Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder

Brooks JO III, Bearden CE, Hoblyn JC, Woodard SA, Ketter TA. Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder.
Bipolar Disord 2010: 12: 866–874. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Reports of sustained attention deficits in the euthymic phase of bipolar disorder have been variable, and have yet to be related to cerebral metabolism. In the present study, we evaluated relationships between cognitive performance deficits and resting cerebral metabolism in euthymic older adults with bipolar disorder. Methods: Sixteen older (mean age 58.7 years) euthymic outpatients with bipolar disorder (10 type I, 6 type II; 44% female) and 11 age‐matched healthy controls received resting positron emission tomography with ¹⁸fluorodeoxyglucose and, within 10 days, the Conners’ Continuous Performance Test‐II, a commonly used measure of sustained attention and inhibitory control. Results: Bipolar disorder patients had significantly more omission errors (z = 2.53, p = 0.01) and a trend toward more commission errors (z = 1.83, p < 0.07) than healthy controls. Relative to healthy controls, among bipolar disorder subjects commission errors were more strongly related to inferior frontal gyrus [Brodmann area (BA) 45/47] hypometabolism and paralimbic hypermetabolism. In bipolar disorder subjects, relative to controls, omission errors were more strongly related to dorsolateral prefrontal (BA 9/10) hypometabolism and greater paralimbic, insula, and cingulate hypermetabolism. Conclusions: In older adults with bipolar disorder, even during euthymia, resting‐state corticolimbic dysregulation was related to sustained attention deficits and inhibitory control, which could reflect the cumulative impact of repeated affective episodes upon cerebral metabolism and neurocognitive performance. The relative contributions of aging and recurrent affective episodes to these differences in bipolar disorder patients remain to be established.     

Lifetime prevalence of substance or alcohol abuse and dependence among subjects with bipolar I and II disorders in a voluntary registry

Objective: To evaluate the prevalence of substance abuse dependence and/or alcohol abuse dependence among subjects with bipolar I versus bipolar II disorder in a voluntary registry.

Method: One hundred randomly selected registrants in a voluntary case registry for bipolar disorder were interviewed, using the Structured Clinical Interview for DSM‐IV Axis I Disorders, to validate the diagnosis of this registry. Corroborative information was obtained from medical records, family members and the treating psychiatrist. Eighty‐nine adults (18–65 years) met criteria for bipolar disorder (bipolar I=71, bipolar II=18) and were included in this analysis.

Results: Forty‐one (57.8%) subjects with bipolar I disorder abused, or were dependent on one or more substances or alcohol, 28.2% abused, or were dependent on, two substances or alcohol, and 11.3% abused or were dependent on three or more substances or alcohol. Nearly 39% of bipolar II subjects abused or were dependent on one or more substances, nearly 17% were dependent on two or more substances or alcohol, and 11% were dependent on three or more substances or alcohol. Alcohol was the most commonly abused drug among either bipolar I or II subjects.

Conclusions: Consistent with other epidemiologic and hospital population studies, this voluntary bipolar disorder registry suggests a high prevalence of comorbidity with alcohol and/or substance abuse dependence. Bipolar I subjects appear to have higher rates of these comorbid conditions than bipolar II subjects; however, as the number of bipolar II subjects was rather small, this suggestion needs confirmation.     

Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients

Valentí M, Pacchiarotti I, Rosa AR, Bonnín CM, Popovic D, Nivoli AMA, Murru A, Grande Í, Colom F, Vieta E. Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients.
Bipolar Disord 2011: 13: 145–154. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: The aim of this study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder. Method: We enrolled a sample of 144 patients followed for up to 20 years in the referral Barcelona Bipolar Disorder Program and compared subjects who had experienced at least one mixed episode during the follow‐up (n = 60) with subjects who had never experienced a mixed episode (n = 84) regarding clinical variables. Results: Nearly 40% of bipolar I disorder patients treated with antidepressants experienced at least one mixed episode during the course of their illness; no gender differences were found between two groups. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, only suicide attempts (p < 0.001), the use of serotonin norepinephrine reuptake inhibitors (p = 0.041), switch rates (p = 0.010), and years spent ill (p = 0.022) were significantly associated with the occurrence of at least one mixed episode during follow‐up. Conclusions: The occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants, especially serotonin norepinephrine reuptake inhibitors.     

