Differences in perceived life stress in bipolar I and II disorder: Implications for future epigenetic quantification

Objective: Few instruments measuring life events over the course of bipolar disorder distinguish the valence of events or consider cumulative stress burden. In the current study, we used a valence-focused life event questionnaire to assess stress in the last 12 months in patients with bipolar I (n = 863) and bipolar II (n = 362) disorder. Methods: Associations between recent stress and lifetime illness severity features were evaluated via linear and logistic regression, adjusting for age and gender. We additionally investigated the feasibility of quantifying recent stress burden by measuring methylation at a known bipolar susceptibility locus, SLC1A2 in a subset of bipolar I patients (n = 150) with or without comorbid substance use. Results: Bipolar II patients endorsed higher total, negative, and positive stress burden than their bipolar I counterparts, but the latter displayed more significant stress-illness severity associations, notably to all forms of substance abuse (e.g., alcohol, nicotine, food, other drugs). Irrespective of bipolar subtype, negative stress burden was significantly associated with illness severity features. High versus low total stress predicted hypomethylation of the SLC1A2 promoter (p < 0.05). Conclusion: Together, these findings reveal substantial differences in how bipolar subtypes experience and perceive stress. The observed degree of association between recent stress and substance abuse in bipolar I lend further support to the multidirectional effects of stress, affective episodes, and substance abuse on illness severity. Quantification of recent total stress using the methylation status of the SLC1A2 promoter is feasible, although a whole-methylome approach will likely prove more effective in disaggregating other environmental influences.