First-degree Relatives Of Bipolar Patients Research Articles

Cortical mediation of relationships between dopamine receptor D2 and cognition is absent in youth at risk of bipolar disorder

Bipolar disorder is associated with cognitive deficits and cortical changes for which the developmental dynamics are not well understood. The dopamine D2 receptor (DRD2) gene has been associated with both psychiatric disorders and cognitive variability. Here we examined the mediating role of brain structure in the relationship between DRD2 genomic variation and cognitive performance, with target cortical regions selected based on evidence of association with DRD2, bipolar disorder and/or cognition from prior literature. Participants (n = 143) were aged 12–30 years and comprised 62 first-degree relatives of bipolar patients (deemed ‘at-risk’), 55 controls, and 26 patients with established bipolar disorder; all were unrelated Caucasian individuals with complete data across the three required modalities (structural magnetic resonance imaging, neuropsychological and genetic data). A DRD2 haplotype was derived from three functional polymorphisms (rs1800497, rs1076560, rs2283265) associated with alternative splicing (i.e., D2-short/-long isoforms). Moderated mediation analyses explored group differences in relationships between this DRD2 haplotype, three structural brain networks which subsume the identified cortical regions of interest (frontoparietal, dorsal-attention, and ventral-attention), and three cognitive indices (intelligence, attention, and immediate memory). Controls who were homozygous for the DRD2 major haplotype demonstrated greater cognitive performance as a result of dorsal-attention network mediation. However, this association was absent in the ‘at-risk’ group. This study provides the first evidence of a functional DRD2-brain-cognition pathway. The absence of typical brain-cognition relationships in young ‘at-risk’ individuals may reflect biological differences that precede illness onset. Further insight into early pathogenic processes may facilitate targeted early interventions.

Neural anomalies during vigilance in schizophrenia: Diagnostic specificity and genetic associations

Impaired vigilance is a core cognitive deficit in schizophrenia and may serve as an endophenotype (i.e., mark genetic liability). We used a continuous performance task with perceptually degraded stimuli in schizophrenia patients (N = 48), bipolar disorder patients (N = 26), first-degree biological relatives of schizophrenia patients (N = 55) and bipolar disorder patients (N = 28), as well as healthy controls (N = 68) to clarify whether previously reported vigilance deficits and abnormal neural functions were indicative of genetic liability for schizophrenia as opposed to a generalized liability for severe psychopathology. We also examined variation in the Catechol-O-methyltransferase gene to evaluate whether brain responses were related to genetic variation associated with higher-order cognition. Relatives of schizophrenia patients had an increased rate of misidentification of nontarget stimuli as targets when they were perceptually similar, suggestive of difficulties with contour perception. Larger early visual responses (i.e., N1) were associated with better task performance in patients with schizophrenia consistent with enhanced N1 responses reflecting beneficial neural compensation. Additionally, reduced N2 augmentation to target stimuli was specific to schizophrenia. Both patients with schizophrenia and first-degree relatives displayed reduced late cognitive responses (P3b) that predicted worse performance. First-degree relatives of bipolar patients exhibited performance deficits, and displayed aberrant neural responses that were milder than individuals with liability for schizophrenia and dependent on sex. Variation in the Catechol-O-methyltransferase gene was differentially associated with P3b in schizophrenia and bipolar groups. Poor vigilance in schizophrenia is specifically predicted by a failure to enhance early visual responses, weak augmentation of mid-latency brain responses to targets, and limited engagement of late cognitive responses that may be tied to genetic variation associated with prefrontal dopaminergic availability. Experimental results illustrate specific neural functions that distinguish schizophrenia from bipolar disorder and provides evidence for a putative endophenotype that differentiates genetic liability for schizophrenia from severe mental illness more broadly.

Risk and coaggregation of major psychiatric disorders among first-degree relatives of patients with bipolar disorder: a nationwide population-based study.