Immune activation by casein dietary antigens in bipolar disorder

Severance EG, Dupont D, Dickerson FB, Stallings CR, Origoni AE, Krivogorsky B, Yang S, Haasnoot W, Yolken RH. Immune activation by casein dietary antigens in bipolar disorder.
Bipolar Disord 2010: 12: 834–842. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Inflammation and other immune processes are increasingly linked to psychiatric diseases. Antigenic triggers specific to bipolar disorder are not yet defined. We tested whether antibodies to bovine milk caseins were associated with bipolar disorder, and whether patients recognized different epitopes of the casein protein than control individuals. Methods: Anti‐bovine casein immunoglobulin G (IgG) levels were measured with solid‐phase immunoassays in 75 individuals with bipolar disorder and 65 controls. Epitope recognition was evaluated in immunoassays by cross neutralization with anti‐bovine casein polyclonal antibodies of defined reactivity. Group‐specific reactivity and associations with symptom severity scores were detected with age‐, gender‐, and race‐controlled regression models. Results: Individuals with bipolar disorder had significantly elevated anti‐casein IgG (t‐test, p ≤ 0.001) compared to controls. Casein IgG seropositivity conferred odds ratios of 3.97 for bipolar disorder [n = 75, 95% confidence interval (CI): 1.31–12.08, p ≤ 0.015], 5.26 for the bipolar I subtype (n = 56, 95% CI: 1.66–16.64, p ≤ 0.005), and 3.98 for bipolar disorder with psychosis (n = 54, 95% CI: 1.32–12.00, p ≤ 0.014). Lithium and/or antipsychotic medication did not significantly affect anti‐casein IgG levels. Casein IgG measures correlated with severity of manic (R² = 0.15, 95% CI: 0.05–0.24, p ≤ 0.02) but not depressive symptoms. Unlike controls, sera from individuals with bipolar disorder did not inhibit binding of casein‐reactive animal sera (t‐test/χ², p ≤ 0.0001). Conclusions: Anti‐casein IgG associations with bipolar I diagnoses, psychotic symptom history, and mania severity scores suggest that casein‐related immune activation may relate to the psychosis and mania components of this mood disorder. Case‐control differences in epitope recognition implicate disease‐related alterations in how the casein molecule is digested and/or how resulting casein‐derived structures are rendered immunogenic.     

The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder

Objectives: Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post‐traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder.

Methods: The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid‐cycling bipolar disorder are summarized. Preliminary data from one pilot dose‐finding, double‐blind, random‐assignment, placebo‐controlled, 3‐week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered.

Results: The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24‐h half‐life, and minimal drug interactions. Open clinical studies suggest a 50–65% response for refractory bipolar mania, and a 40–56% response for refractory bipolar depression in mainly add‐on treatment. Open clinical studies of topiramate for rapid‐cycling subjects and those for comorbid bulimia, substance abuse, post‐traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y‐MRS total scores) of the placebo‐controlled, random assignment parallel group phase II dose‐finding study were not statistically significant. However, once the antidepressant‐associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, the post‐hoc analyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y‐MRS change scores as compared to placebo (p<0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word‐finding difficulty. Weight loss may be seen in several topiramate‐treated subjects with bipolar disorder.

Conclusions: Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited.     

