A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives.

AIMS: Substantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. METHODS: In a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. RESULTS: Compared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12-1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09-1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04-1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02-1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC. Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75-0.77) CONCLUSIONS: Higher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD.

Associations between childhood maltreatment and oxidative nucleoside damage in affective disorders.

BACKGROUND: Childhood maltreatment is an established risk factor for incident unipolar disorder and bipolar disorder. It is separately observed that affective disorders (AD) are also associated with higher nucleoside damage by oxidation. Childhood maltreatment may induce higher levels of nucleoside damage by oxidation and thus contribute to the development of AD; however, this relation is only sparsely investigated. METHODS: In total, 860 participants (468 patients with AD, 151 unaffected first-degree relatives, and 241 healthy control persons) completed the Childhood Trauma Questionnaire (CTQ). The association between CTQ scores and markers of systemic DNA and RNA damage by oxidation as measured by urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels, respectively, was investigated. RESULTS: In multiple regression models adjusted for sex- and age, 8-oxodG and 8-oxoGuo levels were found to be higher in individuals who had experienced more childhood maltreatment. These associations persisted in models additionally adjusted for body mass index, alcohol, and current smoking status. Emotional abuse, sexual abuse, and emotional neglect were principally responsible for the foregoing associations. CONCLUSIONS: Our findings of an association between childhood maltreatment and oxidative stress markers suggest that childhood maltreatment overall, notably emotional abuse and emotional neglect, is associated with enhanced systemic damage to DNA and RNA in adulthood. Further, individuals with AD reported a higher prevalence of childhood maltreatment, which may induce higher levels of nucleoside damage by oxidation in adulthood, possibly leading to increased risk of developing AD. Longitudinal studies are needed to clarify this relationship further.

Associations between oxidative stress markers and patient-reported smartphone-based symptoms in patients newly diagnosed with bipolar disorder: An exploratory study.

Oxidative stress generated nucleoside damage seems to represent key pathophysiological mechanisms of bipolar disorder (BD). Likewise, mood and activity are core features of BD and can be reliably monitored using smartphone-based applications. The aim was to investigate whether oxidative stress generated nucleoside damage could reflect psychopathology in BD using easily available and non-invasive patient-reported smartphone-based symptoms. We included 223 patients newly diagnosed with BD and employed linear mixed-effect regression models to associate baseline measurements of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels with patient-reported smartphone measures of mood, activity, anxiety, stress and sleep duration monitored three days prior to and 30 days after the baseline visit in the longitudinal Bipolar Illness Onset Study. In patients newly diagnosed with BD higher 8-oxoGuo levels were inversely associated with the patient-reported activity level (B = 0.953, 95%CI = 0.909;0.99, p = 0.043) and positively associated with patient-reported anxiety (B = 1.104, 95%CI = 1.022;1.161, p=0.012), perceived stress (B = 1.092, 95%CI = 1.009;1.183, p = 0.014) and sleep duration (B = 1.000, 95%CI = 1.000;1.001, p = 0.001), respectively, in analyses, adjusted for sex and age. The associations between 8-oxoGuo levels and anxiety, perceived stress and sleep duration, respectively, withstood adjustment for sex, age, smoking, BMI and alcohol intake. No associations between 8-oxodG levels and patient-reported smartphone-based data were found and mood was not associated with 8-oxoGuo. Oxidative stress was associated with patient-reported smartphone-based data on activity, anxiety, stress and sleep duration pointing towards that oxidative stress generated nucleoside damage may reflect ongoing psychopathology in BD.

Affective disorders impact prevalence of Flavonifractor and abundance of Christensenellaceae in gut microbiota.

Background Affective disorders (AD) have been associated with a higher prevalence of the gut Flavonifractor genus and a lower abundance of the gut Christensenellaceae family. Objective and methods By pooling two independent study samples of patients with AD (n = 176), their unaffected first-degree relatives (n = 70) and healthy controls (n = 101) we aimed to replicate and extend our prior findings of differential Flavonifractor prevalence and Christensenellaceae abundance when comparing patients with AD and healthy controls. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Results The pattern of higher prevalence of Flavonifractor and lower Centered Log-Ratio (CLR) abundance of Christensenellaceae was associated with AD. In generalized linear models the CLR abundance of Christensenellaceae was lower in patients with AD (p = 0.024), and in smokers (p = 1.9*10-4), and inversely associated with increasing waist circumference (p = 0.031). The prevalence of Flavonifractor was higher in patients with AD (p = 0.033) and in smokers (p = 0.036). No impact of psychotropic medication was found. The CLR abundance of Christensenellaceae (p = 0.041), but not the prevalence of Flavonifractor (p = 0.20) could distinguish non-smoking patients with AD from non-smoking healthy controls, whereas no such associations were found in smokers. Unaffected relatives neither differed from patients with AD nor from healthy controls. Conclusion Compared with findings in healthy controls, AD was associated with a significantly lower CLR abundance of the health-linked Christensenellaceae and a significantly higher prevalence of Flavonifractor; findings that are associated with enhanced oxidative stress and systemic low-grade inflammation. If our observations are validated in future independent studies, they support the notion that parts of aberrant gut microbiota are shared by AD and states of dysmetabolism.