Bipolar disorder is a highly heritable mental illness that transmits intergeneratively. Previous studies supported that first-degree relatives (FDRs), such as parents, offspring, and siblings, of patients with bipolar disorder, had a higher risk of bipolar disorder. However, whether FDRs of bipolar patients have an increased risk of schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) remains unclear. Among the entire population in Taiwan, 87 639 patients with bipolar disorder and 188 290 FDRs of patients with bipolar disorder were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with bipolar disorder. FDRs of patients with bipolar disorder were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 6.12, 95% confidence interval (CI) 5.95-6.30), MDD (RR 2.89, 95% CI 2.82-2.96), schizophrenia (RR 2.64, 95% CI 2.55-2.73), ADHD (RR 2.21, 95% CI 2.13-2.30), and ASD (RR 2.10, 95% CI 1.92-2.29), than the total population did. These increased risks for major psychiatric disorders were consistent across different familial kinships, such as parents, offspring, siblings, and twins. A dose-dependent relationship was also found between risk of each major psychiatric disorder and numbers of bipolar patients. Our study was the first study to support the familial coaggregation of bipolar disorder with other major psychiatric disorders, including schizophrenia, MDD, ADHD, and ASD, in a Taiwanese (non-Caucasian) population. Given the elevated risks of major psychiatric disorders, the public health government should pay more attention to the mental health of FDRs of patients with bipolar disorder.

Cognitive deficits in first-degree relatives of bipolar patients: the use of homogeneous subgroups in the search of cognitive endophenotypes.

Previous studies have demonstrated impairments in attention, memory and executive functions in euthymic bipolar patients (BP) as well as their unaffected first-degree relatives, albeit in an attenuated form. Subsequently, cognitive deficits are discussed as a possible endophenotype of bipolar disorder. However, recent studies showed that only a subgroup of BP shows cognitive impairments. The aim of the present study was to investigate cognitive functioning in relatives compared to BP, to find out if the differentiation in a cognitive deficit vs. non-deficit subgroup is valid for relatives of BP, too. Therefore, the performance of 27 unaffected relatives of BP, 27 euthymic BP and 27 HC were compared using a neuropsychological test battery. The results showed that BP exhibited a reduced psychomotor speed and deficits in working memory compared to relatives and HC. Relatives performed significantly slower (psychomotor speed) as compared to HC (p=0.024); performance in the other test measures lie between BP and HC. Furthermore, a detailed evaluation of the data indicated that only subgroups of BP and relatives exhibited cognitive impairments in the implemented tests. However, the deficit and non-deficit groups did not differ in sociodemographic and clinical variables from each other, possibly due to the small sample size. In conclusion, our results suggest that reduced psychomotor speed could serve as a potential endophenotype for bipolar disorder which should be investigated along the developmental trajectory of this disorder, also to examine whether abnormalities therein precede onset of the first mood episode. Furthermore, the division of relatives into subgroups aids in the identification of stable trait markers and high-risk bipolar groups and could enable early prevention strategies. As to that more research using distinct and homogeneous subgroups is necessary.

Mood and metabolic consequences of sleep deprivation as a potential endophenotype’ in bipolar disorder

It has been commonly recognized that circadian rhythm and sleep/wake cycle are causally involved in bipolar disorder. There has been a paucity of systematic research considering the relations between sleep and mood states in bipolar disorder. The current study examines the possible influences of sleep deprivation on mood states and endocrine functions among first-degree relatives of patients with bipolar disorder and healthy controls. Blood samples were taken at two time points in the consecutive mornings at predeprivation and postdeprivation periods. Participants simultaneously completed the Profiles of Mood States at two time points after giving blood samples. Plasma T3 and TSH levels increased after total sleep deprivation in both groups. Sleep deprivation induced TSH levels were reversely associated with depression–dejection among healthy controls. A paradoxical effect was detected for only the first-degree relatives of the patients that changes in plasma cortisol levels negatively linked to depression–dejection and anger–hostility scores after total sleep deprivation. Plasma DHEA levels became correlated with vigor-activity scores after sleep deprivation among first-degree relatives of bipolar patients. On the contrary, significant associations of depression–dejection, anger–hostility, and confusion–bewilderment with the baseline plasma DHEA levels became statistically trivial in the postdeprivation period. Findings suggested that first-degree relatives of patients with bipolar disorder had completely distinct characteristics with respect to sleep deprivation induced responses in terms of associations between endocrine functions and mood states as compared to individuals whose relatives had no psychiatric problems. Considering the relationships between endocrine functions and mood states among relatives of the patients, it appears like sleep deprivation changes the receptor sensitivity which probably plays a pivotal role on mood outcomes among the first-degree relatives of patients with bipolar disorder.

