Do you feel up when you go up? A pilot study of a virtual reality manic-like mood induction paradigm.

OBJECTIVES: In order to understand the working mechanisms of mania, it is necessary to perform studies during the onset of manic (-like) mood states. However, clinical mania is difficult to examine experimentally. A viable method to study manic mood like states is mood induction, but mood induction tasks thus far show variable effectiveness. METHODS: In this pilot study, a new paradigm to induce mood through virtual reality (VR) is examined. Both state characteristics, namely changes in emotion, and trait characteristics, such as high and low scores on the hypomanic personality scale (HPS), were measured in 65 students. These students participated in either a neutral VR mood induction or an activating VR mood induction in which excitement, goal directedness, and tension (being aspects of mania) were induced. All participants performed a risk-taking behavioural task, Balloon Analogue Risk Task (BART). RESULTS: The experimental VR task induced excitement and tension. In participants with higher sensitivity to hypomanic personality (HPS), irritation increased in response to activation whereas it decreased in the low HPS group, and excitement increased more steeply in the low HPS group. There were no effects on the behavioural task. CONCLUSIONS: The VR task is effective in inducing relevant state aspects of hypomania and is suitable as a paradigm for future experimental studies. Activation of dual affective states (excitement and tension) is an essential aspect in manic-like mood induction paradigms.

Anger and cluster B personality traits and the conversion from unipolar depression to bipolar disorder.

INTRODUCTION: Feelings of anger and irritability are prominent symptoms of bipolar disorder (BD) that may occur during hypomanic, depressive and, especially, during mixed mood states. We aimed to determine whether such constructs are associated with the conversion to BD in subjects with a history of unipolar depression. METHODS: Data were derived from the depressed participants of Netherlands Study of Depression and Anxiety with 9 years of follow-up. Hypomania was ascertained using the Composite International Diagnostic Interview at 2, 4, 6, and 9 years follow-up. Cross-sectionally, we studied the association between prevalent hypomania and anger related constructs with the "Spielberger Trait Anger subscale," the "Anger Attacks" questionnaire, the cluster B personality traits part of the "Personality Disorder Questionnaire," and "aggression reactivity." Prospectively, we studied whether aggression reactivity predicted incident hypomania using Cox regression analyses. RESULTS: Cross-sectionally, the bipolar conversion group (n = 77) had significantly higher scores of trait anger and aggression reactivity, as well as a higher prevalence on "anger attacks," "antisocial traits," and "borderline traits" compared to current (n = 349) as well as remitted (n = 1159) depressive patients. In prospective analyses in 1744 participants, aggression reactivity predicted incident hypomania (n = 28), with a multivariate-adjusted hazard ratio of 1.4 (95% confidence interval: 1.02-1.93; p = .037). CONCLUSION: Anger is a risk factor for conversion from unipolar depression to BD. In addition, patients who converted to BD showed on average more anger, agitation and irritability than people with a history of unipolar depression who had not converted.

Traumatic experiences, family functioning, and mood disorder development in bipolar offspring.

OBJECTIVES: Studies in children of patients affected with bipolar disorder (BD; bipolar offspring) are at high risk to develop mood disorders. Our aim is to investigate how environmental factors such as childhood trauma and family functioning relate to the development of mood disorders in offspring at familial risk for BD. DESIGN: The current study is part of a longitudinal prospective cohort study among offspring of parents with BD. METHODS: The current study is part of the Dutch Bipolar Offspring Study, an ongoing prospective cohort study among adolescent offspring of a parent with BD. Bipolar offspring were psychiatrically evaluated at baseline and at 1-, 5-, and 12-year follow-up. Complete follow-up data over de 12-year follow-up were available for 102 offspring. Childhood trauma was measured with the Childhood Trauma Questionnaire (CTQ) and filled out by the offspring. Family functioning was reported by the mother with the 130-item Questionnaire for Family Problems (QFP). RESULTS: Emotional maltreatment was significantly associated (HR = 1.82, CI 1.18-2.82, p = .007) with mood disorder onset in bipolar offspring. No association was found with the family functioning total score (HR = 1.04, CI 0.94-15, p = .085) nor its subscales. CONCLUSIONS: The current study suggests that emotional maltreatment is associated with mood disorder development in bipolar offspring. Remarkably, the association of offspring-reported emotional maltreatment and mood disorder onset was not reflected in parent-reported family functioning (e.g., support and communication, openness or involvement). Possible explanations are discussed and warrant further study. PRACTITIONER POINTS: Offspring of bipolar patients are at increased risk of developing mood disorders across the life-time. Emotional trauma contributes to the likelihood of developing mood disorders in bipolar offspring. In the daily treatment of bipolar patients having children, attention should be given to parental style and difficulties. Further research using multiple informant methods on childhood trauma an family functioning is needed to further disentangle the effects of these variables on the onset of psychopathology in bipolar offspring.

Recent negative life events increase hair cortisol concentrations in patients with bipolar disorder.

