Mechanisms of Depression and Anhedonia in Adolescents: Linking Sleep to Reward- and Stress-Related Brain Function

The last decade witnessed a steady growth from 8% to 14% in the prevalence of adolescents suffering from major depressive episode within the past year, and depression is expected to be the leading cause of global disability by 2030. The increase in depression incidence and disability is also related to increases in suicidality in adolescents, and the depressive symptom of anhedonia predicts suicidality above and beyond depression diagnosis. The high degree of morbidity and mortality associated with depression and anhedonia in adolescence makes this a key developmental period for research and intervention. Risk for depression and anhedonia is elevated in adolescents with insufficient sleep duration, late sleep timing, or elevated exposure to stressors. Alarmingly, only 30% of adolescents regularly obtain the recommended hours of sleep, and sleep timing is at its latest during mid- to late-adolescence. Adolescents also report high levels of stress related to work- and time-demands, and most will experience at least one major adverse life event before adulthood. Short/late sleep and stressors may also cause disruptions in reward- and stress-related brain function (e.g., medial prefrontal cortex response to monetary reward, autonomic and endocrine function during stressors), which are key biobehavioral mechanisms of depression and anhedonia. Short/late sleep habits are prime targets for depression intervention in adolescents; however, there is insufficient causal evidence that improving sleep opportunity and/or timing will alter the biobehavioral mechanisms of depression.

The overall objective of this R01 is to evaluate a biobehavioral model whereby sufficient sleep duration and/or early sleep timing can reduce depressive symptoms and anhedonia by promoting reward- and stress-related brain function in adolescents. The long-term goal of this research is to leverage sleep and circadian function to promote mental health. A series of studies by the PI and Co-Is indicate that short sleep, late sleep, and stressful life events independently predict reward- and stress-related brain function and depressive symptoms in adolescents. However, these studies do not evaluate the interactive effects of sleep/circadian function and stressful life events, or use experimental designs. More recent research by the PI and Co-Is uses sleep-circadian manipulation to target reward- and stress-related brain function and improve mental health in adolescents. Building from this research, this R01 will test the central hypothesis that extending and/or advancing sleep will alter reward- and stress-related brain function, and decrease depressive symptoms and anhedonia, in adolescents with short and late sleep. This proposal is consistent with the National Institute of Mental Health (NIMH) Strategic Objective to identify clinically meaningful biomarkers and behavioral indicators of mental health.

Inclusion criteria

• 14-18 years of age
• Currently in high school
• short and late sleep (weekday sleep duration ≤ 7 h and bedtime ≥ 22:30 (10:30 pm); n=100) or long and early sleep (weekday sleep duration > 7 hours and bedtime ≤ 22:30 (10:30 pm); n=50), indexed by the Munich Chronotype Questionnaire
• Lifetime stressful event frequency ≥ 2 on the Stress and Adversity Inventory (STRAIN) Screener
• Depressive symptom severity t-score greater than or equal to 45 on the Patient Reported Outcomes (PROMIS) Depression scale
• English language fluency

Exclusion criteria

• Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for current moderate to severe alcohol/substance use disorder (≥4 symptoms);
• Current clinician-provided diagnosis of narcolepsy or idiopathic hypersomnia;
• Lifetime diagnosis of bipolar or schizophrenia spectrum disorder;
• Certain medical conditions (e.g., serious neurological disorder, heart failure or serious heart trouble, history of head injury with unconsciousness > 5 minutes);
• Conditions that are contraindicated for magnetic resonance imaging (MRI; e.g., ferrous metal in the body);
• Positive screen for participant-reported eye disease, epilepsy, or photosensitizing medications that are contraindicated during the manipulation condition when bright light is administered (e.g., psychiatric neuroleptic drugs [e.g., phenothiazine], psoralen drugs, antiarrhythmic drugs [e.g., amiodarone], antimalarial and antirheumatic drugs, porphyrin drugs used in photodynamic treatment of skin diseases);
• Use of melatonin if participant is not willing to discontinue use for the duration of the study.

We will schedule around (i.e., delay appointments as needed) to avoid the timeframe of the following events:

• urgent suicide risk, defined by moderate/severe risk per Columbia Suicide Severity Rating Scale (CSSRS) and clinician determination that current risk requires immediate action;
• travel across two or more time zones within the month prior to the overnight study visits;
• beginning or ending a prescribed medication within 2 months of the observational study;
• prescribed medication dose changes within the timeframe calculated as 5x the drug's half-life [the time to reach pharmacokinetic steady-state] before the initiation of the observational or experimental studies;
• anticipated change in prescribed medications or medication dosing during the observational or experimental studies;
• current symptoms of airborne infectious illness prior to laboratory visits.

Participants with positive breathalyzer screen (blood alcohol level > .02) will be rescheduled for an alternative overnight visit date.