Increased Medial Orbitofrontal and Amygdala Activation: Evidence for a Systems-Level Endophenotype of Bipolar I Disorder

Bipolar I disorder is highly heritable, but endophenotypes of the disorder mediating genetic risk are only beginning to be defined. The authors investigate state- and trait-related neural mechanisms related to motivation in euthymic bipolar patients and unaffected first-degree relatives of bipolar patients to define the status of motivational processing as a neural systems-level endophenotype. Our study comprised two samples; the first consisted of 19 euthymic bipolar patients and 19 matched comparison subjects, and the second included 22 relatives and 22 matched comparison subjects. Motivational processing was assessed with a probabilistic reversal learning task during event-related functional MRI. Data were analyzed using a region-of-interest approach restricting analysis to the medial and lateral orbitofrontal cortex, the amygdala, the anterior cingulate cortex, and the striatum. The authors observed increased activation in response to reward and reward reversal contingencies in the left medial orbitofrontal cortex in patients with bipolar disorder and in the right medial orbitofrontal cortex in their relatives. Activation of the amygdala in response to reward reversal was increased in patients and relatives. In response to reward, activation of the amygdala was greater only in relatives, but there was a significant negative correlation between medication and amygdala activation in patients. These results identify increased activity of the orbitofrontal cortex and the amygdala, related to heightened sensitivity to reward and deficient prediction error signal, as a candidate endophenotype of bipolar disorder. The results support a role of motivational processing in the risk architecture of bipolar disorder and identify a new systems-level therapeutic target for the illness.

Association between Affective Temperaments and Bipolar Spectrum Disorders: Preliminary Perspectives from a Controlled Family Study

Background: The study aimed at determining the temperamental underpinnings of bipolar spectrum disorders (BSD) in the first-degree relatives (FDR) of patients with bipolar I disorder in comparison with control subjects. Sampling and Methods: The sample consisted of 198 subjects: 33 bipolar I probands and their 33 FDR in the experimental group, 33 schizophrenia probands and their 33 FDR in the patient control group, and 33 normal healthy controls and their 33 FDR. The affective temperament and the BSD were assessed using the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire and the criteria of Ghaemi et al. [Can J Psychiatry 2002;47:125–134], respectively. Results: Among the FDR of bipolar I probands, 27.3% satisfied the diagnosis of BSD, which was significantly higher than in the other groups (relative risk = 6, 95% CI = 1.74–20.69). Bipolar probands were significantly more hyperthymic as compared to controls (relative risk = 2, 95% CI = 1.34–2.98), and both the FDR of the bipolar and the FDR of the patient control groups were significantly more hyperthymic as compared to the FDR of the normal controls (relative risk = 1.52, 95% CI = 0.93–2.51). FDR (of bipolar patients) with BSD had a significantly higher total irritable temperament score as compared to FDR (of bipolar patients) without BSD (mean difference = 2.07, 95% CI = 0.64–3.50). Conclusions: Our findings support the fact that the whole spectrum of bipolarity is transmitted in susceptible families. The graded distribution of hyperthymia suggests it to be a milder expression of bipolarity in the FDR of bipolar patients. The irritable temperament appears to be a specific vulnerability marker for the development of BSD.