Life events induce stress, which is considered to negatively impact the course of disease in patients with bipolar disorder (BD), its effects being predominantly mediated by cortisol. Cortisol in scalp hair has been identified as a biomarker for assessing long-term cortisol levels, and allows clarifying the relation between life events, hair cortisol concentrations (HCC), and clinical course over time. In 71 BD patients, we analyzed the proximal 3 cm of hair, reflecting 3 months of cortisol production, and investigated the association between HCC, the number of life events, the amount of social support, and mood in the 3 months prior to the hair assessment and between HCC and mood in the subsequent 3 months. Although the total number of life events was not associated with HCC (p > 0.05), the number of negative life events was associated with increased HCC (r(2)( )= 0.04, p = 0.02). Social support showed an inverse association with HCC in patients reporting negative life events (r(2)( )= 0.07, p = 0.03). HCC and mood were not associated in the 3 months prior to hair sampling or in the subsequent 3 months. This study indicates that patients who experienced recent negative life events have increased hair cortisol levels, which seem to be attenuated by social support.

Association Between the Fronto-Limbic Network and Cognitive and Emotional Functioning in Individuals With Bipolar Disorder: A Systematic Review and Meta-analysis.

Importance: Individuals with bipolar disorder (BD) experience cognitive and emotional dysfunctions. Various brain circuits are implicated in BD but have not been investigated in a meta-analysis of functional magnetic resonance imaging (fMRI) studies. Objective: To investigate the brain functioning of individuals with BD compared with healthy control individuals in the domains of emotion processing, reward processing, and working memory. Data Sources: All fMRI experiments on BD published before March 2020, as identified in a literature search of PubMed, Embase, Web of Science, Cochrane Library, PsycInfo, Emcare, Academic Search Premier, and ScienceDirect. The literature search was conducted on February 21, 2017, and March 2, 2020, and data were analyzed from January 2021 to January 2022. Study Selection: fMRI experiments comparing adult individuals with BD and healthy control individuals were selected if they reported whole-brain results, including a task assessing at least 1 of the domains. In total, 2320 studies were screened, and 253 full-text articles were evaluated. Data Extraction and Synthesis: A total of 49 studies were included after selection procedure. Coordinates reporting significant activation differences between individuals with BD and healthy control individuals were extracted. Differences in brain region activity were tested using the activation likelihood estimation method. Main Outcomes and Measures: A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to stimuli in 3 cognitive domains between individuals with BD and healthy control individuals were different. Results: The study population included 999 individuals with BD (551 [55.2%] female) and 1027 healthy control individuals (532 [51.8%] female). Compared with healthy control individuals, individuals with BD showed amygdala and hippocampal hyperactivity and hypoactivation in the inferior frontal gyrus during emotion processing (20 studies; 324 individuals with BD and 369 healthy control individuals), hyperactivation in the orbitofrontal cortex during reward processing (9 studies; 195 individuals with BD and 213 healthy control individuals), and hyperactivation in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex during working memory (20 studies; 530 individuals with BD and 417 healthy control individuals). Limbic hyperactivation was only found during euthymia in the emotion and reward processing domains; abnormalities in frontal cortex activity were also found in individuals with BD with mania and depression. Conclusions and Relevance: This systematic review and meta-analysis revealed evidence for activity disturbances in key brain areas involved in cognitive and emotion processing in individuals with BD. Most of the regions are part of the fronto-limbic network. The results suggest that aberrations in the fronto-limbic network, present in both euthymic and symptomatic individuals, may be underlying cognitive and emotional dysfunctions in BD.

Effects of the COVID-19 pandemic in a preexisting longitudinal study of patients with recently diagnosed bipolar disorder: Indications for increases in manic symptoms.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic interfered in the daily lives of people and is assumed to adversely affect mental health. However, the effects on mood (in)stability of bipolar disorder (BD) patients and the comparison to pre-COVID-19 symptom severity levels are unknown. METHOD: Between April and September, 2020, symptoms and well-being were assessed in the Bipolar Netherlands Cohort (BINCO) study of recently diagnosed patients with BD I and II. The questionnaire contained questions regarding manic and depressive symptoms (YMRS and ASRM, QIDS), worry (PSWQ), stress (PSS), loneliness, sleep, fear for COVID-19, positive coping, and substance use. As manic, depressive and stress symptoms levels were assessed pre-COVID-19, their trajectories during the lockdown restrictions were estimated using mixed models. RESULTS: Of the 70 invited BD patients, 36 (51%) responded at least once (mean age of 36.7 years, 54% female, and 31% BD type 1) to the COVID-19 assessments. There was a significant increase (X2 = 17.06; p = .004) in (hypo)manic symptoms from baseline during the first COVID-19 wave, with a decrease thereafter. Fear of COVID-19 (X2 = 18.01; p = .003) and positive coping (X2  = 12.44; p = .03) were the highest at the start of the pandemic and decreased thereafter. Other scales including depression and stress symptoms did not vary significantly over time. CONCLUSION: We found a meaningful increase in manic symptomatology from pre-COVID-19 into the initial phases of the pandemic in BD patients. These symptoms decreased along with fear of COVID-19 and positive coping during the following months when lockdown measures were eased.

