Investigating the genetic variation underlying episodicity in major depressive disorder: Suggestive evidence for a bipolar contribution.

BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.

Cognitive features in euthymic bipolar patients in old age.

OBJECTIVES: Studies of cognition in bipolar disorder (BD) have reported impairments in processing speed, working memory, episodic memory, and executive function, but they have primarily focused on young and middle-aged adults. In such studies, the severity of cognitive deficits increases with the duration of illness. Therefore, one would expect more pronounced deficits in patients with longstanding BD. The first aim of the present study was to determine the pattern and the magnitude of cognitive impairment in older euthymic BD patients. The second aim was to explore the interrelationship between these cognitive deficits and determine whether they reflect a single core impairment or the co-occurrence of independent cognitive deficits. METHODS: Twenty-two euthymic elderly BD patients and 22 controls, matched for gender, age, and education, underwent a comprehensive neuropsychological assessment. RESULTS: Compared to controls, BD patients had significantly reduced performance in processing speed, working memory, verbal fluency, and episodic memory, but not in executive function. Hierarchical regression analyses showed that verbal fluency and working memory impairments were fully mediated by changes in processing speed. This was not the case for the episodic memory dysfunction. CONCLUSION: The cognitive profile in older euthymic BD cases is similar to the one described in younger BD cohorts. Our results further suggest that impaired processing speed plays a major role in the cognitive changes observed in BD patients except for deficits in episodic memory, thus providing strong evidence that processing speed and episodic memory are two core deficits in elderly BD patients.

Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models.

Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as a risk factor contributing to their pathophysiology. Recent Advances: Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients, including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display increased stress reactivity, altered social behavior, impaired prepulse inhibition, and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by N-methyl-D-aspartate receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. Critical Issues: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice, but also improves SZ and BD symptoms when given as adjunct to antipsychotic medication. Future Directions: These data demonstrate the usefulness of GSH-deficient rodent models to identify the mechanisms by which a redox imbalance could contribute to the development of SZ and BD pathophysiologies, and to develop novel therapeutic approaches based on antioxidant and redox regulator compounds. Antioxid. Redox Signal. 18, 1428-1443.

Transtorno afetivo bipolar e a ambivalência em relação à terapia medicamentosa: analisando as condições causais

Este estudo buscou compreender as condições causais da ambivalência da pessoa com transtorno afetivo bipolar (TAB) em relação ao seguimento da terapêutica medicamentosa. Foi utilizada a abordagem qualitativa, tendo como referencial metodológico a Teoria Fundamentada nos Dados, à luz do Interacionismo Simbólico. Participaram do estudo 14 pessoas com TAB que estavam em acompanhamento em um Ambulatório de Transtornos do Humor de um hospital universitário e 14 familiares indicados pelas mesmas. A entrevista e observação foram as principais formas de obtenção de dados. Os resultados revelaram três categorias que descrevem as referidas condições causais: vivendo as crises do transtorno; tendo necessidade do medicamento e convivendo com os efeitos colaterais dos medicamentos. Este estudo aponta para necessidade de mudança de atitude dos profissionais de saúde de culpabilizar o paciente pela interrupção do tratamento para aquela de escuta, de valorização do seu universo simbólico e afetivo bem como de parceria no tratamento.

Grupo de psicoeducação no transtorno afetivo bipolar: reflexão sobre o modo asilar e o modo psicossocial

O Transtorno Afetivo Bipolar (TAB), conhecido por sua cronicidade, complexidade e altos índices de morbidade e mortalidade, é uma das principais causas de incapacitação no mundo. Há evidências crescentes de que seu curso pode ser modificado por abordagens psicoterápicas como a psicoeducação, que promove o aumento do funcionamento social e ocupacional, bem como da capacidade de manejarem situações estressantes. Trata-se de um relato de experiência sobre um grupo de psicoeducação para familiares e portadores de TAB, sendo esse pautado pela reflexão dos componentes do paradigma das práticas em saúde mental. A reflexão sobre os modos asilar e psicossocial quanto às concepções de objeto e modo de trabalho, possibilitou situar o grupo no modo psicossocial, pois o conhecimento e a vivência experimentados favorecem a autonomia dos sujeitos, que têm maiores chances de se posicionarem frente às dificuldades que lhes sobrevêm na sua existência-sofrimento.

