Alterations in plasma kynurenine pathway metabolites in children and adolescents with bipolar disorder and unaffected offspring of bipolar parents: A preliminary study.

BACKGROUND: There has been growing scientific evidence in recent years that bipolar disorder (BD) is associated with alterations in the kynurenine (KYN) pathway. However, many of these studies have been limited by their focus on adults. Thus, this preliminary study investigated differences in the peripheral levels of KYN metabolites in children and adolescents with BD, unaffected offspring of parents with BD, and healthy controls (HCs). METHODS: Plasma samples were collected from 49 youths with BD, 19 bipolar offspring, and 31 HCs. Tryptophan (TRP), KYN, and kynurenic acid (KYNA) were separated using electrospray ionization. RESULTS: One-Way ANCOVA after controlling for age, gender, race, BMI-for-age, and smoking status showed that BD had lower levels of KYN, while unaffected high-risk offspring subjects had lower levels of TRP, KYN, and KYNA when compared to HCs. Moreover, we found that KYN, KYN/TRP, and KYNA/KYN levels predicted the severity of depressive symptoms, while the YMRS score was not associated with any metabolite. CONCLUSIONS: In summary, this preliminary study has shown that KYN metabolites are decreased in both affected and unaffected subjects, strengthening the idea that the KYN pathway might underlie the familial risk of BD shown by high-risk offspring individuals. However, longitudinal studies are needed to examine whether the alterations observed in this study represent early markers of risk for later developing BD.

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.

ADHD is associated with migraine: a systematic review and meta-analysis.

An association between primary headaches and attention-deficit/hyperactivity disorder (ADHD) has long been suggested. Moreover, headache is regarded as a common side effect of stimulants, the most effective treatment for ADHD. So far, no systematic review has evaluated the potential association between ADHD and headache. We performed a systematic review of the literature and a meta-analysis of all reported studies on ADHD and primary headaches. Our analysis showed a positive association between ADHD and migraine (OR 1.322, 95% CI 1.018-1717, p value 0.036), but not with tension-type headache. There is a significant association between migraine and ADHD. The mechanisms underlying this association remain to be elucidated, warranting further studies.

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.