Relationship between suicidality and impulsivity in bipolar I disorder: a diffusion tensor imaging study

Mahon K, Burdick KE, Wu J, Ardekani BA, Szeszko PR. Relationship between suicidality and impulsivity in bipolar I disorder: a diffusion tensor imaging study.
Bipolar Disord 2012: 14: 80–89. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Background: Impulsivity is characteristic of individuals with bipolar disorder and may be a contributing factor to the high rate of suicide in patients with this disorder. Although white matter abnormalities have been implicated in the pathophysiology of bipolar disorder, their relationship to impulsivity and suicidality in this disorder has not been well‐investigated. Methods: Diffusion tensor imaging scans were acquired in 14 bipolar disorder patients with a prior suicide attempt, 15 bipolar disorder patients with no prior suicide attempt, and 15 healthy volunteers. Bipolar disorder patients received clinical assessments including measures of impulsivity, depression, mania, and anxiety. Images were processed using the Tract‐Based Spatial Statistics method in the FSL software package. Results: Bipolar disorder patients with a prior suicide attempt had lower fractional anisotropy (FA) within the left orbital frontal white matter (p < 0.05, corrected) and higher overall impulsivity compared to patients without a previous suicide attempt. Among patients with a prior suicide attempt, FA in the orbital frontal white matter region correlated inversely with motor impulsivity. Conclusions: Abnormal orbital frontal white matter may play a role in impulsive and suicidal behavior among patients with bipolar disorder.     

Olfactory acuity is associated with mood and function in a pilot study of stable bipolar disorder patients

Hardy C, Rosedale M, Messinger JW, Kleinhaus K, Aujero N, Silva H, Goetz RR, Goetz D, Harkavy‐Friedman J, Malaspina D. Olfactory acuity is associated with mood and function in a pilot study of stable bipolar disorder patients.
Bipolar Disord 2012: 14: 109–117. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Olfactory dysfunction is described in several neuropsychiatric disorders but there is little research on olfactory processing in bipolar disorder. Methods: We assessed odor detection threshold (sensitivity) and smell identification test scores, along with symptoms, cognition, and social function in 20 DSM‐IV bipolar disorder patients and 44 control subjects. Results: The patient and control groups had similar demographic measures, intelligence, and mean olfaction scores, but significantly differed in social domains, including adjustment, function, and anxiety. Odor detection sensitivity showed significantly opposite correlations for the depressive and manic mood domains in bipolar disorder (r to z = 2.83, p = 0.005). Depressive symptoms were related to increased sensitivity (the ability to detect odors at a lower concentration) and mania symptoms were related to decreased sensitivity for odor detection. Increased sensitivity for odor detection also predicted significantly better employment (r = ?0.642, p = 0.024), whereas less sensitivity was associated with social avoidance (r = 0.702, p = 0.024) and social fear (r = 0.610, p = 0.046). Conclusions: Diminished odor detection sensitivity predicted mania and social avoidance, whereas more sensitive odor detection predicted more depressive symptoms but better employment functioning in bipolar disorder patients. Odor acuity may be an illness state marker of mood syndromes in bipolar disorder. Alternatively, differences in odor acuity may identify heterogeneous subgroups within the bipolar spectrum. Longitudinal assessments in a large, sex‐stratified sample are needed to understand the implications of odor sensitivity in patients with bipolar disorder.     

A prospective latent analyses study of psychiatric comorbidity of DSM‐IV bipolar I and II disorders

Mantere O, Isometsä E, Ketokivi M, Kiviruusu O, Suominen K, Valtonen HM, Arvilommi P, Leppämäki S. A prospective latent analyses study of psychiatric comorbidity of DSM‐IV bipolar I and II disorders.
Bipolar Disord 2010: 12: 271–284. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: To test two hypotheses of psychiatric comorbidity in bipolar disorder (BD): (i) comorbid disorders are independent of BD course, or (ii) comorbid disorders associate with mood. Methods: In the Jorvi Bipolar Study (JoBS), 191 secondary‐care outpatients and inpatients with DSM‐IV bipolar I disorder (BD‐I) or bipolar II disorder (BD‐II) were evaluated with the Structured Clinical Interview for DSM‐IV Disorders, with psychotic screen, plus symptom scales, at intake and at 6 and 18 months. Three evaluations of comorbidity were available for 144 subjects (65 BD‐I, 79 BD‐II; 76.6% of 188 living patients). Structural equation modeling (SEM) was used to examine correlations between mood symptoms and comorbidity. A latent change model (LCM) was used to examine intraindividual changes across time in depressive and anxiety symptoms. Current mood was modeled in terms of current illness phase, Beck Depression Inventory (BDI), Young Mania Rating Scale, and Hamilton Depression Rating Scale; comorbidity in terms of categorical DSM‐IV anxiety disorder diagnosis, Beck Anxiety Inventory (BAI) score, and DSM‐IV‐based scales of substance use and eating disorders. Results: In the SEM, depression and anxiety exhibited strong cross‐sectional and autoregressive correlation; high levels of depression were associated with high concurrent anxiety, both persisting over time. Substance use disorders covaried with manic symptoms (r = 0.16–0.20, p < 0.05), and eating disorders with depressive symptoms (r = 0.15–0.32, p < 0.05). In the LCM, longitudinal intraindividual improvements in BDI were associated with similar BAI improvement (r = 0.42, p < 0.001). Conclusions: Depression and anxiety covary strongly cross‐sectionally and longitudinally in BD. Substance use disorders are moderately associated with manic symptoms, and eating disorders with depressive mood.     

Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder

Singh MK, Spielman D, Libby A, Adams E, Acquaye T, Howe M, Kelley R, Reiss A, Chang KD. Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder.
Bipolar Disord 2011: 13: 189–197. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: We aimed to compare concentrations of N‐acetyl aspartate, myo‐inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at‐risk offspring prior to the onset of mania. Methods: A total of 22 children and adolescents aged 9–17 years with a familial risk for bipolar I or II disorder [at‐risk offspring with non‐bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8‐cc voxel in the cerebellar vermis. Results: Decreased myo‐inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p < 0.01). Conclusions: Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo‐inositol and choline concentrations in this region. These results may be limited by a cross‐sectional design, co‐occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.     

Metabolic effects of second‐generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses

Moreno C, Merchán‐Naranjo J, Álvarez M, Baeza I, Alda JA, Martínez‐Cantarero C, Parellada M, Sánchez B, de la Serna E, Giráldez M, Arango C. Metabolic effects of second‐generation antipsychotics in bipolar youth: comparison with other psychotic and nonpsychotic diagnoses.
Bipolar Disord 2010: 12: 172–184. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Despite known metabolic effects of second‐generation antipsychotics (SGAs) on children and adolescents, comparative effects in youth with different diagnoses remain underreported. We compared differences in metabolic changes three months after starting treatment with SGAs in youth with bipolar disorder and with other psychotic and nonpsychotic disorders. Methods: Weight and metabolic differences among diagnostic groups before and three months after starting treatment with SGAs were compared in a naturalistic cohort of children and adolescents (14.9 ± 3.0 years) diagnosed with bipolar disorder (n = 31), other psychotic disorders (n = 29), and other nonpsychotic disorders (n = 30), with no (35.6%) or very little (6.6 ± 9.0 days) previous exposure to antipsychotics. Composite measurements of significant weight gain [weight increase ≥ 5% at three months or increase ≥ 0.5 in body mass index (BMI) z‐score] and ‘risk for adverse health outcome’ (≥ 95^th BMI percentile, or ≥ 85^th BMI percentile plus presence of one other obesity‐related complication) were included. SGAs (risperidone, olanzapine, and quetiapine) were prescribed in comparable proportion among groups. Results: Baseline weight and metabolic indices were not significantly different among diagnoses. Three months after starting treatment with SGAs, more than 70% patients had significant weight gain, BMI z‐score increased in all diagnostic groups (p < 0.001 for all comparisons), total cholesterol increased in the bipolar (p = 0.02) and psychotic (p = 0.01) disorder groups, low‐density lipoprotein cholesterol increased in the bipolar group (p = 0.02), and free T4 decreased in the psychotic disorder group (p = 0.05). More patients with bipolar disorder presented overweight plus ≥ 1 obesity‐related complication at follow‐up. Conclusions: There are early weight gain and metabolic changes across diagnoses in youth treated with SGAs.     

