Neuroanatomic and Functional Neuroimaging Findings.

The search for brain morphology findings that could explain behavioral disorders has gone through a long path in the history of psychiatry. With the advance of brain imaging technology, studies have been able to identify brain morphology and neural circuits associated with the pathophysiology of mental illnesses, such as bipolar disorders (BD). Promising results have also shown the potential of neuroimaging findings in the identification of outcome predictors and response to treatment among patients with BD. In this chapter, we present brain imaging structural and functional findings associated with BD, as well as their hypothesized relationship with the pathophysiological aspects of that condition and their potential clinical applications.

Are existing self-ratings of acute manic symptoms in adults reliable and valid?-A systematic review.

BACKGROUND: Depression research historically uses both self- and clinician ratings of symptoms with significant and substantial correlations. It is often assumed that manic patients lack insight and cannot accurately report their symptoms. This delayed the development of self-rating scales for mania, but several scales now exist and are used in research. Our objective is to systematically review the literature to identify existing self-ratings of symptoms of (hypo)mania and to evaluate their psychometric properties. METHODS: PubMed, Web of Knowledge, and Ovid were searched up until June 2018 using the keywords: "(hypo)mania," "self-report," and "mood disorder" to identify papers which included data on the validity and reliability of self-rating scales for (hypo)mania in samples including patients with bipolar disorder. RESULTS: We identified 55 papers reporting on 16 different self-rating scales claiming to assess (hypo)manic symptoms or states. This included single item scales, but also some with over 40 items. Three of the scales, the Internal State Scale (ISS), Altman Self-Rating Mania Scale (ASRM), and Self-Report Manic Inventory (SRMI), provided data about reliability and/or validity in more than three independent studies. Validity was mostly assessed by comparing group means from individuals in different mood states and sometimes by correlation to clinician ratings of mania. CONCLUSIONS: ASRM, ISS, and SRMI are promising self-rating tools for (hypo)mania to be used in clinical contexts. Future studies are, however, needed to further validate these measures; for example, their associations between each other and sensitivity to change, especially if they are meant to be outcome measures in studies.

Current understandings of the trajectory and emerging correlates of cognitive impairment in bipolar disorder: An overview of evidence.

OBJECTIVES: Cognitive dysfunction affects a significant proportion of people with bipolar disorder (BD), but the cause, trajectory and correlates of such dysfunction remains unclear. Increased understanding of these factors is required to progress treatment development for this symptom dimension. METHODS: This paper provides a critical overview of the literature concerning the trajectories and emerging correlates of cognitive functioning in BD. It is a narrative review in which we provide a qualitative synthesis of current evidence concerning clinical, molecular, neural and lifestyle correlates of cognitive impairment in BD across the lifespan (in premorbid, prodromal, early onset, post-onset, elderly cohorts). RESULTS: There is emerging evidence of empirical links between cognitive impairment and an increased inflammatory state, brain structural abnormalities and reduced neuroprotection in BD. However, evidence regarding the progressive nature of cognitive impairment is mixed, since consensus between different cross-sectional data is lacking and does not align to the outcomes of the limited longitudinal studies available. Increased recognition of cognitive heterogeneity in BD may help to explain some inconsistencies in the extant literature. CONCLUSIONS: Large, longitudinally focussed studies of cognition and its covariation alongside biological and lifestyle factors are required to better define cognitive trajectories in BD, and eventually pave the way for the application of a precision medicine approach for individual patients in clinical practice.

Accelerated hippocampal biological aging in bipolar disorder.

