Bipolar Disorder Subjects Research Articles

Voxelwise Meta-Analysis of Gray Matter Abnormalities in Bipolar Disorder

We conducted a meta-analysis of gray matter abnormalities in bipolar disorder (BD) using voxel-based morphometry studies to help clarify the structural abnormalities underpinning this condition. A systematic review was conducted for voxel-based morphometry studies of patients with BD. Meta-analyses of gray matter differences between BD and control subjects were undertaken using "signed differential mapping," a novel method that, in contrast to previously used techniques, allows inclusion of negative findings and ensures that single studies do not exert undue influence on the results. Meta-regression and subgroup analyses were used to examine the effect of moderator variables on gray matter abnormalities. A total of 21 studies comparing gray matter volumes of 660 BD patients and 770 healthy control subjects were included. Gray matter reduction in left rostral anterior cingulate cortex (ACC) and right fronto-insular cortex was associated with BD. Fronto-insular cortex abnormality was not evident in early phases of the illness. In chronic patients, longer duration of illness was associated with increased gray matter in a cluster that included basal ganglia, subgenual ACC, and amygdala. Lithium treatment was associated with enlargement of ACC gray matter volumes, which overlapped with the region where gray matter was reduced in BD. The most robust gray matter reductions in BD occur in anterior limbic regions, which may be related to the executive control and emotional processing abnormalities seen in this patient population. Clinical factors such as illness duration and lithium treatment also impact on case-control comparisons of gray matter volume.

A population-based analysis of distinguishers of bipolar disorder from major depressive disorder

BackgroundMany people with bipolar disorder (BD) in the community are misdiagnosed with major depressive disorder (MDD). A probabilistic model has been proposed to assist in the identification of BD among patients with depressive symptoms, however there are limited population-based data on the key distinguishers of BD from MDD. The objective of this study was to identify distinguishers of BD from MDD in a population-based sample. MethodsPopulation-based data were extracted from the Canadian Community Health Survey: Mental Health and Well-Being. Sociodemographic variables, clinical variables, and depressive symptomatology were compared between subjects with BD (N=467) and MDD (N=4145). Logistic regression analysis was used to identify significant correlates of BD, and areas under the receiver operating characteristic curves (AUCs) were determined for each model. ResultsBD and MDD subjects differed across a number of characteristics. Clinical variables significantly associated with BD included greater number of lifetime depressive episodes, earlier age of first depressive episode, lifetime anxiety disorder, problematic substance use, and lifetime suicide attempt. Symptoms significantly more common during a major depressive episode among BD subjects included agitation, suicidal ideation, anxious symptoms, and irritability. AUCs for these models ranged from 0.72 to 0.81. LimitationsData were not available for all potential distinguishers; subgroups of BD could not be determined; cross-sectional data. ConclusionsThese population-based results reinforce the effort to establish a generalizable probabilistic model that incorporates clinical and symptom variables in order to assist clinicians in the diagnostic assessment of BD.

Impact of obsessive‐compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder

To compare antimanic response to olanzapine therapy in youth with bipolar disorder (BPD) based on the status of comorbidity with obsessive-compulsive disorder (OCD). Secondary analysis of identically designed 8-week open-label trials of olanzapine therapy in youth with BPD. Severity of mania assessed with the Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) scales. Of the 52 BPD subjects (mean age 8.4 +/- 3.1 years) enrolled in the olanzapine trials (mean dose 8.5 +/- 4.3 mg/day), 39% (n = 20) met criteria for comorbid OCD. Antimanic response in BPD subjects was significantly worse in the presence of comorbid OCD (YMRS mean reduction: -5.9 +/- 13.1 versus -13.7 +/- 18.8, p = 0.04; > or = 30% reduction: 25% versus 63%, p = 0.008; CGI-Improvement score < or = 2: 25% versus 68%, p = 0.003). There was no difference in the rate of dropouts (50% versus 29%, p = 0.2) or adverse effects in BPD subjects with or without comorbid OCD. Less than expected antimanic response to olanzapine therapy in the presence of comorbidity with OCD suggests that OCD is an important functionally impairing psychiatric comorbidity that may impact the efficacy of antimanic agents in youth with BPD. This study is limited by its design of secondary analysis of data from trials of an uncontrolled nature. Further prospective controlled trials are warranted.

Deficits in attention to emotional stimuli distinguish youth with severe mood dysregulation from youth with bipolar disorder.