Anxiety symptoms and syndromes in bipolar children and adolescents

Anxiety disorders are relatively common in children and adolescents with bipolar disorder. Research to date indicates they may impact the onset, course, and treatment response of bipolar illness in children. Anxiety disorders often precede the onset of pediatric bipolar disorder. Family studies suggest first-degree relatives of bipolar patients are at increased risk for developing mood and anxiety disorders compared with relatives of individuals without mood disorders. Childhood adversity has been associated with higher rates of comorbid anxiety disorders and more severe illness course in bipolar patients. Preliminary study of the neurobiology of bipolar disorder with comorbid anxiety disorders suggests it may be neurophysiologically distinct from bipolar disorder without comorbid anxiety. Bipolar disorder with comorbid anxiety disorders has been associated with greater functional impairment and slower recovery. Prospective, longitudinal studies are needed to help us better understand the relationship between bipolar disorder and comorbid anxiety disorders so that opportunities for early intervention and effective treatment can be realized.

Neurocognitive Impairment and Dementia in Mood Disorders

Neurocognitive Impairment and Dementia in Mood Disorders

Bipolar Disorder Clinical Synthesis: Where Does the Evidence Lead?

Bipolar disorder is a common condition diagnosed by the occurrence of pathological mood elevation but most often dominated by dysphoria states. Over the past 10 years, understanding of bipolar disorder and the number of evidence-based treatments have increased dramatically. This article offers strategies for improving diagnostic confidence and simple benchmarks that facilitate integrating principles of evidence-based medicine into the management of patients with bipolar disorder. Simple systematic assessment techniques such as focusing the evaluation to assess the most extreme episode of mood elevation and longitudinal factors such as age of onset and course of illness can avoid errors of omission and raise diagnostic confidence. An iterative measurement-based treatment model that aims to bring patients and their supports into the collaborative care process for progressively better outcomes is recommended.

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression

Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.

Reply: Pronounced Cognitive Deficits Following an Intravenous L-Tryptophan Challenge in First-degree Relatives of Bipolar Patients Compared to Healthy Controls

Reply: Pronounced Cognitive Deficits Following an Intravenous L-Tryptophan Challenge in First-degree Relatives of Bipolar Patients Compared to Healthy Controls

Red-cell lithium transport and affective disorders in a multigeneration pedigree: Evidence for genetic transmission of affective disorders

We determined if a polymorphism at a major gene locus contributing to variability in the distribution of lithium (Li) across the red cell membrane is associated with vulnerability to affecfive disorders within a multigeneration pedigree. The variability in the ratio of intracellular to extracellular Li concentration (Li ratio) in vivo is primarily determined by variability in a lithium-sodium (Li-Na) counterflow mechanism; the Li ratio and Li-Na counterflow vary inversely (Duhm et al. 1976; Pandey et al. 1978). Dorus et al. (1983) demonstrated that interindividual variability in the Li ratio in vitro is determined both by a major autosomal gene locus and by multifactorial inheritance. Boerwinkle et al. (1983) found evidence for a major gene locus in the control of Li-Na counterflow. Some, but not all, investigators report significantly elevated Li ratios or lowered Li-Na counterflow values among bipolar patients (Rybakowski et al. 1978) and among first-degree relatives of bipolar patients who themselves have a history of an affective disorder (Dorus et al. 1979; Mendlewicz and Verbanck 1981). Dorus et al. (1983) provided evidence for a major gene locus that is involved in the transmission of both variability in the Li ratio and vulnerability to affective disorders among first-degree relatives of bipolar patients. Egeland et al. (1984), however, found no relationship between variability in Li transport measures and a history of an affective illness in four Amish pedigrees. The investigators note the considerable genetic and environmental homogeneity of the Amish population. Such homogeneity could affect the subtypes of affective disorders found in these pedigrees. Waters et al. (1983) found that variability in phloretin-sensitive Li-Na counterflow was not related to history of an affective disorder among relatives of bipolar patients. The authors observed, however, substantial intraindividual variability in their serial determinations of counterflow.

Reduced MAO Activity in First-Degree Relatives of Individuals With Bipolar Affective Disorders

Previous reports have indicated that platelet monoamine oxidase (MAO) activity is reduced in patients with the bipolar form of major affective illness. We present evidence that platelet MAO activity is also significantly reduced in the first-degree relatives of bipolar patients. However, platelet MAO activity did not distinguish ill from well family members. It is possible that reduced platelet MAO may be an indicator of increased familial vulnerability to affective disorders.