OBJECTIVES: Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain, in particular in association with other biological clocks. To investigate this, we interrogated genome-wide DNAm in postmortem hippocampus from 32 BD-I patients and 32 non-psychiatric controls group-matched for age and sex from the NIMH Human Brain Collection Core. METHODS: DNAm age and epigenetic aging acceleration were estimated using the Horvath method. Telomere length (TL) and mitochondrial DNA (mtDNA) copy number were quantified by real-time PCR. Between-group differences were assessed by linear regression and univariate general linear models with age, sex, race, postmortem interval, tissue pH, smoking, and body mass index included as co-variates. RESULTS: Groups did not differ for epigenetic aging acceleration when considering the entire sample. However, after splitting the sample by the median age, an epigenetic aging acceleration was detected in patients compared to controls among older subjects (P = .042). While TL did not differ between groups, a reduction in mtDNA copy number was observed in patients compared to controls (P = .047). In addition, significant correlations were observed between epigenetic aging acceleration and TL (r = -.337, P = .006), as well as between TL and mtDNA copy number (r = .274, P = .028). CONCLUSIONS: Hippocampal aging may underlie neurocognitive dysfunctions observed in BD patients. Moreover, our results suggest a complex cross-talk between biological clocks in hippocampus that may underlie clinical manifestations of premature aging in BD.

Reward sensitivity and the course of bipolar disorder: A survival analysis in a treatment seeking sample.

OBJECTIVES: Reward sensitivity is suggested to be an influence on the onset and reoccurrence of bipolar disorder (BD) in observational longitudinal studies. The current study examined whether reward sensitivity predicted the recurrence of mood episodes in a treatment seeking sample. We also explored if reward sensitivity moderated treatment outcomes of psychosocial treatment. METHODS: Seventy-six euthymic adult patients with BD were randomly assigned to either Cognitive Behavioral Therapy (CBT) or Supportive Therapy (ST) and followed up for 2 years after completing therapy (Meyer and Hautzinger, 2012). The primary outcome measure was recurrence of mood episodes. The final multivariate Cox regression models included potential covariates, therapy conditions, BAS reward sensitivity, and the interaction between BAS and therapy conditions. RESULTS: BAS emerged as the only significant predictor of time till recurrence of mania, but not depression, but the overall model did not reach significance. There was no interaction between treatment and BAS reward sensitivity. Interestingly, a diagnosis of BD II predicted time till recurrence of depression. CONCLUSION: The main result regarding BAS partially confirms prior studies linking BAS and mania, but power and the specific sample seeking psychosocial treatment might have reduced the effect.

The use of component-wise gradient boosting to assess the possible role of cognitive measures as markers of vulnerability to pediatric bipolar disorder.

BACKGROUND AND AIMS: Cognitive impairments are primary hallmarks symptoms of bipolar disorder (BD). Whether these deficits are markers of vulnerability or symptoms of the disease is still unclear. This study used a component-wise gradient (CGB) machine learning algorithm to identify cognitive measures that could accurately differentiate pediatric BD, unaffected offspring of BD parents, and healthy controls. METHODS: 59 healthy controls (HC; 11.19 ± 3.15 yo; 30 girls), 119 children and adolescents with BD (13.31 ± 3.02 yo, 52 girls) and 49 unaffected offspring of BD parents (UO; 9.36 ± 3.18 yo; 22 girls) completed the CANTAB cognitive battery. RESULTS: CGB achieved accuracy of 73.2% and an AUROC of 0.785 in classifying individuals as either BD or non-BD on a dataset held out for validation for testing. The strongest cognitive predictors of BD were measures of processing speed and affective processing. Measures of cognition did not differentiate between UO and HC. CONCLUSIONS: Alterations in processing speed and affective processing are markers of BD in pediatric populations. Longitudinal studies should determine whether UO with a cognitive profile similar to that of HC are at less or equal risk for mood disorders. Future studies should include relevant measures for BD such as verbal memory and genetic risk scores.

Correlates of childhood trauma in children and adolescents with bipolar disorder spectrum: A preliminary study.

