Bipolar Disorder Subjects Research Articles

Changes in density of calcium‐binding‐protein‐immunoreactive GABAergic neurons in prefrontal cortex in schizophrenia and bipolar disorder

There is evidence that GABAergic neurotransmission is altered in mental disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). The calcium-binding proteins (CBPs) calbindin (CB), calretinin (CR), and parvalbumin (PV) are used as markers of specific subpopulations of cortical GABAergic interneurons. We examined the postmortem prefrontal cortical region (Brodmann's area 9) of patients with SCZ and BPD, and of age-matched control subjects, excluding suicide cases. The laminar density of neurons immunoreactive (IR) for three CBPs, namely CB, CR, and PV, was quantified. The densities of CB-IR neurons in layer 2 and PV-IR neurons in layer 4 in the SCZ subjects decreased compared with those in the control subjects. When CBP-IR neurons were classified according to their size, a reduction in the density of medium CB-IR neurons in layer 2 in SCZ subjects and an increase in the density of large CR-IR neurons in layer 2 in BPD subjects were observed. These results suggest that alterations in specific GABAergic neurons are present in mental disorders, and that such alterations may reflect the vulnerability toward the disorders.

Applying Molecular Approaches to Understand the Etiology and Treatment of Bipolar Disorder

Bipolar disorder is characterized by episodes of mania and depression that are frequently acute, debilitating, and conducive to gross social dysfunction and an elevated suicide rate.1-4 While often lifelong and affecting about 1.5% of the population, the condition responds to, and in some cases is controlled by, pharmacologic treatment-particularly with mood-stabilizing agents. Although there is a clear consensus on the importance of factors in the development of bipolar disorder, and a substantial quantity of scientific investigation has been undertaken, the etiology and operative pathophysiologic processes are still unclear. Early research attention focused on monoaminergic neurotransmitter systems distributed in various brain regions, but the corresponding development of novel or improved treatments for bipolar disorder based on this research has not occurred. Long-term administration of mood stabilizers has for many years been used both for treatment of acute manic and depressive episodes and for prophylaxis against future episodes. Mood stabilizers such as lithium and valproate are among the most common treatments with the emergence of secondgeneration antipsychotics. While these treatments have made a vast improvement in our patients' lives, there is room for more effective treatment with even fewer side effects. Understanding the etiology and the specific pathophysiologic processes of bipolar disorder is critical to the development of such new treatment approaches. Among the strongest clues to the basis of bipolar disorder is the large body of evidence suggestive of genetic predisposition. Recent findings indicate that the pathologic process of this disorder is involved in complex interactions between multiple susceptibility genes and environmental factors.5,6 Recent advances in genetics, and cellular biology, neuroscience, and imaging technology have provided a variety of new and sophisticated approaches to evaluate the complex features of this disease. These new genetic, pharmacologic, and and cellular approaches to the study of the etiology of disorders and the mechanism of action of psychotropic drugs have been very instructive in refining our understanding. Given the many widely used advances in investigative approaches and technologies, the term molecular psychiatry has been readily adopted to replace the older biological psychiatry. Important among these advances, high density DNA expression microarray technology has recently been widely adapted by scientists in the search for susceptibility genes for bipolar disorder.7-9 The great advantage of this technology is that it allows us to monitor, on a genomic level, the expression of hundreds of known and unknown genes simultaneously.10-12 In this issue's In Review section, Dr Tadafumi Kato and coauthors13 review recent findings in bipolar disorder studies using DNA microarray analysis. Gene candidates coding for proteins related to mitochondrial function and apoptosis, glutamate receptors, markers of GABAergic neurons, chaperones, and oligodendrocyte proteins are differentially expressed in postmortem brain tissue, peripheral blood cells, and olfactory neuroepithelium between control and bipolar disorder subjects. The next steps are to determine the role these gene candidates played in the pathophysiology of bipolar disorder and to identify which, if any, of these candidates are targeted by mood-stabilizing treatment. As mentioned, mitochondria-related genes are one of the candidate groups revealed by DNA microarray analysis to be abnormally expressed in bipolar disorder. Increasing evidence has shown the presence of mitochondrial dysfunctions such as deletion, mutation and abnormal expression of mitochondria-related genes, increased anaerobic glycolysis, and impaired phospholipid metabolism. Because mitochondrial oxidative phosphorylation is the major resource for the generation of reactive oxygen species, mitochondrial dysfunction indicates that oxidative stress may occur in bipolar disorder and that oxidative stress-induced damage may be prevented by mood-stabilizing treatment. …

Brain systems underlying response flexibility in healthy and bipolar adolescents: an event‐related fMRI study

Previous studies have indicated abnormalities in response flexibility in pediatric bipolar disorder (BD). Dysfunction in response flexibility may contribute to the pattern of behavioral and emotional dysregulation that is characteristic of BD, since depressed and manic patients respond inflexibly to emotional stimuli (i.e., anhedonia in the case of depression or inappropriate positive affect in the case of mania). The present study was undertaken to determine if neuronal responses differed between BD and control subjects on a simple motor response flexibility task. To elucidate the neural substrates mediating response flexibility in pediatric BD, we studied 25 youth with BD and 17 age-, gender- and IQ-matched controls (CON) as they performed the change task while undergoing event-related functional magnetic resonance imaging (fMRI). The change task is a new fMRI task that requires subjects to both inhibit and replace a prepotent motor response with another motor response after the initial response has been cued. On correctly performed change trials relative to correctly performed go trials, BD patients generated significantly more activity in the left dorsolateral prefrontal cortex (DLPFC) and in the primary motor cortex than did healthy controls, even though performance levels did not differ across groups. These results indicate that functional deficits within the left DLPFC may mediate deficits in response flexibility in pediatric BD. This deficit may extend beyond the realm of motor control and also affect emotion regulation.

Comparison of Antidepressant Use Between Subjects With Bipolar Disorder and Major Depressive Disorder With or Without Comorbid Anxiety

Antidepressants are recommended for the treatment of depressive and anxiety symptoms in patients with major depressive disorder, but caution is urged when used for the treatment of these symptoms in bipolar disorder. It is not known whether these differing recommendations are reflected in clinical practice, as comparative analyses of rates of antidepressant use between bipolar disorder and major depressive disorder subjects with or without comorbid anxiety have not been reported. Data source was the Canadian Community Health Survey on Mental Health and Well-Being, a large, representative mental health survey conducted from May to December 2002. Rates of antidepressant use were compared for subjects with bipolar disorder according to the World Mental Health-Composite International Diagnostic Interview or major depressive disorder according to DSM-IV criteria, with or without comorbid anxiety (DSM-IV). The independent effects of the diagnostic group and of a comorbid anxiety disorder were determined by controlling for sociodemographic and clinical variables using logistic regression. Rate of antidepressant use was significantly higher among all subjects with bipolar disorder (N = 756) compared with all subjects with major depressive disorder (N = 3863) (27.2% vs. 23.1%, p = .02), but this difference was no longer significant when other factors were controlled for in the regression analysis. With the major depressive disorder without anxiety group as the reference, the likelihood of antidepressant use was significantly higher in both the bipolar disorder with anxiety group (OR = 1.83, 95% CI = 1.02 to 3.27, p = .04) and the major depressive disorder with anxiety group (OR = 1.45, 95% CI = 1.00 to 2.09, p = .05). After sociodemographic and clinical variables were controlled for, similar rates of antidepressant use were identified among bipolar disorder and major depressive disorder subjects. Further efforts are needed to enhance screening for bipolar disorder among depressed patients and to re-examine the risk/benefit analysis of antidepressants for bipolar disorder patients in light of emerging alternatives. Significantly increased rates of antidepressant use in subjects with a comorbid anxiety disorder suggest that anxiety symptoms may be a key reason why physicians are choosing to prescribe antidepressants for patients with bipolar disorder and major depressive disorder.

Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuit

Pediatric bipolar disorder (BD), a highly debilitating illness, is characterized by amygdala abnormalities, i.e., volume reduction and hyperactivation during face processing. Evidence of perturbed amygdala functional connectivity with other brain regions would implicate a distributed neural circuit in the pathophysiology of BD, and would further elucidate the neural mechanisms associated with BD face emotion misinterpretation. Thirty-three BD and 24 healthy age, gender, and IQ-matched subjects completed a functional magnetic resonance imaging (fMRI) task of face emotion identification in which attention was directed to emotional (hostility, fearfulness) and nonemotional (nose width) aspects of faces. Voxel-wise analyses examined whole brain functional connectivity with the left amygdala. Compared to healthy subjects, BD subjects had significantly reduced connectivity between the left amygdala and two regions: right posterior cingulate/precuneus and right fusiform gyrus/parahippocampal gyrus. Deficits were evident regardless of mood state and comorbid diagnoses. BD youth exhibit deficient connectivity between the amygdala and temporal association cortical regions previously implicated in processing facial expressions and social stimuli. In conjunction with previously documented volumetric and functional perturbations in these brain regions, dysfunction in this distributed neural circuit may begin to clarify the pathophysiology of the face emotion misperceptions and social deficits seen in BD youth.

Neural activation during encoding of emotional faces in pediatric bipolar disorder

Neurobiological understanding of bipolar disorder (BD) is limited by a paucity of functional magnetic resonance imaging (fMRI) research examining correlates of psychological processes. To begin to address these limitations, the current study tests the hypothesis that pediatric BD (PBD) subjects exhibit altered neural activation during encoding of emotional faces compared to typically developing controls. Pediatric BD subjects (n=23; mean age=14.2+/-3.1 years) and controls (n=22; mean age=14.7+/-2.3 years) were matched on age, gender, and IQ. In this event-related fMRI study, subjects were scanned while viewing emotional faces and given a surprise recognition memory test 30 min postscan. Our main outcome measure was between-group differences in neural activation during successful versus unsuccessful face encoding. Pediatric BD youth exhibited reduced memory for emotional faces, relative to healthy comparisons, particularly on fearful faces. Event-related fMRI analyses controlling for this behavioral difference showed that PBD subjects, compared to controls, had increased neural activation in the striatum and anterior cingulate cortex when successfully encoding happy faces and in the orbitofrontal cortex when successfully encoding angry faces. There were no between-group differences in neural activation during fearful face encoding. Our results extend what is known about memory and face emotion processing impairments in PBD subjects by showing increased fronto-striatal activation during encoding of emotional faces. Further work is required to determine the impact of mood state, medication, and comorbid illnesses on these findings.

Relevance of Family History of Suicide in the Long-Term Outcome of Bipolar Disorders

This study examined the association between family history of completed suicide and suicidal behavior and other clinical variables in subjects with bipolar disorder. 374 outpatients aged from 19 to 88 years (mean +/- SD age = 41.9 +/- 4.1 years) (54.3% female) meeting DSM-IV criteria for bipolar disorder type I or II or schizoaffective disorder, bipolar subtype, were included in the study. Forty-eight subjects with a family history of completed suicide were compared to 326 subjects without a family history of completed suicide regarding several clinical and demographic variables. The study was conducted from 2001 to 2004. There were no statistically significant demographic differences between bipolar disorder subjects with and without a family history of suicide. Bipolar disorder subjects with a family history of suicide showed higher rates of cluster C personality disorders than subjects without a family history of suicide (14.9% vs. 2.5%, OR = 6.72, 95% CI = 2.31 to 19.51, p < .001). Subjects with a family history of suicide also demonstrated a significantly greater lifetime prevalence of suicide attempts (52.2% vs. 25.5%, OR = 3.19, 95% CI = 1.7 to 6.0, p < .001). Results remained significant after controlling for all possible interactions. Family history of completed suicide is a significant risk factor associated with suicidal attempts in patients with bipolar disorder. These findings underscore the importance of identifying patients with a family history of suicide in order to provide prompt treatment and careful follow-up.

Gene and Expression Analyses Reveal Enhanced Expression of Pericentrin 2 ( PCNT2) in Bipolar Disorder

DISC1 has been suggested as a causative gene for psychoses in a large Scottish kindred. PCNT2 has recently been identified as an interacting partner of DISC1. In this study, we investigated the role of PCNT2 in bipolar disorder, by gene expression analysis and genetic association study. By TaqMan real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we examined the messenger RNA (mRNA) levels of PCNT2 in the postmortem prefrontal cortex of bipolar disorder (n = 34), schizophrenia (n = 31), and control subjects (n = 32), obtained from Stanley Array Collection. We also compared the mRNA levels of PCNT2 in the peripheral blood lymphocytes of bipolar disorder (n = 21), schizophrenia (n = 21), depression (n = 33), and control subjects (n = 57). For the association study, 23 single nucleotide polymorphisms (SNPs) were analyzed in 285 bipolar disorder patients and 287 age-and gender-matched control subjects, all of Japanese origin. The genotypes were determined by TaqMan assay. Significantly higher expression of PCNT2 was observed in the brain samples of bipolar group, compared with the control (p = .001) and schizophrenia (p = .018) groups. In the peripheral blood lymphocytes also, a significantly higher expression of PCNT2 was observed in the bipolar group, compared with the control subjects (p = .043). However, none of the SNPs analyzed in our study showed a significant association with bipolar disorder; a weak tendency toward association was observed for two intronic SNPs. Our findings suggest that elevated levels of PCNT2 might be implicated in the pathophysiology of bipolar disorder.

Neuron Numbers and Volume of the Amygdala in Subjects Diagnosed with Bipolar Disorder or Schizophrenia

Growing evidence supports a pivotal role for the amygdala in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). However, the occurrence of morphologic changes in the amygdala is currently controversial. Total number and numeric density of neurons, neuronal somata size, and volume of the lateral (LN), basal (BN), accessory basal (ABN), and cortical (CO) nuclei of the amygdala were measured in 12 normal control, 10 BD, and 16 SZ subjects. In BD subjects, reductions of total numbers (41.1%; p = .01) and numeric densities of neurons (14.5%, p = .01), as well as volume (29.0%; p = .01), were detected in LN. Density of neurons was also decreased in ABN of the same subjects (20.8%; p = .0005). These changes were not related to antipsychotics or lithium salt exposure. In SZ subjects, a decrease of total numbers of neurons was detected in LN (23.6%; p = .04). This effect was no longer significant once exposure to antipsychotics was taken into account. These findings offer structural evidence for an involvement of the amygdala in BD. Consequent loss of amygdalar function may account for abnormalities in emotion processing typical of BD subjects. In contrast, changes in SZ were limited and may have been induced by pharmacologic treatment.

Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder

The aim of this study was to examine whether glutamatergic inputs onto GABA interneurons via the kainate receptor in the anterior cingulate cortex may be altered in schizophrenia and bipolar disorder. Hence, in a cohort of 60 post-mortem human brains from schizophrenia, bipolar disorder, and normal control subjects, we simultaneously labeled the mRNA for the GluR5 or GluR6 subunit of the kainate receptor with [ 35S] and the mRNA for the 67 kD isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) 67 with digoxigenin using an immunoperoxidase method. The density of the GAD 67 mRNA-containing neurons that co-expressed GluR5 mRNA was decreased by 43% and 40% in layer 2 of the anterior cingulate cortex in schizophrenia and bipolar disorder, respectively. In contrast, the density of the GAD 67 mRNA-containing cells that expressed GluR6 mRNA was unaltered in either condition. Furthermore, the amount of GluR5 or GluR6 mRNA in the GAD 67 mRNA-expressing cells that contained a detectable level of these transcripts was also unchanged. Finally, the density of cells that did not contain GAD 67 mRNA, which presumably included all pyramidal neurons, but expressed the mRNA for the GluR5 or GluR6 subunit was not altered. Thus, glutamatergic modulation of inhibitory interneurons, but not pyramidal neurons, via kainate receptors containing the GluR5 subunit appears to be selectively altered in the anterior cingulate cortex in schizophrenia and bipolar disorder.

Facial Emotion Processing in Acutely Ill and Euthymic Patients With Pediatric Bipolar Disorder

Past investigations indicate facial emotion-processing abnormalities in pediatric bipolar disorder (PBD) subjects. However, the extent to which these deficits represent state- and trait-related factors is unclear. We investigated facial affect processing in acutely ill and clinically stabilized children with PBD and matched healthy subjects. Subjects (N = 86) consisted of unmedicated/acutely ill (n = 29) and medicated/clinically stabilized (n = 29) PBD youths and matched healthy subjects (n = 28) who completed tasks of facial affect identification and differentiation. Subjects with PBD, regardless of clinical and treatment status, showed marked impairments in the ability to correctly identify emotionally intense happy and sad facial expressions, with both groups tending to misjudge extreme facial expressions as being moderate to mild in intensity. However, when differentiating subtle variations of happy or sad expressions, only unmedicated/acutely ill PBD patients performed more poorly than healthy subjects. Younger age at onset was associated with more impaired emotion processing only in the PBD sample. PBD subjects with comorbid attention-deficit/hyperactivity disorder (ADHD) performed more poorly than subjects without ADHD when processing sad facial expressions, but not happy ones. This study found evidence of both state-of-illness and trait-related deficits in emotion processing in PBD. Treatments are needed to better reduce this impairment and to reduce its developmental impact on interpersonal functioning.

Suicidal attempters and non-attempters with bipolar disorder in Iran

This is the study of the prevalence of suicidal attempt and its demographic association in bipolar disorder (BPD) subjects in an emergency department in a non-Western culture. The subjects were 176 adults with DSM-IV BPD-type I (BPD-I). The mean age was 30.2 years and 66.2% of them were male. About 33.9% of the subjects made a suicidal attempt at least once in their life. The majority of suicide attempters (69.8%) had only one suicidal attempt. Lifetime suicidal attempts were not associated with age, gender, level of education, residential area, and type of occupation. The rate of suicidal attempt in the bipolar patients is very high and it is very similar to the rates reported in other cultures. It seems that the association of suicidal attempt in BPD is less related to the culture than the disorder itself.

Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication‐free individuals with bipolar disorder: an in vivo1H MRS study

While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy ((1)H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N-acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr). Thirty-two medication-free BD subjects (33.8 +/- 10.2 years) and 32 matched controls (33.8 +/- 9.0 years) underwent a short echo-time (TE = 30 ms) (1)H MRS. An 8-cm(3) single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo-inositol, and glutamate were obtained, using the water signal as an internal reference. BD subjects had lower Cr + PCr [F((1,62)) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [F((1,62)) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites. These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.

Longitudinal Course of Pediatric Bipolar Disorder

Longitudinal Course of Pediatric Bipolar Disorder

Longitudinal Course of Pediatric Bipolar Disorder

Longitudinal Course of Pediatric Bipolar Disorder

Glutamine and Glutamate Levels in Children and Adolescents With Bipolar Disorder: A 4.0-T Proton Magnetic Resonance Spectroscopy Study of the Anterior Cingulate Cortex

The purpose of this study was to use proton magnetic resonance spectroscopy, at 4.0 T, to explore the glutamine and glutamate levels in the anterior cingulate cortex of children and adolescents with bipolar disorder (BPD; medicated and unmedicated) and healthy comparison subjects (HCSs). We hypothesized that unmedicated children with BPD would have reduced glutamine and glutamate levels compared with HCSs and medicated children with BPD. Spectra were acquired from the anterior cingulate cortex in 22 children and adolescents with DSM-IV-TR BPD, type 1 (13 female: age 12.6 +/- 4.4 years: 7 of the subjects with BPD were unmedicated at the time of the scan) and 10 HCSs (7 female: age 12.3 +/- 2.5 years). Unmedicated subjects with BPD had significantly lower glutamine levels than HCSs or medicated subjects with BPD. There were no differences in glutamate levels between the three groups. These results are consistent with there being an abnormality in anterior cingulate cortex glia in untreated children and adolescents with BPD. The results of this pilot study may be important in helping us better understand the pathophysiology of child and adolescent BPD. In addition, this observation may help to develop better and more targeted treatments, in particular those affecting the metabolism of glutamine, perhaps by regulation of glutamine synthetase activity.

Soft neurological signs do not increase with age in euthymic bipolar subjects

Background Soft neurological signs (SNS) are found to be in excess in bipolar disorder (BD). This paper explores changes in SNS with ageing to ascertain whether BD is associated with a progressive neurological decline or a relatively fixed, persistent deficit. Methods 53 euthymic BD subjects and controls, aged 15–55 years, were for examined for the presence of SNS which were rated using a modified Kolakowska battery. Results In controls, SNS scores increased slowly and significantly with age whereas in BD subjects high scores occurred throughout the age range and were not age dependent. This confirms and extends an earlier, smaller, study which is reanalysed. Limitations The study design was cross-sectional whereas a longitudinal study would better reveal changes in soft signs with ageing. Conclusions The studies suggest strongly that BD is accompanied by a significant neurobiological deficit which may progress only minimally with increasing age.

Different Psychophysiological and Behavioral Responses Elicited by Frustration in Pediatric Bipolar Disorder and Severe Mood Dysregulation

Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children). Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.

Different Psychophysiological and Behavioral Responses Elicited by Frustration in Pediatric Bipolar Disorder and Severe Mood Dysregulation

Objective: Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children). Method: Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. Results: The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. Conclusions: Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.

Neurocognitive impairment in middle-aged and older adults with bipolar disorder: Comparison to schizophrenia and normal comparison subjects

Background The frequency, pattern, and correlates of neurocognitive impairment in older patients with bipolar disorder have received little study. We examined neurocognitive abilities in middle-aged and older adults with bipolar disorder to groups with schizophrenia or normal subjects, as well as the relation of neurocognition to clinical characteristics. Method We administered a battery of neurocognitive and clinical measures to older (45–85 years) outpatients with bipolar disorder ( n = 67), schizophrenia ( n = 150), and normal comparison subjects ( n = 85). Within the bipolar group, we assessed the association between neurocognitive performance and psychiatric symptoms, quality of life, and medication status. Results The group with bipolar disorder differed on nearly all neuropsychological tests compared to normal subjects, with medium effect sizes. Bipolar patients as impaired as those with schizophrenia on half of the tests administered, and performed better on the remaining tests, with small effect sizes. Neurocognitive deficits in bipolar disorder group related to lower quality of life, but not to psychiatric symptom severity or duration of illness. Limitations Samples were outpatients with mild-moderate symptoms, and findings may not generalize to acutely ill populations. We lacked data on illness history to examine the cumulative impact of psychopathology. Conclusions Among clinically stable middle-aged and older outpatients, bipolar disorder was associated with substantial neurocognitive impairment, with a pattern that was somewhat distinct from that found in schizophrenia. Deficits in the bipolar group were not related to severity or duration of psychiatric symptoms, but were related to quality of life. Bipolar disorder often involve disabling and enduring cognitive impairments in older outpatients.