Table 3 Reverse translation research agenda for circadian-based mood disorders

1. Identify cohorts with clear indicators of circadian-based pathophysiology [58, 60, 99, 167, 168]

1. Establish relevant clinical cohorts. For example:

a. early-onset depression with family history of mania;

b. less than 10 years of active illness with lithium-responsive mania;

c. early-onset depression with evidence seasonal change in disorder severity or preferential response to behavioral or pharmacological circadian-based interventions;

2. Introduce circadian-based phenotypes or markers to other relevant epidemiological, clinical or longitudinal studies. For example:

a. sleep-wake cycle and circadian phenotypes into relevant developmental, family, genetic or twin studies;

b. sleep-wake cycle and circadian phenotypes into relevant population-based studies of illness-onset or course.

2. Introduce specific biomarker strategies to the study of cohorts with circadian-based pathophysiology

Introduce objective markers of 24 sleep-wake and circadian activity cycle to descriptive, longitudinal and interventional studies. For example:

a. use of smart-phone technologies to track sleep cycles;

b. use of ecological monitoring application technologies to study behavioral rhythm patterns;

c. use of actigraphy to study timing and stability of activity cycles;

d. use of dim-light melatonin assays to study patterns of melatonin onset.

3. Design prevention or clinical intervention studies that are relevant to cohorts characterized by circadian-based dysfunction (for example [104, 123, 125, 169–175])

Trial designs include:

a. selection of young patients with depressive disorders and concurrent phase-delay syndromes for evaluation of efficacy of circadian-based behavioral interventions, light therapy, melatonin or agomelatine, remelton or tasimelteon;

b. selection of young patients with depression and phase-delay, and family history of mania or psychosis or family history of response to lithium, for evaluation of behavioral or pharmacological strategies to prevent first episode of mania;

c. evaluating whether those with bipolar disorder who are most responsive to lithium also have depressive disorders that are preferentially responsive to light therapy, melatonin or agomelatine;

d. evaluating the effects of circadian-based interventions on the course of metabolic parameters in young persons treated for depression or bipolar disorder.

4. Initiate specific genetic or pathophysiological studies in those with specific circadian-parameters [176, 177]

Examples include:

a. specific genetic association for circadian markers in those cohorts who are responsive to lithium or other circadian-specific interventions;

b. specific genetic association for circadian markers in family members of those with lithium-responsive bipolar disorder;

c. specific genetic association for circadian markers in family members of those with depression who are responsive to light therapy, melatonin or agomelatine;

d. evaluate the capacity of cross-sectional and longitudinal dim-light melatonin onset assays to predict the response to treatment or rate of recurrence in those with circadian-based depressive disorders;

e. evaluate the capacity of cross-sectional and longitudinal dim-light melatonin onset assays to predict the response to treatment or rate of recurrence in those with bipolar disorders.

5. Designing relevant animal model systems to evaluate the likely therapeutic effect of novel behavioral or pharmacological interventions or better understand the effects of effective interventions on the circadian clock [122, 178–180]

1. Development of Zebra fish based assays of effects of differing pharmacologies on circadian-dependent locomotor function in fish larvae;

2. Design studies using effective circadian therapies for mood disorders (as defined by human response) in genetically-informative mice to study changes in underlying mechanisms of the circadian clock and its output systems;

3. Test novel pharmacological strategies (that is, agents which target molecular mechanisms of the circadian clock) in animal models of depression.

6. Development of novel biomarkers of the circadian system for use in risk factor and treatment systems (for example, [181–185])

1. Optimization of measurements of circadian disruption in humans with major affective disorders, via new systems and technologies (for example, circadian phase in fibroblasts) - with a focus on easy repeatable measures not only of phase-shifts but also internal desynchrony;

2. Relating measures of disruption of the circadian systems to other measures of chronic distress (for example, hair cortisol measures).