OBJECTIVE: Histories of childhood trauma (CT) are risk factors for affect dysregulation and poor clinical outcomes in women with bipolar disorder (BD). While much is known about the link between BD and CT in adult patients, there is limited data on this research topic in pediatric BD (PBD). The present study aims to investigate the impact of CT on irritability, aggressive and suicidal behaviors in PBD patients across gender types. METHODS: From 2013 to 2015, 59 PBD patients Aged 6-17 (30 female) were administered the Childhood Trauma Questionnaire (CTQ) along with scales assessing irritability (Affective Reactivity Index), aggression (Modified Overt Aggression Scale) and suicidal thoughts and behaviors (Columbia-Suicide Severity Rating Scale). We examined the severity of these behaviors across types of CT and gender using univariate regression analyses. Findings were adjusted for age, number of traumas, and CTQ denial score. RESULTS: In PBD patients, analyses showed that the effect of physical abuse depended on gender, whereby females were more likely than males to engage in suicidal thoughts and behaviors (p < 0.05). Male gender and CT were strong determinants of irritability (p < 0.05). Violence against property and people was found to be reduced in females, and increased in males with a history of emotional and sexual abuse, respectively (p < 0.05). CONCLUSION: These preliminary findings highlight the significant impact of CT in PBD and suggest that gender may predict the risk for dysfunctional behaviors in PBD patients with CT. Future large scale, longitudinal, investigations focusing on fear processing and extinction may provide a deeper understanding of these gender differences, and their role in the course of BD.

Biomarkers for bipolar disorder: current status and challenges ahead.

INTRODUCTION: Bipolar disorder (BD) is a chronic psychiatric disorder marked by clinical and pathophysiological heterogeneity. There is a high expectation that personalized approaches can improve the management of patients with BD. For that, identification and validation of potential biomarkers are fundamental. Areas covered: This manuscript will critically review the current status of different biomarkers for BD, including peripheral, genetic, neuroimaging, and neurophysiological candidates, discussing the challenges to move the field forward. Expert commentary: There are no lab or complementary tests currently recommended for the diagnosis or management of patients with BD. Panels composed by multiple biomarkers will probably contribute to stratifying patients according to their clinical stage, therapeutic response, and prognosis.

A Double-Blind, Randomized, Placebo-Controlled Study of Aspirin and N-Acetylcysteine as Adjunctive Treatments for Bipolar Depression.

OBJECTIVE: Neuroinflammation has been implicated in the pathophysiology of bipolar disorder. Some evidence shows that nonsteroidal anti-inflammatory drugs (NSAIDs) have promising antidepressant effects. The antioxidant N-acetylcysteine (NAC) may enhance the effects of NSAIDs. No study has, however, tested the adjunctive therapeutic benefits of an NSAID and NAC in bipolar disorder. METHODS: The sample included 24 medicated patients diagnosed with DSM-IV-TR bipolar disorder who were aged 18-65 years and had a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20. Participants were randomly assigned to receive either aspirin (1,000 mg), NAC (1,000 mg), combined aspirin and NAC (1,000 mg each), or placebo. Data were collected between 2013 and 2017. The primary outcome was a ≥ 50% reduction in MADRS scores. Participants completed mood and global functioning questionnaires. They also underwent blood tests prior to and following 8 and 16 weeks of treatment. A Bayesian analytic method was adopted, and posterior probability distributions were calculated to determine the probability of treatment response. RESULTS: Following the first 8-week treatment phase, individuals on treatment with placebo and NAC + aspirin had a similar probability for successful treatment response (about 70%). Following a 16-week treatment period, NAC + aspirin was associated with higher probability of treatment response (67%) compared to placebo (55%), NAC (57%), and aspirin (33%). There was no treatment effect on interleukin-6 and C-reactive protein levels at either 8 or 16 weeks. CONCLUSIONS: The coadministration of NAC and aspirin during a period of 16 weeks was associated with a reduction in depressive symptoms. The adverse effects were minimal. These preliminary findings may serve as a starting point for future studies assessing the efficacy, tolerability, and safety of anti-inflammatory and antioxidant agents in the treatment of bipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01797575.

Predictors of cognitive performance in bipolar disorder: The role of educational degree and inflammatory markers.

