Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and serious neurodevelopmental disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Chronic and childhood stress is involved in ADHD development, and ADHD is highly comorbid with anxiety. Similarly, inflammatory diseases and a pro-inflammatory state have been associated with ADHD. However, while several works have studied the relationship between peripheral inflammation and stress in affective disorders such as depression or bipolar disorder, fewer have explored this association in ADHD. In this narrative review we synthetize evidence showing an interplay between stress, anxiety, and immune dysregulation in ADHD, and we discuss the implications of a potential disrupted neuroendocrine stress response in ADHD. Moreover, we highlight confounding factors and limitations of existing studies on this topic and critically debate multidirectional hypotheses that either suggest inflammation, stress, or anxiety as a cause in ADHD pathophysiology or inflammation as a consequence of this disease. Untangling these relationships will have diagnostic, therapeutic and prognostic implications for ADHD patients.

Bipolar disorder (BD) and borderline personality disorder (BPD) are serious and prevalent psychiatric diseases that share common phenomenological characteristics: symptoms (such as anxiety, affective lability or emotion dysregulation), neuroimaging features, risk factors and comorbidities. While several studies have focused on the link between stress and peripheral inflammation in other affective disorders such as anxiety or depression, fewer have explored this relationship in BD and BPD. This review reports on evidence showing an interplay between immune dysregulation, anxiety and stress, and how an altered acute neuroendocrine stress response may exist in these disorders. Moreover, we highlight limitations and confounding factors of these existing studies and discuss multidirectional hypotheses that either suggest inflammation or stress and anxiety as the primum movens in BD and BPD pathophysiology, or inflammation as a consequence of the pathophysiology of these diseases. Untangling these associations and implementing a transdiagnostic approach will have diagnostic, therapeutic and prognostic implications for BD and BPD patients.

Serotonin 3A receptor (5-HT_3AR) is associated at the genetic and epigenetic levels with a variety of psychiatric disorders and interacts with early-life stress such as childhood maltreatment. We studied the impact of childhood maltreatment on the methylation status of the 5-HT_3AR and its association with clinical severity outcomes in relation with a functional genetic polymorphism. Clinical severity indexes of 346 bipolar, borderline personality, and adult attention deficit hyperactivity disorders patients were tested for association with the DNA methylation status of eight 5-HT_3AR gene CpGs. Relationship between the functional variant rs1062613 (C > T) and methylation status on severity of the disorders were also assessed. Childhood maltreatment was associated with higher severity of the disease (higher number of mood episodes, history of suicide attempts, hospitalization, and younger age at onset) across disorders and within each individual disorder. This effect was mediated by two 5-HT_3AR CpGs. Compared to T allele carriers, CC carriers had higher methylation status at one CpG located 1 bp upstream of this variant. This study shows that epigenetic modification of the 5-HT_3AR is involved in the mechanism underlying the relationship between maltreatment in childhood and the severity of several psychiatric disorders in adulthood.

Background: Early-life adversities represent risk factors for the development of bipolar affective disorder and are associated with higher severity of the disorder. This may be the consequence of a sustained alteration of the hypothalamic–pituitary–adrenal (HPA) axis resulting from epigenetic modifications of the gene coding for the glucocorticoid receptor (NR3C1).Aims: To investigate whether severity of childhood maltreatment is associated with increased methylation of the exon? 1_FNR3C1promoter in bipolar disorder.Method: A sample of people with bipolar disorder (n= 99) were assessed for childhood traumatic experiences. The percentage ofNR3C1methylation was measured for each participant.Results: The higher the number of trauma events, the higher was the percentage ofNR3C1methylation (β = 0.52, 95% CI 0.46–0.59,P<<0.0001). The severity of each type of maltreatment (sexual, physical and emotional) was also associated withNR3C1methylation status.Conclusions: Early-life adversities have a sustained effect on the HPA axis through epigenetic processes and this effect may be measured in peripheral blood. This enduring biological impact of early trauma may alter the development of the brain and lead to adult psychopathological disorder.