A 15-year prospective follow-up of bipolar affective disorders: comparisons with unipolar nonpsychotic depression

Goldberg JF, Harrow M. A 15‐year prospective follow‐up of bipolar affective disorders: comparisons with unipolar nonpsychotic depression.
Bipolar Disord 2011: 13: 155–163. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Outcome studies have previously documented substantial functional disability among individuals with bipolar disorder, although few follow‐up studies have examined the prospective course of illness beyond 10 years’ duration. Methods: A total of 95 patients with mood disorders (46 with bipolar I disorder and 49 with unipolar nonpsychotic depression) were assessed 15 years after index hospitalization. Logistic and linear regression models were used to identify predictors of global functioning, work disability, and social adjustment. Results: At 15‐year follow‐up, good overall functioning was significantly less common among subjects with bipolar disorder (35%) than unipolar depression (73%) (p < 0.001). Work disability was significantly more extensive in bipolar than unipolar disorder subjects (p < 0.001). Logistic regression indicated that good outcome 15 years after index hospitalization was significantly predicted by a unipolar rather than bipolar disorder diagnosis and the absence of a depressive episode in the preceding year. Past‐year depressive, but not past‐year manic, syndromes were associated with poorer global outcome and greater work disability. In addition, subsyndromal depression was significantly associated with poorer global, work, and social outcome among bipolar, but not unipolar disorder subjects. Conclusions: A majority of individuals with bipolar I disorder manifest problems with work and global functioning 15 years after an index hospitalized manic episode Recurrent syndromal and subsyndromal depression disrupts multiple domains of functional outcome more profoundly in bipolar than unipolar mood disorders. The prevalence, and correlates, of impaired long‐term outcome parallel those reported in shorter‐term functional outcome studies of bipolar disorder.     

Development and psychometric evaluation of the Bipolar Functional Status Questionnaire (BFSQ)

Goldberg JF, McLeod LD, Fehnel SE, Williams VSL, Hamm LR, Gilchrist K. Development and psychometric evaluation of the Bipolar Functional Status Questionnaire (BFSQ). Bipolar Disord 2010: 12: 32–44. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Persistently impaired psychosocial functioning has been recognized in many individuals with bipolar disorder. However, existing measures of functional disability have been adapted for use in bipolar disorder based mainly on those developed for use in other conditions. The present study involved the development and validation of a new patient self‐report measure specific to bipolar disorder, the Bipolar Functional Status Questionnaire (BFSQ). Methods: Relevant constructs were identified, evaluated, and refined through an expert advisory panel in conjunction with patient interviews. Questionnaire items were vetted through iterative patient interviews. Psychometric properties were determined based on patient responses from implementation of the proposed 33‐item questionnaire in an 11‐site study of 596 patients with bipolar disorder across varied phases of illness. Results: Eight constructs were identified as fundamental to functional status in bipolar disorder: cognitive function, sleep, role functioning, emotional functioning, energy/vitality, social functioning, personal management, and sexual functioning. Psychometric validation supported item reduction to a 24‐item unidimensional scale, with high internal consistency (coefficient α’s = 0.93–0.95), high test‐retest reliability (intraclass correlation coefficient = 0.86, 95% confidence interval = 0.82–0.89), strong convergent validity with other functional disability measures (r’s > 0.70), and highly significant discriminant validity across illness phases, with large effect sizes (Cohen’s d > 0.70). Conclusions: The BFSQ is a psychometrically sound self‐report measure that can be used to effectively quantify functional status across different clinical states in patients with bipolar disorder.     

Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study

Chou Y‐H, Wang S‐J, Lin C‐L, Mao W‐C, Lee S‐M, Liao M‐H. Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study.
Bipolar Disord 2010: 12: 312–318. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Previous positron emission tomography studies have demonstrated that serotonin transporter (SERT) binding in the midbrain is decreased in the depressive state of bipolar disorder (BD). The aim of this study was to assess SERT binding in the midbrain of patients in a euthymic state of BD. Methods: Twenty‐eight healthy controls and 24 patients in a euthymic state of medicated BD were recruited. Euthymic state was defined as Montgomery‐Åsberg Depression Rating Scale scores < 10 and Young Mania Rating Scale scores < 7 within a consecutive eight‐week period. Single photon emission computed tomography with the radiotracer ¹²³I‐ADAM was used to measure SERT binding in the midbrain. An equilibrium ratio model was used for data analysis. Specific uptake ratio (SUR), which represents availability of SERT binding in the midbrain, was the primary measurement outcome. Results: The averaged SURs were not different between healthy controls and BD patients in euthymic state (p = 0.27). However, a three‐way ANCOVA analysis comparing SURs in healthy controls, bipolar I disorder (BD I) patients, and bipolar II disorder (BD II) patients, covarying education duration and sex, showed that the averaged SURs were significantly lower in BD I than BD II patients and healthy controls (p = 0.042). The decreased SURs in BD I patients were well correlated with duration of illness (R = ?0.742, p = 0.014) only. Conclusions: Our findings demonstrate that there is differential biological regulation in BD I and BD II patients after stable treatment, which may support the existence of a dichotomy in BD.     