Higher cortisol levels may proceed a manic episode and are related to disease severity in patients with bipolar disorder.

BACKGROUND: Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathogenesis of bipolar disorder (BD). However, the relationship between HPA-activity and disease severity is not fully elucidated. In this pilot study we aimed to explore the temporal relationship between HPA-activity and the risk of a manic episode in BD patients type I, by assessing long-term hair cortisol concentrations (HCC). Second, we explored the relation between HCC and the number of previous episodes. METHODS: Hair samples were collected from 45 BD I patients in euthymic or manic state and compared to 17 controls. From each participant, two hair samples of 3 cm length were used to measure long-term cortisol, reflecting retrospect time frames of 1-3 months and 4-6 months respectively prior to sampling. RESULTS: HCC in the BD group was slightly higher than in the control group in both hair segments (p = 0.049 and 0.03; after adjustment for age, sex, BMI and hair washing frequency p = 0.222 and 0.139). A significant peak in hair cortisol was observed prior to a manic episode (p = 0.036). Furthermore, we found a positive correlation between the number of mood episodes HCC (p = 0.03). CONCLUSIONS: Our results indicate that long-term cortisol levels are slightly higher in BD, and in particular elevated in the months prior to a manic relapse. In addition HCC are positively associated with the number of previous mood episodes in the course of BD type I.

T Cell Deficits and Overexpression of Hepatocyte Growth Factor in Anti-inflammatory Circulating Monocytes of Middle-Aged Patients with Bipolar Disorder Characterized by a High Prevalence of the Metabolic Syndrome.

BACKGROUND: We previously reported T cell deficits and pro-inflammatory gene activation in circulating monocytes of two cohorts of bipolar disorder (BD) patients, a cohort of postpartum psychosis patients and in bipolar offspring. Pro-inflammatory gene activation occurred in two clusters of mutually correlating genes, cluster 1 for inflammation-related cytokines/factors, cluster 2 for motility, chemotaxis, and metabolic factors. AIM: To verify these cellular immune abnormalities in yet another cohort [the bipolar stress study (BiSS) cohort] of relative old (52 years, median) BD patients and to relate immune abnormalities to hair cortisol levels, measured in this cohort and representing long-term systemic cortisol levels, and to the presence of the metabolic syndrome (MetS), which was prevalent in 29% of the BiSS patients. METHODS: Monocyte immune gene activation (quantitative polymerase chain reaction) and T cell deficits (fluorescence-activated cell sorting analysis) were determined in 97 well-controlled, largely euthymic BiSS BD patients. Monocyte genes included the cluster 1 and 2 genes, the genes for the glucocorticoid receptor (GR) α and GRß, and the gene for hepatocyte growth factor [HGF, a marker of monocyte-derived circulating angiogenic cells (CACs)]. CACs serve vessel repair. Abnormal numbers are found in patients with MetS and vascular damage. RESULTS: As compared to healthy controls: (1) the pro-inflammatory cluster 1 genes were downregulated, and the GRα and the HGF gene were upregulated in the monocytes of the BiSS patients and (2) T cell deficits were shown (reduced numbers of lymphocytes in particular of T cells). Within the reduced T cell population, a shift had taken place in the T-helper populations: T-helper 17 and T-helper 2 increased and T regulatory cells decreased. Correlations between hair cortisol, the MetS, monocyte gene activation, and T cell deficits were not found. CONCLUSION: T cell deficits most likely are a trait phenomenon of BD, since they have also been found in the other cohorts of BD patients and in bipolar offspring. Monocytes of this cohort showed an anti-inflammatory set point, suggesting that pro- and anti-inflammation are state characteristics of BD. The monocyte gene profile indicated an increased CAC activity; the question arises whether this is due to putative vessel damage in these relatively old patients with a high prevalence of the MetS.

Effects of mood state on divided attention in patients with bipolar disorder: evidence for beneficial effects of subclinical manic symptoms.

A relatively small number of studies have been dedicated to the differential effects of the current mood state on cognition in patients with a bipolar disorder (BD). The aim of the current study was to investigate the effect of current mood state on divided attention (DA) performance, and specifically examine possible beneficial effects of the (hypo-) manic state. Over a maximum period of 24 months, medication use, divided attention test (a subtest of the Test for Attentional Performance (TAP)) was assessed every 6 months in 189 outpatients with BD. Data were analyzed with multilevel regression analysis (i.e. linear mixed models). DA performance varied considerable over time within patients. Corrected for psychotropic medication a significant quadratic relationship between manic symptoms and DA performance was found, with mild hypomanic symptoms having a positive influence on divided attention scores and moderate to severe manic symptoms having a negative influence. No association between depressive symptoms and DA performance was found. In future research on mania and cognition as well as in the clinical practice both the beneficial and negative effects of mania should be taken into account.