Clinical and genetic correlates of a circadian subtype of depression in the Australian Genetics of Depression Study.

Background

Although commonly accepted depressive subtypes reflect phenotypic differences, there has been minimal progress in identification of discrete pathophysiological pathways, biomarkers or differential therapeutic approaches to effectively guide clinical management.

Aims

To test the biological validity and clinical utility of a circadian subtype of depression on the basis of clinical course, differential medication response (self-reported) and genetic risk profile.

Method

Cross-sectional data were drawn from the nationwide Australian Genetics of Depression Study. Participants were classified as having a 'circadian' or 'non-circadian' subtype of depression on the basis of meeting criteria for at least three binary circadian-associated features: social jetlag, seasonality, delayed sleep midpoint, evening chronotype, morning tiredness and hypersomnia. Clinical course characteristics were compared. Associations with response to commonly prescribed antidepressants and polygenic risk scores for mental disorders and sleep, circadian, metabolic and inflammatory traits were investigated using logistic regression models.

Results

A total of 2604 participants (23%; 80% female; mean age 37.87 ± 13.62 years) had a circadian subtype. They reported an earlier age at onset (P < 0.001), more severe clinical features including (hypo)manic-like and psychotic-like experiences, suicidality, psychological distress and somatic complaints (all P < 0.001), weight gain during depressive episodes (P < 0.001), poorer response to selective serotonin reuptake inhibitors (odds ratio 0.88 [95% CI 0.82, 0.94]) and serotonin-noradrenaline reuptake inhibitors (odds ratio 0.89 [95% CI 0.83, 0.97]), and more side-effects compared with those with a non-circadian subtype. Having a circadian subtype was associated with higher polygenic risk scores for attention-deficit hyperactivity disorder (odds ratio 1.11 [95% CI 1.06, 1.17]), major depression (odds ratio 1.11 [95% CI 1.06, 1.16]), anxiety (odds ratio 1.10 [95% CI 1.04, 1.15]), bipolar disorder (odds ratio 1.09 [95% CI 1.04, 1.14]), body mass index (odds ratio 1.09 [95% CI 1.05, 1.14]), triglycerides (odds ratio 1.10 [95% CI 1.06, 1.16]), interleukin-6 (odds ratio 1.08 [95% CI 1.03, 1.13]), higher insulin resistance (odds ratio 1.08 [95% CI 1.04, 1.13]), later sleep midpoint (odds ratio 1.15 [95% CI 1.10, 1.21]), insomnia (odds ratio 1.08 [95% CI 1.03, 1.13]) and later chronotype (odds ratio 0.68 [95% CI 0.65, 0.71]).

Conclusions

These findings support the face validity and potential clinical utility of a circadian subtype of depression as a clinical profile. Pending independent replication, investigation of its biology and predictive utility are warranted.