Circadian disturbances as pathophysiological mechanisms of mood disorders
- Emiliana Tonini
- 5 minutes ago
- 4 min read
Research Spotlight Blog No. 8
Dr Emiliana Tonini is a postdoctoral research associate in the Youth Mental Health & Technology team at the Brain and Mind Centre, The University of Sydney. Her research investigates circadian disturbances as proposed pathophysiological mechanism of mood disorders by combining clinical, genetic, and wearable data and using large-scale genetically informative cohorts. Her goal is to help inform treatment selection strategies for mood disorders by identifying biological and behavioural markers to guide personalised interventions.
Depression is a highly heterogeneous disorder. Two patients rarely share the same combination of symptoms, risk factors, or treatment outcomes. Several subtypes of depression have been proposed; however, most have limited clinical utility, especially for early intervention. Additionally, treatment guidelines largely rely on severity, persistence or recurrence of episodes, which often leads to a potentially lengthy process of trial-and-error prescribing of common antidepressants. One factor potentially impeding optimisation of treatment selection is the lack of clear delineation in the underlying pathophysiological mechanisms of mood disorders.
In 2019, my team (Youth Mental Health and Technology Team from the Brain and Mind Centre, The University of Sydney) developed a transdiagnostic framework incorporating two independent but complementary dimensions to classify common mood syndromes in young people (Reference). These dimensions are clinical stage, capturing the severity and persistence of illness, and pathophysiological mechanisms, reflecting the underlying mechanisms of illness (the “cause”). Three distinct but common illness trajectories in young people with emerging mood disorders were proposed as underlying pathophysiological mechanisms: neurodevelopmental-psychotic; hyperarousal-anxious; and circadian-bipolar spectrum. Following this initial work (and here, I voluntarily skip important studies that contributed to building this hypothesis to get to the part where I joined the story), “circadian depression” was proposed as a mood disorder phenotype based on clinicopathological evidence (Reference). The clinical utility of this phenotype resides in its potential to identify individuals that may particularly benefit from chronotherapies.
I joined the team in 2023, and my current research focuses on investigating the validity and clinical utility of circadian depression. The first step has been to define circadian depression – and ideally, to do so in a way that could eventually be applied by clinicians in everyday practice; for this reason, we started to look at self-reported measures over objective and potentially more reliable measures. Using data from the Australian Genetics of Depression Study, a large genetically informative cohort of adults with more severe and recurrent forms of depression, we first defined six binary circadian criteria based on markers of circadian disturbances: hypersomnia, sleep inertia, evening chronotype, delayed sleep midpoint, social jetlag, and seasonality. Individuals meeting criteria for several of these features were classified as having circadian depression.
Compared to those with non-circadian depression, the circadian depression group showed more severe clinical presentation and course, including a younger age of onset, more depressive episodes, and higher hypo-manic-like experiences, psychotic-like experiences, suicidality, psychological distress and somatic complaints. Additionally, circadian depression was associated with higher genetic risk for some major mood and developmental disorders, including depression, bipolar disorder and ADHD; higher genetic risk for some metabolic and inflammatory markers, including BMI and insulin resistance; and higher genetic risk for delayed sleep midpoint and evening preference. Importantly, the circadian depression group reported lower efficacy of SSRI and SNRI, and more frequent side effects of SSRI compared to those with non-circadian depression. Overall, these findings start to draw a potential validation and clinical utility of circadian depression as a subtype of mood disorders.
The overarching goal of this project is to be able to preferentially recommend a treatment to an individual that will work for them on the first try, with the idea that people with circadian depression will benefit more from a chronotherapy than conventional medications. A lot more work is needed to be able to meet this goal, but we have started to explore this subtype in different populations, notably in a community-based twin sample followed longitudinally from age 12 to 25 years old (and findings a similar pattern of results), and using different approaches. One that I am currently working on is to further explore the genetics of circadian depression by conducting a genome-wide association study of circadian depression in the UK Biobank. While analyses are still ongoing, preliminary findings have identified some genetic variants associated with this phenotype, some of which are relevant to mood disorders (notably bipolar disorder) and chronotype. Stay tuned for more on that soon.
Finally, another approach to explore circadian depression has been to investigate the objective markers of circadian disturbances, such as 24-hour skin temperature rhythm or actigraphy-derived rest-activity patterns. In some of my work, I focus on light exposure and light sensitivity. In our Neurobiology Youth Follow-Up Study, light sensitivity is measured using a pupillometry device. Our preliminary findings suggest that, on average, young people with emerging mood disorders have a lower dim light sensitivity compared to healthy controls. However, one interesting observation is the large variance in our sample. Because light sensitivity is known to vary greatly between people, we are now exploring factors that may influence it within our clinical sample and whether light sensitivity could serve as a marker of different illness trajectories.
So overall, my research explore circadian disturbances has potential pathophysiological mechanism of a subgroup of mood disorders, using several approaches and modalities. I am very grateful for the support from the Circadian Mental Health Network which allowed me to attend last year’s conference of the International Society for Bipolar Disorders (ISBD) and indirectly contributed to being able to present the findings summarise in this blog at this year’s ISBD conference in Japan.
Blog by Emiliana Tonini
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