Background Bipolar disorder and schizophrenia are hypothesized to share some genetic background. Methods In a two-phase study, we evaluated the effect of five promising candidate genes for psychotic disorders, DAOA , COMT , DTNBP1 , NRG1 , and AKT1 , on bipolar spectrum disorder, psychotic disorder, and related cognitive endophenotypes in a Finnish family-based sample ascertained for bipolar disorder. Results In initial screening of 362 individuals from 63 families, we found only marginal evidence for association with the diagnosis-based dichotomous classification. Those associations did not strengthen when we genotyped the complete sample of 723 individuals from 180 families. We observed a significant association of DAOA variants rs3916966 and rs2391191 with visuospatial ability (Quantitative Transmission Disequilibrium Test [QTDT]; p = 4 × 10 −6 and 5 × 10 −6 , respectively) ( n = 159) with the two variants in almost complete linkage disequilibrium. The COMT variant rs165599 also associated with visuospatial ability, and in our dataset, we saw an additive effect of DAOA and COMT variants on this neuropsychological trait. Conclusions The ancestral allele (Arg) of the nonsynonymous common DAOA variant rs2391191 (Arg30Lys) was found to predispose to impaired performance. The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits.

Association of a Nonsynonymous Variant of DAOA with Visuospatial Ability in a Bipolar Family Sample

The behavioural activation system (BAS) theory of bipolar disorder proposes that BAS abnormality is aetiologically linked to bipolar disorder. The present project investigated this theory from a vulnerability trait perspective, utilising non-clinical participants. The novel approach was taken of examining BAS as both self-reported trait and as risky decision-making responses on behavioural tasks, a putative behavioural manifestation of BAS. Across studies, trait bipolar disorder vulnerability was measured using the 7 Up 7 Down Inventory (7U7D), whilst trait BAS was measured using the BIS/BAS Scales (BBS). Three studies were conducted. Factor analysis of the 7U7D and BBS was conducted in Study 1, and bivariate correlations between traits were examined. Risky decision-making and set-shifting, the ability to adapt to changing task demands, were examined in Study 2, using the Balloon Analogue Risk Task (BART), Iowa Gambling Task, Game of Dice Task, and Wisconsin Card-Sorting Test. Interaction between trait and mood state during repeated BART administrations was examined in Study 3. Although trait bipolar disorder vulnerability and trait BAS were correlated, no behavioural support for the BAS hypothesis of bipolar disorder was observed, and the degree to which risky decision-making tasks assessed BAS remained questionable. Discussion of findings focused on (i) the continuity of trait bipolar disorder; (ii) alternate perspectives of trait BAS; and (iii) difficulties in accounting for individual state, strategy, and motivation during risky decision-making tasks.

https://researchbank.swinburne.edu.au/file/3f4a86e1-ee4e-4447-92a8-75d9550dbb7d/1/James Daniel Collett Thesis.pdf

It's not all about that bas: trait bipolar disorder vulnerability weakly correlated with trait bas and not predictive of risky decision-making

Objective Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls). Method Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score. Results After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041). Conclusion BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability.

Traumatic Stress Interacts With Bipolar Disorder Genetic Risk to Increase Risk for Suicide Attempts

Bipolar disorder is a severe and enduring mental health condition. Although early identification is associated with better outcomes, research has shown that many people wait over a decade after first experiencing affective symptoms before a correct diagnosis is made. A misdiagnosis of unipolar depression often leads to the inappropriate prescription of potentially mood-destabilising antidepressant medications. The aim of this study was to consider service user and carer experiences and their often overlooked views on diagnostic issues.

Participants were recruited via the charity Bipolar UK. Initially a focus group discussed the diagnostic process and relevant issues, then the transcript was analysed thematically and used to develop a detailed survey questionnaire. The survey was piloted before being launched online and completed by 262 service users and 65 carers.

Survey respondents reported an average delay of over eleven years between first seeking help for bipolar symptoms and being correctly diagnosed. Almost 70% reported a previous misdiagnosis of depression, and over half had experienced mania/hypomania whilst taking antidepressant medication. Nearly a third consulted a doctor over 20 times with bipolar symptoms before receiving help for bipolar disorder. Participants considered that improvements are needed in primary care mental health assessment and that GPs need more training. Many reported that their condition had led them to be discriminated against and agreed that society’s lack of understanding was a major problem. Carers indicated similar opinions and emphasised the potential benefits of including carers in the assessment process. 

This study suggests that the identification of bipolar disorder is often poor and that assessment of the condition in primary care needs to be improved. Service users offered suggestions for improvements, including recognition of early indicators, appropriate assessment questions and better training which could be adopted by service providers. Limitations of the study and implications for future research were discussed.

The diagnostic process in bipolar disorder : a service user perspective

Le trouble bipolaire est une maladie invalidante caracterisee par une alternance d’episodes maniaques et depressifs. Malgre des efforts de recherche notables, la physiopathologie et les mecanismes d’action des traitements du trouble bipolaire demeurent peu connus. La proteine kinase C (PKC) est recemment apparue comme une cible moleculaire potentielle pour le traitement du trouble bipolaire. Dans ce travail de these, nous avons cherche a etudier le role de la PKC dans les phases maniaque et depressive du trouble bipolaire. Nous avons montre que l’inhibition de la PKC a un effet antimaniaque non seulement chez le rat naif, mais aussi dans un modele de manie base sur une privation de sommeil, que nous avons valide au cours de notre etude. De plus, les inhibiteurs de la PKC sont capables de retablir les deficits de proliferation cellulaire hippocampique que presentent les rats prives de sommeil. Ces effets proliferatifs et antimaniaques seraient independants, puisque le blocage de la proliferation cellulaire n’abolit pas l’efficacite antimaniaque des inhibiteurs de la PKC dans le modele de privation de sommeil. En parallele, nous avons montre que l’activation de la PKC a un effet antidepresseur chez le rat naif, alors que son inhibition provoque un phenotype pseudodepressif qui s’accompagne d’une diminution de la proliferation cellulaire hippocampique. L’ensemble de ces donnees revele une implication de la PKC dans les deux phases du trouble bipolaire, et soutient l’hypothese qu’une suractivation du systeme PKC serait a l’origine des perturbations de neuroplasticite associees a la manie.

Implication de la protéine kinase C dans les troubles bipolaires : vers de nouvelles cibles thérapeutiques

PART I CLINICAL DESCRIPTION AND DIAGNOSIS 1. Conceptualizing Manic-Depressive Illness: The Bipolar-Unipolar Distinction and the Development of the Manic-Depressive Spectrum 2. Clinical Description 3. Diagnosis PART II CLINICAL STUDIES 4. Course and Outcome 5. Epidemiology 6. Children and Adolescents 7. Comorbidity 8. Suicide PART III PSYCHOLOGICAL STUDIES 9. Neuropsychology 10. Personality, Personality Disorders, and Interpersonal Functioning 11. Assessment 12. Creativity PART IV PATHOPHYSIOLOGY 13. Genetics 14. Neurobiology 15. Neuroanatomy and Neuroimaging 16. Sleep and Circadian Rhythms PART V TREATMENT 17. Fundamentals of Treatment 18. Medical Treatment of Hypomania, Mania, and Mixed States 19. Medical Treatment of Depression 20. Maintenance Medical Treatment 21. Medication Adherence 22. Psychotherapy 23. Treatment of Children and Adolescents 24. Treatment of Comorbidity 25. Clinical Management of Suicide Risk

F. K. Goodwin

Papers

Manic-Depressive Illness. Bipolar Disorders and Recurrent Depression. Oxford (Oxford University Press) 2007.