. Several hypotheses have been postulated, including alteration in genetic factors, protein expression, calcium signalling, neuropathological alteration, mitochondrial dysfunction and oxidative stress in BD. In the following paper, we will attempt to integrate these data in a manner which is to understand targets of treatment and how they may be, in particular, relevant to combination treatment. In summary, the data suggested that BD might be associated with neuronal and glial cellular impairment in specific brain areas, including the prefrontal cortex. From molecular and genetics: (1) alterations in dopaminergic system, through catechol-O-aminotransferase; (2) decreased expression and polymorphism on brain-derived neurotrophic factor; (3) alterations cyclic-AMP responsive element binding; (4) dysregulation of calcium signalling, including genome-wide finding for voltage-dependent calcium channel α-1 subunit are relevant findings in BD. Future studies are now necessary to understand how these molecular pathways interact and their connection to the complex clinical manifestations observed in BD.

Background To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. Methods This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime ( n = 12), or long-term ongoing ( n = 17) lithium treatment. Results Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p p p Conclusions Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.

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.

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

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.

Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN. Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. Bipolar Disord 2012: 14: 478–487. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Bipolar disorder (BD) is a common and highly disabling disease characterized by substantial cognitive and functional impairment. The exact neurobiological mechanisms underlying the expression of symptoms in this condition remain unknown but there is growing evidence that glutamate might play an important role. Using proton magnetic resonance spectroscopy (1H-MRS), a number of studies have examined brain glutamate/glutamine levels in patients with bipolar disorder, but they have produced conflicting results. The objective of this paper was to conduct a systematic review and meta-analysis of the literature on brain glutamate/glutamine in BD as measured by 1H-MRS. Methods: A Medline search for the period January 1980–April 2010 was conducted to identify published studies that used 1H-MRS to measure glutamate + glutamine (Glx), the Glx/creatine (Cr) ratio, glutamate (Glu), or the Glu/Cr ratio in any brain region in adult or child/adolescent patients with BD and healthy subjects. A meta-analysis of the pooled data was conducted. Results: BD patients were found to have increased Glx compared to healthy subjects when all brain areas were combined. This finding remained true in medicated and non-medicated patients, and in frontal brain areas in adults. There was a non-significant trend (p = 0.09) for an increase in whole-brain Glx/Cr and Glu in patients compared with healthy subjects. No significant difference was found in Glu/Cr. Conclusions: The results of this meta-analysis suggest that brain Glx levels are elevated in BD patients and support the idea that glutamate might play an important role in the pathophysiology of BD.

Objective Bipolar disorder is insufficiently controlled by medication, so several adjunctive psychosocial interventions have been tested. Few studies have compared these psychosocial treatments, all of which are lengthy, expensive, and difficult to disseminate. We compared the relative effectiveness of a brief psychoeducation group intervention to a more comprehensive and longer individual cognitive-behavioral therapy intervention, measuring longitudinal outcome in mood burden in bipolar disorder. Method This single-blind randomized controlled trial was conducted between June 2002 and September 2006. A total of 204 participants (ages 18-64 years) with DSM-IV bipolar disorder type I or II participated from 4 Canadian academic centers. Subjects were recruited via advertisements or physician referral when well or minimally symptomatic, with few exclusionary criteria to enhance generalizability. Participants were assigned to receive either 20 individual sessions of cognitive-behavioral therapy or 6 sessions of group psychoeducation. The primary outcome of symptom course and morbidity was assessed prospectively over 72 weeks using the Longitudinal Interval Follow-up Evaluation, which yields depression and mania symptom burden scores for each week. Results Both treatments had similar outcomes with respect to reduction of symptom burden and the likelihood of relapse. Eight percent of subjects dropped out prior to receiving psychoeducation, while 64% were treatment completers; rates were similar for cognitive-behavioral therapy (6% and 66%, respectively). Psychoeducation cost $180 per subject compared to cognitive-behavioral therapy at $1,200 per subject. Conclusions Despite longer treatment duration and individualized treatment, cognitive-behavioral therapy did not show a significantly greater clinical benefit compared to group psychoeducation. Psychoeducation is less expensive to provide and requires less clinician training to deliver, suggesting its comparative attractiveness. Trial registration ClinicalTrials.gov identifier: NCT00188838.