BACKGROUND: The aim of this article was to evaluate the cognitive status of remitted patients with bipolar disorder (BD) using Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and Brief Assessment of Cognition in Affective Disorders (BAC-A). The BAC-A is a comprehensive test battery addressing the cognitive domains compromised in BD. We also aimed to analyze potential clinical and immune predictors of cognitive performance in BD. METHODS: Remitted patients with BD (M ±â€¯S.E: 43.80 ±â€¯10.87 years) and age-matched controls (M ±â€¯S.E: 43.52 ±â€¯11.72) were administered clinical questionnaires and cognitive tests. Inflammatory plasma levels (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNFα, IL-17A, sTNFR1, and sTNFR2) were measured using an enzyme-linked immunosorbent assay. We generated a global cognitive performance index based on BAC-A scores. Multivariate analyses compared cognitive and immune measures across groups. A regression analysis was performed to examine the relationship between global cognitive performance, clinical and immune parameters in BD. RESULTS: Remitted patients with BD performed poorly on tasks of affective processing, verbal memory, working verbal memory, and executive functioning. Patients with BD presented higher plasma levels sTNFR1, TNFα, IFN, IL2, IL4, IL6, IL10, and IL17compared with controls. Education and MMSE were found to be positively correlated with global cognitive performance. IL6 plasma levels were negatively correlated with global cognitive performance. CONCLUSION: The major determinants of poor cognitive performance in BD were education and IL6 plasma levels.

A qualitative study investigating bipolar patients' expectations of a lifestyle intervention: A self-management program.

BACKGROUND: There is some evidence supporting the efficacy of lifestyle interventions in changing unhealthy habits and reduce the risk of developing comorbid conditions in Bipolar Disorder (BD). AIMS: This qualitative study aimed to identify what an optimal lifestyle intervention would look like for individuals with BD. METHODS: The current findings are based on one focus group and two paired interviews including a total of 10 individuals with BD (44.20 ±â€¯11.11 years; 6 females). Groups' transcripts were analyzed using a narrative approach. Primary themes included facilitating factors and barriers, general content, outcomes, format of the intervention, and background factors. RESULTS: Participants were in favor of a group-based lifestyle intervention as part of their usual treatment. The optimal group format would include 4 to 10 individuals, and comprise of 12 to 18 sessions lasting 1 to 1.5 h each. Accountability, motivation, interaction, and group activities were identified as contributing to the success of a lifestyle intervention. CONCLUSIONS: This qualitative study provides important information regarding aspects of lifestyle intervention format and delivery for individuals with BD. We identified barriers and facilitating factors that should be addressed in health promotion interventions delivered within community mental health settings.

Effects of valproate on brain volumes in pediatric bipolar disorder: A preliminary study.

Sodium valproate (VPA) has well-established neuroprotective effects and is recommended as treatment in bipolar disorder patients. The neural effects of VPA in pediatric bipolar disorder (PBD) have yet to be established. This preliminary study explored the effects of VPA on brain structure in PBD. Fourteen PBD patients (10 males; mean = 13.43 ± 3.05 years old) underwent a structural MRI before and after a 6-week VPA treatment period. Bayesian linear mixed modeling explored seven brain region volumes as a function of dichotomous pre/post time. Results showed a decrease in amygdala volume over time. These findings need to be confirmed by large-scale, longitudinal studies.

Changes in amygdala, cerebellum, and nucleus accumbens volumes in bipolar patients treated with lamotrigine.

The neural mechanisms underlying the therapeutic effects of lamotrigine in bipolar depression are still unexplored. This preliminary study compares the effects of a 12-week treatment with lamotrigine on brain volumes in adults with bipolar disorder (BD).12 BD type II patients (age: 49.33 ± 9.95 years, 3 males, 9 females) and 12 age and gender-matched healthy controls (HC) (HC; age: 41 ± 8.60 years, 3 males, 9 females). BD patients were initially administered 25 mg/day of lamotrigine, which was progressively escalated to 200 mg/d. BD participants underwent brain imaging prior to and following lamotrigine treatment. A 50% reduction in depressive scores indicated "remission". Bayesian general linear models controlled for age, gender and intracranial volume were used to examine changes in relevant brain region following treatment. A posterior probability > 0.90 indicated evidence that there was an effect of diagnosis or remission on brain volumes. Probability distributions of interaction effects between remission and time indicated that BD responders displayed decreased amygdala, cerebellum and nucleus accumbens volumes following lamotrigine treatment. No serious adverse side effects were reported. The antidepressant effects of lamotrigine may be linked to volumetric changes in brain regions involved in mood and emotional regulation. These findings are preliminary and replication in a larger sample is warranted.