Studying attention in the context of emotional stimuli may aid in differentiating pediatric bipolar disorder (BD) from severe mood dysregulation (SMD). SMD is characterized by chronic irritability, arousal, and hyper-reactivity; SMD youth frequently receive a BD diagnosis although they do not meet DSM-IV criteria for BD because they lack manic episodes. We compared 57 BD (14.4 +/- 2.9 years old, 56% male), 41 SMD (12.6 +/- 2.6 years old, 66% male), and 33 control subjects (13.7 +/- 2.5 years old, 52% male) using the Emotional Interrupt task, which examines how attention is impacted by positive, negative, or neutral distracters. We compared reaction time (RT) and accuracy and calculated attention interference scores by subtracting performance on neutral trials from emotional trials. Between-group analyses indicated that SMD subjects had significantly reduced attention interference from emotional distracters relative to BD and control subjects. Thus, attention in SMD youth was not modulated by emotional stimuli. This blunted response in SMD youth may contribute to their affective and behavioral dysregulation.

Markers of Glutamate Synaptic Transmission and Plasticity Are Increased in the Anterior Cingulate Cortex in Bipolar Disorder

Cortical glutamate levels are elevated in bipolar disorder, but the interpretation of this increase is unclear because glutamate has metabolic as well as neurotransmitter roles. We investigated this by measuring vesicular glutamate transporter 1 (VGluT1) expression, which reflects activity at glutamate synapses. We also measured netrin-G1 and netrin-G2 messenger RNAs because these genes are involved in the formation and plasticity of glutamatergic connections. Using quantitative polymerase chain reaction, we quantified transcripts for VGluT1, netrin-G1 (isoforms G1c, G1d, and G1f), and netrin-G2 in the anterior cingulate cortex from subjects with bipolar disorder (n = 34), schizophrenia (n = 35), and healthy control subjects (n = 35). Vesicular glutamate transporter 1, netrin-G2, and netrin-G1d and G1f were increased in bipolar disorder but not in schizophrenia. Netrin-G1c did not differ between groups. Netrin-G1c and netrin-G1f expression showed left-right asymmetries. Vesicular glutamate transporter 1 messenger RNA correlated with brain weight. Increased VGluT1 expression is supportive of elevated glutamate neurotransmission in the anterior cingulate cortex in bipolar disorder. The netrin-G1 and netrin-G2 findings suggest there may be an underlying difference in the plasticity of the affected circuitry.

Bipolar disorder and comorbid attention deficit hyperactivity disorder. A distinct clinical phenotype? Clinical characteristics and temperamental traits1

Objectives. It has been suggested that bipolar disorder (BD) with comorbid ADHD represents a distinct clinical phenotype of BD. There are no data regarding potential heterogeneity between BD subjects with a diagnosis of ADHD in childhood whose ADHD remitted in adulthood (cADHD-BD) vs. BD patients with persistent ADHD diagnosis in adulthood (aADHD-BD). This heterogeneity may constitute a confounder in investigations of the nature of the co-occurrence between BD and ADHD. The aim of this paper is to compare BD patients without ADHD, to those with aADHD-BD, and those with cADHD-BD on clinical and temperamental characteristics, hypothesizing that maladaptive temperament will be increased in BD subjects with a stable diagnosis of ADHD in adulthood compared to those whose ADHD remitted. We further hypothesize that maladaptive temperament will be associated with the severity of both illnesses. Methods. A total of 100 outpatients (aged 18–30 years) with BD in remission were included. The assessment of ADHD was made according to a procedure aimed to reduce potential recall biases. Subjects had to have a parent available and had never been treated with stimulants. Temperamental traits were assessed with the California Child Q-sort (CCQ) and the Early Adolescent Temperament Questionnaire (EATQ). Results. Rate of co-occurrence of ADHD-BD was 18% lifetime and 10% current diagnosis. Patients with ADHD-BD (aADHD-BD+cADHD-BD) reported a significantly earlier onset of mood disorder, higher number of previous mood episodes, and significantly higher impulsivity than BD patients without ADHD. aADHD-BD showed a significantly earlier BD onset, higher number of previous mood episodes, higher impulsivity, decreased Reactive Control and higher Negative Emotionality temperamental scores than cADHD patients. Conclusion. Findings suggest that patients with aADHD-BD present a clinical phenotype distinct from that of patients with BD without ADHD or with a childhood ADHD diagnosis that remitted with the age. This appealing hypothesis of a BD-distinct phenotype that can be detected early due to its associated maladaptive temperamental traits requires further investigation in larger samples, supported by neuropsychological, genetic and imaging data.

Association between Serotonin-Related Polymorphisms in 5HT2A, TPH1, TPH2 Genes and Bipolar Disorder in Korean Population

ObjectiveThe aim of the present study was to examine the association between serotonin-related gene polymorphisms and bipolar disorder in the Korean population. In addition, we sought to explore the relationship between the clinical characteristics of bipolar patients and serotonin-related gene polymorphisms.MethodsInpatients with bipolar disorder (n=103) and control subjects (n=86) were genotyped for 5HT2A 1438A/G, tryptophan hydroxylase 1 (TPH1) 218 A/C, and TPH2 703G/T. We divided patients with bipolar disorder into two groups according to the presence of psychotic symptoms. The severity of their symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).ResultsThere were no significant differences in the genotype distributions or allelic frequencies in the three serotonergic polymorphisms between patients with bipolar disorder and normal controls. There were significant differences in genotype distributions and allele frequencies of the 5-HT2A -1438A/G polymorphism between the psychotic mania group and the non-psychotic mania group (genotype: χ2=7.50, p=0.024; allele: χ2=5.92, p=0.015). However, after Bonferroni correction this signifact difference disappeared. We did not find significant differences in the genotype distributions or allelic frequencies in the TPH1 218 A/C and TPH2 703G/T polymorphisms between the psychotic mania group and non-psychotic mania group.ConclusionWe failed to found the statistically significant association between three polymorphisms and bipolar disorder. However, there was a trend towards association between 5-HT2A -1438A/G polymorphism and psychotic symptom in bipolar disorder. Future research should seek to clarify this association.

P03-104 - Linguistic production and comprehension deficits in schizophrenia and bipolar disorder

IntroductionAlthough language deficits have often been reported in schizophrenia, the specific relevance of single linguistic levels of processing is still under debate. Moreover, little is known about language disturbances in bipolar disorder.ObjectivesThe aims of this study were to:1)investigate micro-linguistic (lexicon, morphology, syntax) and macro-linguistic (discourse coherence, pragmatics) dimensions of speech production and2)evaluate syntactic comprehension skills in both schizophrenia and, for the first time, bipolar disorder.MethodsA story telling task and a computer-based test of syntactic comprehension were administered to 30 Italian speaking DSM-IV patients suffering from schizophrenia, 30 participants with bipolar disorder and 30 healthy controls, comparable for age and educational level (p&gt;0.05). Analysis of variance with post-hoc correction was performed to compare linguistic performance between groups.ResultsIn comparison to healthy participants, patients with schizophrenia had significantly impaired productivity, syntactic complexity and local/global discourse coherence and bipolar disorder subjects showed deficits in mean length of utterance (p&lt; 0.05). Also, both groups of patients collected more grammatical errors than controls (p&lt; 0.05), but they differed in regard to the grammatical type of construction they missed (passive-affirmative and active-negative, respectively).ConclusionsOur results showed the presence of both micro and macro-linguistic deficits in linguistic production in schizophrenia, but not in bipolar disorder, suggesting that these abnormalities are specific for schizophrenia. On the contrary, syntactic construction comprehension was altered in both schizophrenia and bipolar disorder, potentially representing the target of innovative rehabilitation strategies.

A preliminary study of the neural mechanisms of frustration in pediatric bipolar disorder using magnetoencephalography.

Irritability is prevalent and impairing in pediatric bipolar disorder (BD) but has been minimally studied using neuroimaging techniques. We used magnetoencephalography (MEG) to study theta band oscillations in the anterior cingulate cortex (ACC) during frustration in BD youth. ACC theta power is associated with attention to emotional stimuli, and the ACC may mediate responses to frustrating stimuli. We used the affective Posner task, an attention paradigm that uses rigged feedback to induce frustration, to compare 20 medicated BD youth (14.9+/-2.0 years; 45% male) and 20 healthy controls (14.7+/-1.7 years; 45% male). MEG measured neuronal activity after negative and positive feedback; we also compared groups on reaction time, response accuracy, and self-reported affect. Patients met strict DSM-IV BD criteria and were euthymic. Controls had no psychiatric history. BD youth reported more negative affective responses than controls. After negative feedback, BD subjects, relative to controls, displayed greater theta power in the right ACC and bilateral parietal lobe. After positive feedback, BD subjects displayed lower theta power in the left ACC than did controls. Correlations between MEG, behavior, and affect were nonsignificant. In this first MEG study of BD youth, BD youth displayed patterns of theta oscillations in the ACC and parietal lobe in response to frustration-inducing negative feedback that differed from healthy controls. These data suggest that BD youth may display heightened processing of negative feedback and exaggerated self-monitoring after frustrating emotional stimuli. Future studies are needed with unmedicated bipolar youth, and comparison ADHD and anxiety groups.

Anterior genu corpus callosum and impulsivity in suicidal patients with bipolar disorder

Suicidality is a life-threatening symptom in patients with bipolar disorder (BD). Impulsivity and mood instability are associated with suicidality in mood disorders. Evidence suggests that gray and white matter abnormalities are linked with impulsivity in mood disorders, but little is known about the association between corpus callosum (CC) and impulsivity in BD. We examined the relationship between CC areas, impulsivity and suicidality in BD patients. We studied 10 female BD patients with a history of suicide attempt (mean±SD age 36.2±10.1 years), 10 female BD patients without suicide attempt history (44.2±12.5 years) and 27 female healthy subjects (36.9±13.8 years). Impulsivity was evaluated by the Barratt Impulsivity Scale (BIS). We traced MR images to measure the areas of the CC genu, anterior body, posterior body, isthmus and splenium. The genu was divided into anterior, middle and posterior regions. The suicidal and non-suicidal BD patients had significantly higher BIS total, attention and non-planning scores than the healthy subjects (ps<0.01), and the suicidal BD patients had significantly higher BIS motor scores than the non-suicidal BD and healthy subjects (ps<0.01). There were no significant differences among the three groups on any regional CC areas, although the suicidal BD patients had the smallest areas. The suicidal BD patients showed a significant inverse correlation between anterior genu area and the BIS total (r=−0.75, p=0.04), motor (r=−0.79, p=0.02) and non-planning scores (r=−0.79, p=0.02). These correlations were not found in the non-suicidal BD patients or healthy subjects. The results suggest that the anterior medial frontal region may be involved in the pathophysiology of impulsive and suicidal behaviors in BD.

Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: The impact of medication

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55×0.55×0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11±10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

Opposite relationships between cannabis use and neurocognitive functioning in bipolar disorder and schizophrenia

Cannabis use is associated with altered neurocognitive functioning in severe mental disorders, but data are still inconclusive and there are no studies of bipolar disorder. The aim of this study was to investigate the association between cannabis use and neurocognition in bipolar disorder compared with schizophrenia in a naturalistic setting. A total of 133 patients with bipolar disorder and 140 patients with schizophrenia underwent neuropsychological assessments and clinical characterization including measures of substance use. Relationships between cannabis users and neurocognitive function were explored in the two diagnostic groups. Possible interactions between diagnosis and cannabis use were investigated, and findings were controlled for possible confounders. In bipolar disorder subjects, cannabis use was associated with better neurocognitive function, but the opposite was the case for the schizophrenia subjects. There was a statistically significant interaction effect of diagnosis and cannabis use on focused attention (p=0.019), executive functioning (verbal fluency--set shifting) (p=0.009), logical memory-learning (p=0.007) and on logical memory-recall (p=0.004). These differences in neurocognitive function could not be explained by putative confounders. The findings suggest that cannabis use may be related to improved neurocognition in bipolar disorder and compromised neurocognition in schizophrenia. The results need to be replicated in independent samples, and may suggest different underlying disease mechanisms in the two disorders.

Differences in Prevalence and Treatment of Bipolar Disorder among Immigrants: Results from an Epidemiologic Survey

To add to the limited data on the prevalence, clinical characteristics, and treatment of bipolar disorder (BD) among immigrants. Data were obtained from a large epidemiologic survey, the Canadian Community Health Survey-Mental Health and Well-Being (CCHS 1.2). Lifetime prevalence rates of BD were compared between immigrant and nonimmigrant respondents. Among BD subjects (n = 831), sociodemographic, clinical, and mental health treatment use variables were compared based on immigrant status. Logistic regression was used to determine the correlates of lifetime contact with a mental health professional and 12-month psychotropic medication use. Lifetime prevalence rate of CCHS 1.2-defined BD was significantly lower among immigrant, compared with nonimmigrant, participants (1.50% and 2.27%, P = 0.01). There were few sociodemographic or clinical differences, yet immigrants with BD were significantly less likely to report any lifetime contact with mental health professionals (OR = 0.25, 95% CI 0.13 to 0.50, P < 0.001). Past-year psychotropic medication use was numerically lower among immigrants with BD (24.5% and 41.0%); however, this did not reach statistical significance when controlling for other factors (OR = 0.49, 95% CI 0.24 to 1.01, P = 0.05). Based on the results of this study, there are in the range of 56 000 to 104 000 immigrants with BD in Canada. Further efforts are needed to better understand and address the barriers to mental health treatment use among immigrants who have BD.

Expression of Kinase Interacting with Stathmin (KIS, UHMK1) in human brain and lymphoblasts: effects of schizophrenia and genotype

Single nucleotide polymorphisms (SNPs) within the gene encoding the serine/threonine kinase KIS (Kinase Interacting with Stathmin, also known as UHMK1) have recently been associated with schizophrenia. As none of the disease associated SNPs are coding, they may confer susceptibility by altering some facet of KIS expression. Here we have characterised the cellular distribution of KIS in human brain using in situ hybridisation and immunohistochemistry, and quantified KIS protein and mRNA in two large brain series to determine if KIS expression is altered in schizophrenia or bipolar disorder or in relation to a schizophrenia-associated SNP (rs7513662). Post-mortem tissue from the superior temporal gyrus of schizophrenia and control subjects, and also dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum from schizophrenia, bipolar disorder, and control subjects were used. KIS expression was measured by quantitative PCR (mRNA) and immunoautoradiography (protein), and was also quantified by immunoblot in lymphoblast cell lines derived from schizophrenia and control subjects. Our results demonstrate that KIS is expressed in neurons, and its encoded protein is localised to the nucleus and cytoplasm. No difference in KIS expression was found between diagnostic groups, or in the lymphoblast cell lines, and no effect of rs7513662 genotype on KIS expression was found. Hence, these data do not provide support for the hypothesis that altered expression is the mechanism by which genetic variation of KIS may increase susceptibility to schizophrenia, nor evidence that KIS expression is altered in the disease itself, at least in terms of the parameters studied here.

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder

Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD. Sixty-three BD patients were studied (mean +/- SD age = 38.2 +/- 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions. Left rostral ACC GM volume was inversely correlated with the BIS total score (t = 3.95, p(corrected) = 0.003) and the BIS motor score (t = 5.22, p(corrected) < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance. Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.

Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia

Recent studies indicate the presence of mitochondrial dysfunction in brains of subjects with bipolar disorder (BD). Because the mitochondrial electron transport chain is a major source for production of reactive oxygen species that cause oxidative stress, we sought to determine in the present study if BD is associated with oxidative stress. Postmortem anterior cingulate brain sections from subjects with BD, major depressive disorder (MDD), or schizophrenia, and from nonpsychiatric, non-neurologic comparison controls were generously provided by the Stanley Foundation Neuropathology Consortium. Oxidative stress was determined by analyzing 4-hydroxynonenal (4-HNE), a major product of lipid peroxidation. The level of 4-HNE was determined by measuring 4-HNE protein adducts using immunohistochemistry. We found that 4-HNE levels were significantly increased by 59% in BD subjects and by 47% in schizophrenia subjects, but not in MDD subjects, when compared with controls. Levels of 4-HNE were negatively correlated with pH in all 60 subjects. When pH was used as covariate, 4-HNE levels were still significantly increased in BD subjects when compared with controls. Further, 4-HNE levels were significantly correlated with pH values only in BD subjects, but not in MDD, schizophrenia, or control subjects. Oxidative damage in the brain may contribute in part to the pathological process in BD and schizophrenia. This finding also suggests antioxidative stress as a probable alternative approach to the pharmacological treatment of these psychiatric disorders.

Sequence variation in the human dopamine transporter gene in subjects with bipolar disorder

The dopamine (DA) transporter (hDAT, SLC6A3) plays a critical role in terminating synaptic DA neurotransmission and maintaining DA homeostasis. Dysfunction of hDAT is believed to contribute to various neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder (BPD). Recently, we identified a rare hDAT variant, Ala559Val, in two ADHD subjects, which has also been identified in a subject with BPD [Grunhage et al., 2000]. In this study, we are evaluating whether functional variants in hDAT exist in BPD and ascertain the transmission pattern and functional nature of identified polymorphisms. We utilize PCR and temperature‐gradient capillary electrophoresis (TGCE) to screen for mutations in the entire coding region and adjacent non‐coding sequence of the hDAT gene in a cohort of &gt;400 BPD (Type 1 and II) subjects. Preliminary analyses reveal a number of both novel and common single nucleotide polymorphisms (SNPs) across the gene. Our study constitutes the largest analysis to date of DAT coding sequences in BPD, permitting the identification of both common and rare variants that could contribute to DAT dysfunction in the disorder. Supported by NIH grant #T32NS06120106 and T32MH064913; NIMH grant # MH073991, MH47612, MH59567, MH68503 and Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.

A review of EEG and ERP studies in bipolar disorder

Objective:The electroencephalogram (EEG) can be a useful tool in determining differences in general neural activity and specific waveforms in individuals with a number of psychiatric disorders. This paper aims to outline and discuss significant findings in EEG and event-related potential (ERP) research into bipolar disorder (BD).Methods:A literature review was performed through searches of MedLine, EMBASE, CINAHL and PsycInfo medical research databases for papers published from 1985 onwards. References of selected articles were also examined for other relevant studies.Results:Differences in general EEG data were found in subjects with BD, namely increased theta and delta and decreased alpha wave bands. Changes in EEG were also found in euthymic BD subjects and those undergoing medication programmes. ERP studies commonly report prolonged latencies and reduced amplitudes in the P300 component. Hyperfunctioning of the right hemisphere in BD was also reported in some studies, although further confirmation of this finding is required. Finally, the effects of medication and the role that genetics plays in EEG still remain unclear.Conclusions:The literature reviewed demonstrates supporting evidence for the presence of significant differences in EEG and ERP data in subjects with BD. However, methodological considerations such as varying mood states and medication status of the patients need to be followed more stringently for future research to bring about a robust model of the cognitive deficits of BD.

Family Illness History, Obstetric Complications and Age of Onset in Bipolar Patients

The study examined the relationship between obstetric complications, genetic risk and age of illness onset in bipolar disorder. Thirty DSM-IV bipolar I patients in remission (ages 21-39yr, mean 30.7 + 6.1yr.) and twenty seven healthy controls (ages 19-39yr, mean 27.7 + 7.0yr.) were investigated using structured interview, life chart and pregnancy and birth complica- tions questionnaire. Family history, pregnancy and birth complications and age of illness onset were collected. Compari- sons were made between patients and controls and also between patient groups with age of illness onset before and after the age of 21 years. Obstetric complications were more common in patients (effect size= 0.48) than controls but this was not significant statis- tically (Fisher's exact test, p=0.13). There was a non-significant excess in early onset patients. Family histories of mood disorder were found in 22 out of 30 bipolar subjects, but rates in early and late onset groups did not differ (p=0.35). The study failed to find evidence of either increased rates of obstetric complications in bipolar disorder patients or of a link between age of illness onset and a family history of mood disorders. The power of the study was limited by a sample size and difficulties in obtaining unequivocal obstetric data. The finding is in agreement with a recent metanalysis. The large effect size indicates that larger study of obstetric complications in bipolar disorder subjects is justified, looking par- ticularly for subgroups for which there may be an association between complications and clinical variables.

Neuronal Correlates of Brain-derived Neurotrophic Factor Val66Met Polymorphism and Morphometric Abnormalities in Bipolar Disorder

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been proposed as a possible candidate for involvement in the pathophysiology of bipolar disorder (BD). To determine whether an association exists between the BDNF Val66Met genotype and morphometric abnormalities of the brain regions involved in memory and learning in BD and healthy subjects. Forty-two BD patients and 42 healthy subjects were studied. Interactions between BDNF Val66Met genotype and diagnosis in gray (GM) volumes were analyzed using an optimized voxel-based morphometry technique. Declarative memory function was assessed with the California Verbal Learning Test II. Left and right anterior cingulate GM volumes showed a significant interaction between genotype and diagnosis such that anterior cingulate GM volumes were significantly smaller in the Val/Met BD patients compared with the Val/Val BD patients (left P=0.01, right P=0.01). Within-group comparisons revealed that the Val/Met carriers showed smaller GM volumes of the dorsolateral prefrontal cortex compared with the Val/Val subjects within the BD patient (P=0.01) and healthy groups (left P=0.03, right P=0.03). The Val/Met healthy subjects had smaller GM volumes of the left hippocampus compared with the Val/Val healthy subjects (P<0.01). There was a significant main effect of diagnosis on memory function (P=0.04), but no interaction between diagnosis and genotype was found (P=0.48). The findings support an association between the BDNF Val66Met genotype and differential gray matter content in brain structures, and suggest that the variation in this gene may play a more prominent role in brain structure differences in subjects affected with BD.