Methods: We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naive, young BD participants (15-30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction. Results: The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naive BD patients close to the typical age of onset had comparable hippocampal volumes to controls. Conclusions: Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naive BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Recently, the 9(th) International Conference on Bipolar Disorder (ICBD) took place in Pittsburgh, PA, June 9-11, 2011. The conference focused on a number of important issues concerning the diagnosis of bipolar disorders across the life span, advances in neuroscience, treatment strategies for bipolar disorders, early intervention, and medical comorbidity. Several of these topics were discussed in four plenary sessions. This meeting report describes the major points of each of these sessions and included (1) strategies for moving biology forward; (2) bipolar disorder and the forthcoming new DSM-5 nomenclature; (3) management of bipolar disorders-both theory and intervention, with an emphasis on the medical comorbidities; and, (4) a review of several key task force reports commissioned by the International Society for Bipolar Disorder (ISBD).

High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). There are few published reports on the efficacy of sequential bilateral rTMS compared to HFL and sham rTMS. Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD.Subjects between the ages of 18 and 85 were recruited from a tertiary care university hospital. Seventy-four subjects with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. The rates of remission were compared among the three treatment groups.The remission rates differed significantly among the three treatment groups using a modified intention to treat analysis that excluded subjects who did not respond to electroconvulsive therapy (ECT) during the current episode. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the unilateral group did not differ from either group.These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.

Antioxidant defence systems have received increasing attention in the pathophysiology of psychiatric disorders, including: bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Recently, we reported decreased glutathione (GSH) levels in post-mortem prefrontal cortex from patients with BD, MDD, and SCZ. To explore this further, we evaluated the levels of two glutathione S -transferase (GST) isoforms via immunoblotting: GST Pi and GST Mu. GST Pi levels were not affected in any of the patients groups vs. controls. GST Mu levels were significantly decreased in patients with MDD and SCZ but not BD. Compared to controls, GST Mu levels were not different in BD patients who had been treated with mood stabilizers at the time of death but were significantly lower in those not taking mood stabilizers at the time of death. These data suggest that GST Mu may be a target for mood stabilizers.

Background: Oxidative damage in the central nervous system is increasingly recognized as an important pathological process in many diseases. Previously, our laboratory found that oxidative damage to lipids and proteins was increased in postmortem brain tissue from patients with bipolar disorder and schizophrenia. In the current study, we analyzed oxidative damage to nucleic acids in the CA1, CA3 and dentate gyrus regions of postmortem hippocampus tissue from patients with bipolar disorder, schizophrenia and major depression. Methods: We examined oxidative damage to nucleic acids by performing immunohistochemistry with a monoclonal antibody that recog nizes both 8-hydroxy-guanosine in RNA and 8-hydroxy-2’-deoxyguanosine in DNA. Results: We found that the amount of oxidative damage to nucleic acids was elevated in the CA1, CA3 and dentate gyrus regions of the hippocampus among patients with bipolar disor der, schizophrenia and major depressive disorder. This damage was predominantly in the cytoplasm, suggesting that the damage was primarily to RNA. Compared with oxidative damage in control samples, the magnitude of damage was high in patients with schizophre nia, modest in patients with bipolar disorder and lower in patients with major depression. Limitations: The interpretation of our results is limited by a number of factors, including the retrospective review of patient history, the relatively small sample size and the inclusion of patients who had substance abuse and were undergoing various drug treatments at the time of death. Conclusion: Our results suggest that oxidative damage to RNA, rather than to DNA, occurs in vulnerable neurons of the brain in patients with major mental illness and may contribute to the pathology of these disorders. The magnitude of RNA oxidative damage may be associated with the severity of mental illness.

Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. The aim of this study was to determine if mood disorders and SCZ are associated with abnormal GSH and its functionally related enzymes. Post-mortem prefrontal cortex from patients with BD, MDD, SCZ, and from non-psychiatric comparison controls were provided by the Stanley Foundation Neuropathology Consortium. Spectrophotometric analysis was utilized for the quantitative determination of GSH, while immunoblotting analyses were used to examine expression of glutamyl-cysteine ligase (GCL), GSH reductase (GR), and GSH peroxidase (GPx). We found that the levels of reduced, oxidized, and total GSH were significantly decreased in all psychiatric conditions compared to the control group. Although GCL and GR levels did not differ between groups, the levels of GPx were reduced in MDD and SCZ compared to control subjects. Since oxidative damage has been demonstrated in MDD, BD, and SCZ, our finding that GSH levels are reduced in post-mortem prefrontal cortex suggests that these patient groups may be more susceptible to oxidative stress.

Fundamento Se considera que el estres oxidativo media los procesos neuropatologicos de una serie de enfermedades neuropsiquiatricas y los datos recientes indican que puede participar en la fisiopatologia del trastorno bipolar (TB). En el presente estudio condujimos un metaanalisis de los estudios que evaluaban los marcadores de estres oxidativo en individuos con TB, en comparacion con individuos de control sanos. Metodos Se efectuo una busqueda en la base de datos MEDLINE para identificar los estudios que evaluaron los marcadores perifericos de estres oxidativo en el trastorno. Los datos se sometieron a metaanalisis usando un modelo de efectos aleatorios para examinar los tamanos del efecto de los resultados combinados. Tambien se llevo a cabo una evaluacion del sesgo (prueba de Egger) y una evaluacion de la heterogeneidad (I 2 ). Resultados En el TB se identifico un aumento significativo de las sustancias reactivas al acido tiobarbiturico (SRATB) (p = 0,001), al igual que de la actividad del oxido nitrico (p = 0,02), con un mayor tamano del efecto para SRATB y un tamano moderado del efecto para el aumento de la actividad de NO. No se observaron tamanos significativos del efecto para las enzimas antioxidantes superoxido dismutasa, catalasa y glutation peroxidasa (todas las p > 0,05). Limitaciones: en la interpretacion de estos resultados se requiere precaucion: a) la prueba de Egger fue positiva para SOD, lo que indica que los resultados para esta enzima podrian haber estado influidos por un sesgo de publicacion, y b) analizamos los valores absolutos de cada enzima antioxidante por separado y los estudios publicados senalan que un desequilibrio entre estas enzimas es una mejor indicacion de la presencia de estres oxidativo. Conclusiones El presente metaanalisis indica que en el TB aumentan los marcadores de estres oxidativo y que este podria desempenar un papel en la fisiopatologia del trastorno.

The anticonvulsant lamotrigine and atypical antipsychotic olanzapine, as therapeutic alternative mood stabilizing drugs to lithium and valproate, are well-tolerated maintenance treatments for bipolar disorder. Previous studies in our laboratory showed that both lithium and valproate increased expression of glutathione s-transferase (GST)-M1 subtype in primary cultured rat cerebral cortical cells. GST conjugates glutathione, the major antioxidant in brain, with a variety of oxidized products to form non-toxic and excretable products, and plays an important role in cellular protection against oxidative stress. The purpose of the present study is to determine whether lamotrigine and olanzapine also regulate GST-M1. Using immunoblotting analysis and spectrophotometric assay, we examined the effect of lamotrigine or olanzapine on GST-M1 protein levels and GST enzyme activity in primary cultured rat cerebral cortical cells. We found that chronic treatment with lamotrigine or olanzapine increased both GST-M1 protein levels and GST enzyme activity. These results suggest that GST-M1 may contribute a significant component to the treatment of bipolar disorder with mood stabilizing drugs.

Previous studies have implicated a number of biochemical pathways in the etiology of bipolar disorder (BD). However, the precise abnormalities underlying this disorder remain to be established. To investigate novel factors that may be important in the pathophysiology of BD, we utilized cDNA expression arrays to examine differences in expression of up to 1200 genes known to be involved in potentially relevant biochemical processes. This investigation was undertaken in post-mortem samples of frontal cortex tissue from patients with BD and matched controls, obtained (n = 10/group) from the Stanley Foundation Neuropathology Consortium. Results include significant (greater than 35% change in signal intensity) differences between BD and controls in a number of genes (n = 24). Selected targets were analyzed by RT-PCR, which confirmed a decrease in transforming growth factor-beta1 (TGF-beta 1), and an increase in both caspase-8 precursor (casp-8) and transducer of erbB2 (Tob) expression in BD. We further observed a significant decrease of TGF-beta 1 mRNA levels in BD by RT-PCR in individual post-mortem samples. Given the neuroprotective role attributed to this inhibitory cytokine, our results suggest that the down-regulation of TGF-beta 1 may lead to various neurotoxic insults potentially involved in the etiology of certain mood disorders.

The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients.To our knowledge, no longitudinal volumetric study has been performed in patients with BD, which would allow for an examination of whether lithium therapy used to treat BD can exert a long-term effect on hippocampal volume.We examined the effects of lithium on hippocampal volumes and recollective memory performance over a period of 2 to 4 years in 12 patients with BD who had never received pharmacotherapy before lithium initiation.We found bilateral increases in volume of the hippocampus over time. We also found some evidence of improvement in verbal memory performance over the 4-year measurement period as assessed by the California Verbal Learning Test.Consistent with preclinical literature supporting the neuroprotective effects of lithium, long-term treatment is associated with preservation of recollective memory function and increased hippocampal size in vivo.

Insulin-like growth factors (IGFs) regulate cellular proliferation and death, and their bioactivity is controlled by IGF binding proteins (IGFBPs). Since IGFBP-2 is the major brain resident IGFBP, and we have demonstrated lithium-mediated changes in its mRNA and protein levels in neuronal cultures, we examined IGFBP-2 expression in prefrontal cortex postmortem brain tissue from subjects with mood disorders. We found decreased IGFBP-2 expression in bipolar disorder patients compared with controls; this was especially pronounced in subjects not treated with lithium. These results suggest a role for IGFBPs in the etiology and pharmacotherapy of mood disorders.

Impairment of neuroplasticity is considered to play a role in the pathogenesis of psychiatric disorders. To further characterize the impairment of neuroplasticity in psychiatric disorders, expression of the neuronal plasticity marker 43 kDa growth-associated protein (GAP-43) was detected in postmortem hippocampal sub-regions from psychiatric patients including major depressive disorder, bipolar disorder and schizophrenia subjects, and matched control subjects. We found that GAP-43 protein levels in the hippocampal hilar region were significantly lower in bipolar disorder and schizophrenia subjects than in control subjects. We also found that GAP-43 protein levels in the inner molecular layer of the dentate gyrus and the stratum radiatum of CA2 region were reduced in a trend in bipolar disorder and schizophrenia subjects when compared with control subjects. These results suggest that impairment of neuroplasticity may occur in the hippocampus of bipolar disorder and schizophrenia patients.

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.

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.

Lithium has been shown to possess cytoprotective properties in both cellular and animal models. Moreover, previous studies indicate that lithium treatment alters the expression of insulin-like growth factor binding protein-1 (IGFBP-1), a critical modulator of insulin-like growth factor bioactivity. Given the critical roles played by insulin-like growth factors in cellular mitogenesis, differentiation, and cell death, and that IGFBP-2 is the major brain resident IGFBP, we assessed IGFBP-2 expression in primary cortical neuroncultures subsequent to lithium treatment. We report that 7 days of lithium treatment at therapeutically relevant doses attenuates the expression of IGFBP-2 mRNA and protein in a dose and time-dependent manner. Therefore, these results suggest a possible role for the insulin-like growth factor system in lithium's mechanism of action.

The authors previously identified depression-specific differences in brain responses to an emotional challenge in patients with bipolar and unipolar mood disorder. In this study, potential markers of bipolar risk and resilience were examined in a new cohort of lithium-responsive bipolar patients and their healthy siblings.Changes in regional cerebral blood flow (rCBF) were measured with [(15)O]water positron emission tomography after induction of transient sadness in nine euthymic lithium responders and nine healthy siblings. The patterns of change in these groups were compared, and then they were contrasted with previous findings on bipolar responders to valproate.Common to all three groups with induced sadness were rCBF increases in the dorsal/rostral anterior cingulate and anterior insula and decreases in the orbitofrontal and inferior temporal cortices. Distinguishing the groups were decreases in the medial frontal cortex in the patients but an increase in this region in the siblings.Common changes with emotional challenge were identified in bipolar patients and their healthy siblings. These were not seen previously in healthy subjects without a family history of mood disorder, suggesting a potential marker of bipolar risk. The siblings' unique increases in the medial frontal cortex appear to identify a compensatory response in this at-risk group, as this pattern was not seen previously in healthy subjects without depression risk factors. This differential change pattern in patients and their siblings highlights the role of the anterior cingulate and medial frontal regions in mediating resiliency and vulnerability in bipolar disorder families.

Attempts to map susceptibility genes for bipolar disorder have been complicated by genetic complexity of the illness and, above all by heterogeneity. This paper reviews the genetic research of bipolar disorder aiming to reduce the heterogeneity by focusing on definite responders to long-term lithium treatment. The available evidence strongly suggests that lithium-responsive bipolar disorder is the core bipolar phenotype, characterized by a more prominent role of genetic factors. Responders to lithium have typically a family history of bipolar disorder (often responsive to lithium). They differ from responders to other mood stabilizing drugs in their family histories as well as in other clinical characteristics. The molecular genetic investigations of bipolar disorder responsive to lithium indicate possibly several loci linked to and/or associated with the illness. A combination of research strategies employing multiple methods such as linkage, association, and gene-expression studies will be needed to clarify which of these represent true susceptibility loci.

Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.

Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI. The evolution of CANMAT Bipolar Disorder Guidelines: past, present, and future. Bipolar Disord 2013: 15: 58–60. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Using differential display PCR, we found that chronic treatment with mood stabilizer valproate at a therapeutically relevant concentration increased expression of 78-kDa glucose-regulated protein (GRP78), an endoplasmic reticulum (ER) stress protein, in rat brain. Chronic valproate treatment not only increased GRP78 mRNA level, but also increased GRP78 gene transcription and protein levels. Chronic treatment with lithium, the most commonly used mood stabilizer, also increased GRP78 mRNA and protein levels in primary cultured rat cerebral cortical cells. Unlike the classic GRP78 inducer thapsigargin, an inhibitor of the ER Ca2+-ATPase, both lithium and valproate moderately increase GRP78 expression in neuronal cells without effecting basal intracellular free Ca2+ concentration and cell viability, indicating that these two drugs increase GRP78 expression without causing cell stress. Since GRP78 exhibits molecular chaperone activity, binds calcium and folds damage proteins, and has been shown to inhibit oxidative stress and apoptosis, our findings suggest that both lithium and valproate generate a neuroprotective effect against cell damage. Expression of two other closely related ER stress proteins, GRP94 and calreticulin, has also been shown to increase by chronic treatment with lithium and valproate. Consequences of ER stress protein regulation by mood stabilizers, and its implications for mood stabilizer treatment, are discussed in this review.

Chronic restraint stress, psychosocial stress, as well as systemic or oral administration of the stress-hormone corticosterone induces a morphological reorganization in the rat hippocampus, in which adrenal steroids and excitatory amino acids mediate a reversible remodeling of apical dendrites on CA3 pyramidal cell neurons of the hippocampus. This stress-induced neuronal remodeling is accompanied also by behavioral changes, some of which can be prevented with selective antidepressant and anticonvulsive drug treatments. Lithium is an effective treatment for mood disorders and has neuroprotective effects, which may contribute to its therapeutic properties. Thus, we wanted to determine whether lithium treatment could prevent the effects of chronic stress on CA3 pyramidal cell neuroarchitecture and the associated molecular and behavioral measures. Chronic lithium treatment prevented the stress-induced decrease in dendritic length, as well as the stress-induced increase in glial glutamate transporter 1 (GLT-1) mRNA expression and the phosphorylation of cAMP-response element binding in the hippocampus. Lithium treatment, however, did not prevent stress effects on behavior in the open field or the plus-maze. These data demonstrate that chronic treatment with lithium can protect the hippocampus from potentially deleterious effects of chronic stress on glutamatergic activation, which may be relevant to its therapeutic efficacy in the treatment of major depressive disorder and bipolar disorder.

Oligonucleotide microarray technology was used to analyze gene expression profiles after chronic treatment with the mood stabilizing drug valproate at a therapeutically relevant concentration in primary cultured rat cerebral cortical cells. We discovered that valproate regulates expression of 28 genes, including three isoenzymes (M1, A3 and A4) of glutathione S-transferase (GST), an important protective factor against oxidative stress. Because previous studies in our laboratory found that chronic valproate treatment protected cultured neurons against oxidative stress, further experiments on the regulation of GST were performed. Regulation of GST M1, GST A3 and GST A4 was verified using northern blotting hybridization. Chronic valproate treatment increased mRNA levels of M1 and A4, but decreased the A3 mRNA level dose-dependently, indicating further complexities in the regulation of GST by valproate. The level of GST M1 protein and GST activity were also increased by chronic valproate treatment. In addition, chronic treatment with lithium, another commonly prescribed mood stabilizer, also increased levels of GST M1 mRNA and protein. The present findings suggest that regulation of GST M1, and possibly GST A4, may mediate the anti-oxidative effects of valproate treatment, and regulation of GST may be involved in the mood stabilizing effect of valproate and lithium.

Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these candidate lithium-regulated genes, including alpha1B-adrenoceptor (alpha1B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMP-dependent 3',5'-cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northern blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that alpha1B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that alpha1B-AR may play an important role in the mechanism of action of lithium treatment.