Implicações de um grupo de Psicoeducação no cotidiano de portadores de Transtorno Afetivo Bipolar

Há evidências crescentes de que o curso Transtorno Afetivo Bipolar (TAB) pode ser modificado por abordagens psicoterápicas, tais como a Psicoeducação. Assim, o objetivo deste trabalho foi identificar as implicações do grupo de Psicoeducação no cotidiano dos portadores. Para tanto, optou-se pelo estudo qualitativo, do tipo Estudo de Caso. Foram incluídos doze portadores de TAB que tiveram pelo menos seis participações no Grupo de Psicoeducação desenvolvido na Faculdade de Medicina de São José do Rio Preto (FAMERP). Foram realizadas entrevistas semi-estruturadas, gravadas, transcritas e trabalhadas por meio da Análise Temática. Este estudo demonstrou que tal experiência grupal favoreceu a aquisição de conhecimento; a conscientização da doença e adesão ao tratamento; a realização de mudanças positivas na vida; a possibilidade de ajudar outros portadores a se beneficiarem do aprendizado construído no grupo; a descoberta de outras realidades e estratégias de enfrentamento, obtidas por meio da troca de experiências entre os participantes.

Transtorno afetivo bipolar: perfil farmacoterapêutico e adesão ao medicamento

Este estudo teve como objetivos verificar a adesão de portadores de transtorno afetivo bipolar (TAB) à terapêutica medicamentosa e identificar possíveis causas de adesão e não adesão ao medicamento de acordo com o perfil farmacoterapêutico. Trata-se de estudo transversal, descritivo, realizado em Núcleo de Saúde Mental de um município do interior paulista. Participaram do estudo 101 pacientes com TAB. Para coleta dos dados, utilizou-se a entrevista estruturada e o teste de Morisky-Green e, para a análise dos mesmos, o programa Statistical Package for the Social Science. Os resultados mostraram que a maioria (63%) dos sujeitos investigados não adere ao medicamento. Apesar de não ter ocorrido diferenças significativas entre o grupo de aderentes e não aderentes, para as variáveis investigadas, foi possível verificar a utilização de polifarmacoterapia e regimes terapêuticos complexos no tratamento do TAB. Permanece como desafio a implementação de estratégias que possam melhorar, na prática, a adesão de pacientes ao tratamento medicamentoso.

Model endophenotype for bipolar disorder: Qualitative Analysis, etiological factors, and research areas

The aim of this study is to present an updated view of the writings on the endophenotype model for bipolar disorder using analytical methodologies. A review and analysis of networks was performed through descriptors and keywords that characterize the composition of the endophenotype model as a model of health. Information was collected from between 1992 and 2014, and the main thematic areas covered in the articles were identified. We discuss the results and question their cohesion, emphasizing the need to strengthen and identify the points of connection between etiological factors and characteristics that make up the model of endophenotypes for bipolar disorder.

Behavioral phenotyping of glutathione-deficient mice: Relevance to schizophrenia and bipolar disorder.

Redox-dysregulation represents a common pathogenic mechanism in schizophrenia (SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate-cysteine-ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease.

Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder.

Background: Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear. Methods: We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI). Results: We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls. Limitations: The major limitation of our study is the small number of patients with bipolar disorder. Conclusion: Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.

Psychological needs of adolescents in the early phase of bipolar disorder: implications for early intervention.

Aim: This paper will describe the rationale for, and importance of, psychological interventions for young people early in the course of bipolar disorder. Methods: Emerging literature in this field will be discussed in addition to describing specific clinical challenges and opportunities with this population. Results: In order to be more developmentally appropriate for young people with bipolar disorder, eight aspects of clinical work which may require modification were identified. Conclusions: The evidence base for the effectiveness of psychological interventions for people diagnosed with bipolar disorder is growing. However, some aspects relating to working with adults with bipolar disorder require modification to be effective in working with young people early in the course of the disorder.

Psychotherapeutic case conceptualization using plan analysis for bipolar affective disorder.

Valid individualized case conceptualization methodologies, such as plan analysis, are rarely used for the psychotherapeutic treatment conceptualization and planning of bipolar affective disorder (BD), even if data do exist showing that psychotherapy interventions might be enhanced by applying such analyses for treatment planning for several groups of patients. We applied plan analysis as a research tool (Caspar, 1995) to N=30 inpatients presenting BD, who were interviewed twice. Our study aimed at producing a prototypical plan structure encompassing the most relevant data from the 30 individual case conceptualizations. Special focus was given to links with emotions and coping plans. Inter-rater reliability of these plan analyses was considered sufficient. Results suggest the presence of two subtypes based on plananalytic principles: emotion control and relationship control, along with a mixed form. These subtypes are discussed with regard to inherent plananalytic conflicts, specific emotions and coping plans, as well as symptom level and type. Finally, conclusions are drawn for enhancing psychotherapeutic practice with BD patients, based on the motive-oriented therapeutic relationship.

Mental disorders in offspring of parents with bipolar and major depressive disorders.

OBJECTIVES: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. METHODS: A total of 376 offspring (aged 6.0-17.9 years; mean=11.5years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co-parents were interviewed by psychologists blind to proband diagnoses, using a semi-structured diagnostic interview. RESULTS: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). CONCLUSIONS:   These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence.