European collaborative study of early-onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset.

Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms.

Health-related quality of life and functioning in bipolar disorder: the impact of pharmacotherapy.

Bipolar disorder has a major deleterious impact on many aspects of a patient's functioning and health-related quality of life. Although the formal measurement of these deficits has been neglected until recently, many well-designed trials now include an assessment of functioning and health-related quality of life using one or more rating scales. This review describes recent developments in the measurement of functioning and health-related quality of life in bipolar disorder, and discusses the evidence that medications that improve symptoms in bipolar disorder also offer clinically relevant benefits in functioning and health-related quality of life. Direct comparisons of the benefits of medications including atypical antipsychotics are problematic due to differences in trial populations, study durations and rating scales. Data from quetiapine trials indicate that this medication offers prompt and sustained improvement of functioning in patients with mania and enhancement of health-related quality of life in patients with bipolar depression, to accompany the significant improvements in mood episodes.

Neuroanatomical and neuropsychological features of euthymic patients with bipolar disorder.

OBJECTIVE: Previous studies reported that the severity of cognitive deficits in euthymic patients with bipolar disorder (BD) increases with the duration of illness and postulated that progressive neuronal loss or shrinkage and white matter changes may be at the origin of this phenomenon. To explore this issue, the authors performed a case-control study including detailed neuropsychological and magnetic resonance imaging analyses in 17 euthymic elderly patients with BD and 17 healthy individuals. METHODS: Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal cortex, and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. Periventricular and deep white matter were assessed semiquantitatively. Differences in cognitive performances and structural data between BD and comparison groups were analyzed using paired t-test or analysis of variance. Wilcoxon test was used in the absence of normal distribution. RESULTS: Compared with healthy individuals, patients with BD obtained significantly lower performances in processing speed, working memory, and episodic memory but not in executive functions. Morphometric analyses did not show significant volumetric or white matter differences between the two groups. CONCLUSIONS: Our results revealed impairment in verbal memory, working memory, and processing speed in euthymic older adults with BD. These cognitive deficits are comparable both in terms of affected functions and size effects to those previously reported in younger cohorts with BD. Both this observation and the absence of structural brain abnormalities in our cohort do not support a progressively evolving neurotoxic effect in BD.

Advance directives based cognitive therapy in bipolar disorder

Background and Aims: Mental Health Advance Directives (ADs) are potentially useful for bipolar patients due to the episodic characteristic of their disease. An advanced directives based cognitive therapy (ADCBT) involving the self-determination model for adherence, the cognitive representation of illness model, and the concordance model is studied on this article. The aim of the study is to evaluate ADBCT's impact on the number and duration of hospitalization as well as commitment and seclusion procedures. Methods: Charts of all patients who have written their ADs following an ADBCT intervention since at least 24 months were included in the study. Number and duration of psychiatric hospitalization for a mood or a psychotic episode as well as commitment and seclusion procedures were recorded for each patient two years before ADBCT and during a follow up of at least 24 months. Results: Number of hospitalizations, number of commitment procedures and number of days spent in psychiatric hospital reduced significantly after ADCBT in comparison of the two years who preceded the intervention. Conclusions: ADBCT seems to be effective in patients with compliance and coercion problems in this retrospective study. Its effect remains however to be confirmed in large prospective studies.

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.

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.

Anterior cingulate cortex pathology in schizophrenia and bipolar disorder.

To explore possible morphological abnormalities in the dorsal and subgenual parts of anterior cingulate cortex in mood disorders and schizophrenia, we performed a quantitative postmortem study of 44 schizophrenic patients, 21 patients with sporadic bipolar disorder, 20 patients with sporadic major depression, and 55 age- and sex-matched control cases. All individuals were drug naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Neuron densities and size were estimated on cresyl violet-stained sections using a stereological counting approach. The distribution and density of microtubule-associated (MAP2, MAP1b) and tau proteins were assessed by immunocytochemistry and quantitative immunodot assay. Mean total and laminar cortical thicknesses as well as mean pyramidal neuron size were significantly decreased in the dorsal and subgenual parts of areas 24 (24sg) in schizophrenic cases. Patients with bipolar disorder showed a substantial decrease in laminar thickness and neuron densities in layers III, V, and VI of the subgenual part of area 24, whereas patients with major depression were comparable to controls. Immunodot assay showed a significant decrease of both MAP2 and MAP1b proteins in bipolar patients but not in patients with schizophrenia and major depression. The neuroanatomical and functional significance of these findings are discussed in the light of current hypotheses regarding the role of areas 24 and 24sg in schizophrenia and bipolar disorder.

Understanding Van Gogh's Night: bipolar disorder

Vincent Van Gogh (1853-1890) imparted in his art a deep essence of life, and in such a unique way that many would say it is possible to experience it vicariously by looking at his paintings even once. In 10 years, while exerting mental and physical efforts that may well have contributed to his premature death, he produced an impressive number of masterpieces. However, the specific neurological disorder Van Gogh suffered and how this may have influenced his art is still not clear. The combination of his eccentric personality, irascible temper, unstable moods and prolific creativity, makes the understanding of his illness a very complex endeavor and therefore poses a great challenge to those who investigate the relationships between the 'artistic mind', the brain and illness. In fact, most of the diagnoses (nearly 30) proposed for Van Gogh, during the last century, are not based on medical evidence but are ascertainable from analyses of his paintings and biographical data. Although no definitive diagnosis can be made based on such evidence, we conclude that according to DSM-IV criteria and findings extrapolated from his letters, Van Gogh is most likely to have suffered a bipolar disorder, affective or schizoaffective, which caused his death by suicide.