Relational memory in psychotic bipolar disorder

Sheffield JM, Williams LE, Cohen N, Heckers S. Relational memory in psychotic bipolar disorder.
Bipolar Disord 2012: 14: 537–546. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Recent research has highlighted the phenotypic and genetic overlap of bipolar disorder and schizophrenia. Cognitive deficits in bipolar disorder parallel those seen in schizophrenia, particularly for bipolar disorder patients with a history of psychotic features. Here we explored whether relational memory deficits, which are prominent in schizophrenia, are also present in patients with psychotic bipolar disorder. Methods: We tested 25 patients with psychotic bipolar disorder on a relational memory paradigm previously employed to quantify deficits in schizophrenia. During the training, participants learned to associate a set of faces and background scenes. During the testing, participants viewed a single background overlaid by three trained faces and were asked to recall the matching face, which was either present (Match trials) or absent (Non‐Match trials). Explicit recognition and eye‐movement data were collected and compared to those for 28 schizophrenia patients and 27 healthy subjects from a previously published dataset. Results: Contrary to our prediction, we found psychotic bipolar disorder patients were less impaired in relational memory than schizophrenia subjects. Bipolar disorder subjects showed eye‐movement behavior similar to healthy controls, whereas schizophrenia subjects were impaired relative to both groups. However, bipolar disorder patients with current delusions and/or hallucinations were more impaired than bipolar disorder patients not currently experiencing these symptoms. Conclusions: We found that patients with psychotic bipolar disorder had better relational memory performance than schizophrenia patients, indicating that a history of psychotic symptoms does not lead to a significant relational memory deficit.     

Pain and rejection sensitivity in bipolar depression

Ehnvall A, Mitchell PB, Hadzi‐Pavlovic D, Loo C, Breakspear M, Wright A, Roberts G, Frankland A, Corry J. Pain and rejection sensitivity in bipolar depression.
Bipolar Disord 2011: 13: 59–66. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Little is known regarding the correlates of pain in bipolar disorder. Recent neuroimaging studies support the contention that depression, as well as pain distress and rejection distress, share the same neurobiological circuits. In a recently published study, we confirmed the hypothesis that perception of increased pain during treatment‐refractory depression, predominantly unipolar, was related to increased rejection sensitivity. In the present study, we aimed to test this same hypothesis for bipolar depression. Methods: The present study analysed data from 67 patients presenting to the Black Dog Institute Bipolar Disorders Clinic in Sydney, Australia. The patients all met DSM‐IV criteria for bipolar disorder and had completed a self‐report questionnaire regarding perceived pain and rejection sensitivity during depression. Results: A significant increase in the experience of headaches (p = 0.003) as well as chest pain (p = 0.004) during bipolar depression was predicted by a major increase in rejection sensitivity when depressed, i.e., state rejection sensitivity. Being rejection sensitive in general, i.e., trait rejection sensitivity, did not predict pain during depression. Conclusions: The experience of increased headaches and chest pain during bipolar depression is related to increased rejection sensitivity during depression. Research to further elucidate this relationship is required.     

The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis

Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant‐induced mania: a systematic review and meta‐analysis.
Bipolar Disord 2010: 12: 702–706. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Antidepressant‐induced mania (AIM) has been associated with the serotonin‐transporter‐linked promoter region (5‐HTTLPR) polymorphism in some studies but not in others. We conducted a meta‐analysis of those studies and other studies of genetic predictors of AIM. Methods: MEDLINE‐based searches of genetic studies of AIM were conducted, and a meta‐analysis of six studies of 5‐HTTLPR was performed. Other polymorphisms were insufficiently studied to allow for meta‐analysis. Results: There was an association of the short (s) variant of 5‐HTTLPR and AIM [risk ratio (RR) = 1.35, 95% confidence interval (CI): 1.04–1.76, p = 0.02]. There was a higher frequency of s carriers (sl and ss genotypes) in those who developed AIM [RR = 1.38, 95% CI: 0.98–1.93), p = 0.06]. Conclusion: The 5‐HTTLPR polymorphism appears to have a moderate effect size association with AIM in patients with bipolar disorder.     

Neuroimaging in bipolar disorder

Objective: The authors reviewed neuroimaging studies of bipolar disorder in order to evaluate how this literature contributes to the current understanding of the neurophysiology of the illness.

Method: Papers were reviewed as identified, using the NIMH PubMed literature search systems that reported results of neuroimaging studies involving a minimum of five bipolar disorder patients compared with healthy comparison subjects.

Results: Structural neuroimaging studies report mixed results for lateral and third ventriculomegaly. Recent studies suggest subcortical structural abnormalities in the striatum and amygdala, as well as the prefrontal cortex. Proton spectroscopic studies suggest that abnormalities in choline metabolism exist in bipolar disorder, particularly in the basal ganglia. Additionally, phosphorous MRS suggests that there may be abnormalities in frontal phospholipid metabolism in bipolar disorder. Functional studies have identified affective state‐related changes in cerebral glucose metabolism and blood flow, particularly in the prefrontal cortex during depression, but no clear abnormalities specific to bipolar disorder have been consistently observed.

Conclusions: The current literature examining the neurophysiology of bipolar disorder using neuroimaging is limited. Nonetheless, abnormalities in specific frontal‐subcortical brain circuits seem likely. Additional targeted studies are needed to capitalize on this burgeoning technology to advance our understanding of the neurophysiology of bipolar disorder.     

The common adolescent bipolar phenotype shows positive biases in emotional processing

Rock PL, Goodwin GM, Harmer CJ. The common adolescent bipolar phenotype shows positive biases in emotional processing.
Bipolar Disord 2010: 12: 606–615. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Bipolar disorder is associated with abnormalities in emotional processing that persist into periods of remission. However, studies of euthymic bipolar disorder patients may be confounded by the experience of mood episodes and medication. We therefore assessed an adolescent group for vulnerability markers associated with the bipolar phenotype. Methods: The Mood Disorder Questionnaire (MDQ) is a screening tool for bipolar disorder that targets mood‐elevation symptoms. We selected 32 high‐scoring students (≥ 7 symptoms) with the adolescent bipolar phenotype and 30 low‐scoring controls (≤ 3 symptoms) and screened them with the Mini International Neuropsychiatric Interview–Plus for bipolar disorder and other psychiatric disorders. We investigated emotional processing by assessing facial expression recognition, emotional memory, emotion‐potentiated startle, and a dot‐probe task. Results: Of the high‐MDQ participants, 12 were in remission from bipolar disorder defined by DSM‐IV‐TR and interview (bipolar II disorder/bipolar disorder not otherwise specified) and 3 from major depressive disorder. High‐MDQ participants had higher levels of neuroticism, low mood, and lifetime anxiety comorbidity and alcohol dependence compared with low‐MDQ participants. The high‐MDQ group showed facilitated recognition of surprised and neutral facial expressions and enhanced processing of positive versus negative information in emotional recognition memory and emotion‐potentiated startle. There were no effects on emotional categorisation/recall memory or attentional bias in the dot‐probe task. Conclusions: These results suggest that students with the common adolescent bipolar phenotype show positive emotional processing biases despite increased levels of neuroticism, low mood, and anxiety. Such effects may represent a psychological vulnerability marker associated with the bipolar phenotype.     

Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.