A mania-related memory bias is associated with risk for relapse in bipolar disorder.

OBJECTIVE: Previous work has shown that neuropsychological performance can predict outcome of psychotherapy. The present paper explores whether an affective bias in verbal memory is associated with recurrence of mood episodes in patients with Bipolar Disorder (BD). METHOD: 76 euthymic adult patients with BD were randomly assigned to either 9 months of Cognitive Behavioral Therapy (CBT) or Support Therapy (ST), and followed up for 2 years after completing therapy. At baseline, affective learning memory (Emotional Auditory Verbal Learning Test; EMO-AVLT) and other measures were assessed. Recurrence of a mood episode was the primary outcome. RESULTS: The survival analyses revealed that the interaction between therapy condition, more specifically ST, and a recognition bias in favor of mania-related, but not depression-related words predicted recurrence of mania. Recurrence of depression was predicted by neither affective memory bias nor their interaction with treatment. CONCLUSIONS: A mania-related memory bias emerged as a predictor of mania recurrence, specifically in an unstructured setting such as ST. Perhaps mania-related schemata are more salient or more easily activated in those at high risk for recurrence. Interventions targeting patients' insight into their internal states as potential indicators of prodromal manic symptoms could be the key to improve the outcome of psychological interventions in BD. Additional research in the role of cognitive factors in relapse prevention is warranted.

Increased reward-oriented impulsivity in older bipolar patients: A preliminary study.

OBJECTIVE: Impulsivity is a well-established trait of bipolar disorder (BD) that persists across mood phases. It is, however, still unknown whether, in BD, impulsivity remains stable or varies in intensity over the lifespan. This cross-sectional study compared impulsive behavior in older euthymic BD patients and healthy individuals using a range of self-rating and behavioral measures of impulsivity. METHODS: 28 BD patients (56.07 ± 4.08 years, 16 women) and 15 healthy controls (HC; 55.1 ± 3.95 years, 6 women) were administered the Barratt Impulsivity Scale (BIS) and selected tasks of the Cambridge Neuropsychological Test Automated Batter (CANTAB) reflecting impulsivity. Multivariate analysis of variance controlled for age compared impulsivity measures across BD and HC. RESULTS: BD patients displayed poor decision making, risk taking, and increased delay aversion. Other measures of impulsivity such as response inhibition, sustained cognitive control, and BIS scores were, overall, comparable between BD and HC. CONCLUSIONS: These preliminary findings suggest that, in BD, aspects of impulsivity related to reward-based decision making persist into late adulthood. Large scale, longitudinal studies are needed to evaluate the relationship of age to impulsivity over time, and explore the link between impulsivity and illness progression in elderly individuals with BD.

Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder.

Bipolar disorder (BD) has been previously associated with accelerated aging; yet, the mechanisms underlying this association are largely unknown. The epigenetic clock has been increasingly recognized as a valuable aging marker, although its association with other biological clocks in BD patients and high-risk subjects, such as telomere length and mitochondrial DNA (mtDNA) copy number, has never been investigated. We included 22 patients with BD I, 16 siblings of BD patients, and 20 healthy controls in this analysis. DNA was isolated from peripheral blood and interrogated for genome-wide DNA methylation, mtDNA copy number, and telomere length. DNA methylation age (DNAm age) and accelerated aging were calculated using the Horvath age estimation algorithm in blood and in postmortem brain from BD patients and nonpsychiatric controls using publicly available data. Older BD patients presented significantly accelerated epigenetic aging compared to controls, whereas no difference was detected among the younger subjects. Patients showed higher levels of mtDNA copy number, while no difference was found between controls and siblings. mtDNA significantly correlated with epigenetic age acceleration among older subjects, as well and with global functioning in our sample. Telomere length did not show significant differences between groups, nor did it correlate with epigenetic aging or mtDNA copy number. These results suggest that BD may involve an accelerated epigenetic aging, which might represent a novel target for treating BD and subjects at risk. In particular, our results suggest a complex interplay between biological clocks to determine the accelerated aging and its consequences in BD.