Background: Many patients with bipolar disorder (BD) do not regain full function following an acute illness episode, but the extent to which this impairment is the result of persistent symptoms has not been well established. This study examined factors associated with persistent subsyndromal symptoms in a well characterized group of BD patients who were prospectively followed for an average of 3 years. Methods: Detailed life charting data from 138 patients with BD were reviewed. Patients were categorized into euthymic, subsyndromal or syndromal groups according to the clinical state during their most recent year of follow-up. The three groups were then examined with respect to comorbidity, function and treatment received. Results: Patients with subsyndromal symptoms had high rates of comorbid anxiety disorders, and were more likely to have increased rates of eating disorders as well. Patients with subsyndromal symptoms had lower global assessment of function (GAF) scores than euthymic patients, and had as many clinic contacts and medication trials as patients with full episodes of illness. Conclusions: Persistent subsyndromal symptoms in BD patients are associated with high rates of comorbidity that is important to recognize and treat in order to optimize mood and functioning.

Lithium remains the gold standard in the treatment of bipolar disorder. Long-term treatment with lithium may lead to specific adaptational changes in gene expression that contribute to a neuroprotective effect. In this study, the pilocarpine model of spontaneous limbic epilepsy was used to induce mossy fiber sprouting (axonal growth of the dentate granule cells that synapse on the pyramidal cells of the CA3 region) to examine the prophylactic neuroprotective effects of lithium in vivo. There were four groups of animals: pilocarpine treated (Pil+/Li-); pilocarpine treated followed by lithium (Pil+/Li+); lithium alone (Pil-/Li+); control (Pil-/Li-). Timm staining was used to obtain density measurements in the stratum oriens and the inner molecular layer of the hippocampus. Mossy fiber density was higher in the pilocarpine-treated animals compared to controls. Chronic lithium following pilocarpine treatment attenuated the density of mossy fibers but lithium alone had no effect. No changes in hilar volume or neuronal number were detected using stereological procedures. The ability of lithium to attenuate activation-induced reorganization in the hippocampus provides evidence for its role as a neuroprotective agent in an in vivo model that may be relevant to its clinical effects in bipolar disorder.

Objectives: Few studies have examined the question of how personality features impact outcome in bipolar disorder (BD), though results from extant work and studies in major depressive disorder suggest that personality features are important in predicting outcome. The primary purpose of this paper was to examine the impact of DSM-IV personality disorder symptoms on long-term clinical outcome in BD. Methods: The study used a ‘life-charting’ approach in which 87 BD patients were followed regularly and treated according to published guidelines. Outcome was determined by examining symptoms over the most recent year of follow-up and personality symptoms were assessed with the Structured Clinical Interview for DSM-IV (SCID-II) instrument at entry into the life-charting study. Results: Patients with better outcomes had fewer personality disorder symptoms in seven out of 10 disorder categories and Cluster A personality disorder symptoms best distinguished euthymic and symptomatic patients. Conclusions: These results raise important questions about the mechanisms linking personality pathology and outcome in BD, and argue that conceptual models concerning personality pathology and BD need to be further developed. Treatment implications of our results, such as need for psychosocial interventions and treatment algorithms, are also described.

Stress and elevated stress hormone levels are known to alter cognition, learning, memory, and emotional responses. Three weeks of chronic stress or glucocorticoid exposure is reported to alter neuronal morphology in the hippocampus, the amygdala, and the prefrontal cortex, and to decrease neurogenesis in the dentate gyrus. Here we examine the effects of acute and chronic restraint stress exposure on the incidence of emotional responses throughout a 3-week period among adult rat conspecifics. Our data indicate that acute restraint stress (i.e., a single 6-h exposure) results in a significant reduction in aggressive conflicts among stressed males compared to experimental controls. In contrast, on Days 14 and 21, repeatedly restrained rats exhibited significantly more aggressive behaviors than controls. Blood samples taken 18 h after the last restraint session indicate that plasma concentrations of the stress hormone corticosterone (CORT) in stressed rats were equivalent to those of unstressed rats; however, the number of individually initiated aggressive acts observed positively correlated with plasma CORT measures taken at the end of the study. In contrast to studies of psychosocial stress or intruder paradigms, here we observe spontaneous emotional responses to an uncontrollable stressor in the homecage. This study provides a novel examination of the effects of chronic restraint stress on emotional responses in the home environment among cagemates. These results indicate that acute and chronic restraint stress alter the incidence of aggression, and emphasize the relevance of this model of chronic stress to studies of stress-responsive disorders characterized by aggressive behavior.