Thirty-year cardiovascular risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives.

OBJECTIVES: Bipolar disorder is associated with a decreased life expectancy of 8-12 years. Cardiovascular disease is the leading cause of excess mortality. For the first time, we investigated the Framingham 30-year risk score of cardiovascular disease in patients with newly diagnosed/first-episode bipolar disorder, their unaffected first-degree relatives and healthy individuals. METHODS: In a cross-sectional study, we compared the Framingham 30-year risk score of cardiovascular disease in 221 patients with newly diagnosed/first-episode bipolar disorder, 50 of their unaffected first-degree relatives and 119 healthy age- and sex-matched individuals with no personal or first-degree family history of affective disorder. Among patients with bipolar disorder, we further investigated medication- and illness-related variables associated with cardiovascular risk. RESULTS: The 30-year risk of cardiovascular disease was 98.5% higher in patients with bipolar disorder (p = 0.017) and 85.4% higher in unaffected first-degree relatives (p = 0.042) compared with healthy individuals in models adjusted for age and sex. When categorizing participants in low cardiovascular risk without considering age and sex distribution among participants, 81% of patients were at low risk, versus 92% of unaffected relatives and 89% of healthy individuals. Of the patients 209 (94.6%) were diagnosed within the preceding 2 years. Smoking was more prevalent among patients with bipolar disorder (45.2%) and their unaffected first-degree relatives (20.4%) compared with healthy individuals (12.8%). Similarly, dyslipidemia was more common among patients with bipolar disorder compared with healthy individuals. Treatment with psychotropic medication with metabolic adverse effects was associated with higher 30-year cardiovascular disease risk score, whereas we did not find illness-related variables associated with cardiovascular risk among patients with bipolar disorder. CONCLUSION: We found an enhanced cardiovascular disease risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives, which points to a need for specific primary preventive interventions against smoking and dyslipidemia in these populations.

Gut microbiota composition in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives.

OBJECTIVE: An aberrant gut microbiota may be associated with a broad spectrum of diseases including mental illness. The gut microbiota is scarcely studied in bipolar disorder (BD). We examined the gut microbiota composition in patients with newly diagnosed BD, their unaffected first-degree relatives and healthy individuals. METHODS: Stool samples were collected from 113 patients with BD, 39 unaffected first-degree relatives and 77 healthy individuals and the microbiota was profiled using 16S rRNA gene amplicon sequencing. RESULTS: The gut microbiota community membership of patients with BD differed from that of healthy individuals (R2 = 1.0%, P = 0.008), whereas the community membership of unaffected first-degree relatives did not. Flavonifractor was present in 61% of patients with BD, 42% of their unaffected relatives and 39% of healthy individuals. Presence of Flavonifractor was associated with an odds ratio of 2.9 (95%CI: 1.6-5.2, P = 5.8 × 10-4, Q = 0.036) for having BD. When excluding smokers, presence of Flavonifractor was associated with an odds ratio of 2.3 (95%CI: 1.1-5.3, P = 0.019) for having BD. However, when considering the subsample of non-smokers only, BD and presence of Flavonifractor were no longer associated when adjusted for all possible tests at genus level (Q = 0.6). Presence of Flavonifractor in patients with BD was associated with smoking and female sex, but not with age, waist circumference, exercise level, high-sensitive C-reactive protein, current affective state, subtype of BD, illness duration or psychotropic medication, respectively. CONCLUSION: Flavonifractor, a bacterial genus that may induce oxidative stress and inflammation in its host, was associated with BD. Higher prevalence of smoking among patients with BD contributed to our findings, and it cannot be excluded that findings are influenced by residual confounding.