Erratum to: Prediction of vulnerability to bipolar disorder using multivariate neurocognitive patterns: a pilot study.

In the original version of this article (Wu et al. 2017), published on 1 September 2017, the name of author 'Bo Cao' was wrongly displayed. In this Erratum the incorrect name and correct name are shown. The original publication of this article has been corrected.

Prediction of vulnerability to bipolar disorder using multivariate neurocognitive patterns: a pilot study.

Bipolar disorder (BD) is a common disorder with high reoccurrence rate in general population. It is critical to have objective biomarkers to identify BD patients at an individual level. Neurocognitive signatures including affective Go/No-go task and Cambridge Gambling task showed the potential to distinguish BD patients from health controls as well as identify individual siblings of BD patients. Moreover, these neurocognitive signatures showed the ability to be replicated at two independent cohorts which indicates the possibility for generalization. Future studies will examine the possibility of combining neurocognitive data with other biological data to develop more accurate signatures.

The Link between Refractoriness and Neuroprogression in Treatment-Resistant Bipolar Disorder.

Treatment refractoriness remains one of the biggest challenges in the field of bipolar disorder (BD) as treatments are often suboptimal or unsatisfactory. Recent evidence points towards a potential link between the progressively evolving nature of BD, increased inflammation, and reduced treatment response. There are several medications and other somatic treatments available, but remission rates are low, and medication compliance is still problematic. Psychotherapeutic techniques appear to be promising in several disease states and in relapse prevention, but additional research is needed to determine who will benefit from what strategy the most. Current knowledge on the link between neuroprogression in BD and poor treatment response promotes the use of anti-inflammatory and neuroprotective strategies in the early phases of BD. In the later stages of BD, mood stabilization and medication adherence would be essential in preventing additional brain changes and loss of cognitive reserve. Additional large-scale, longitudinal, and methodologically robust studies are urgently needed to develop effective therapeutic interventions for treatment-resistant BD.

Are self-rated and behavioural measures of impulsivity in bipolar disorder mainly related to comorbid substance use problems?

INTRODUCTION: Impulsivity is a multidimensional feature observed in bipolar disorder (BD) and substance use disorder (SUD). We previously found a relationship between SUD and risk taking in BD. It is still unclear whether self-rated and behavioral impulsivity measures differ between BD with and without comorbid SUD, or are specific to BD. METHODS: 93 adults with BD with comorbid SUD, 91 BD without SUD, and 93 healthy controls (HC) were administered the Barratt Impulsivity Scale (BIS), the Behavioral Inhibition/Behavioral Activation System Scale (BIS/BAS), and the Cambridge Neuropsychological Test Automated Battery. Analyses compared impulsivity measures across groups controlling for age. Discriminant function analyses (DFA) assessed the combination of variables effectively predicting group membership. RESULTS: BD displayed increased BIS, BIS/BAS scores, reduced performance on the Cambridge Gambling and Rapid Visual Processing, and Affective Go/No-Go tasks compared to HC. Comparisons between BD with and without SUD showed increased BIS Motor impulsiveness. The overall predictive power of DFA was weak. CONCLUSIONS: Some facets of impulsivity are a core trait of BD and are partially independent from the presence of SUD. Motor impulsiveness may be distinctive of BD+SUD. More research is needed to understand the role of impulsive behaviors as risk factors for relapse in SUD.