Table 3 |
|
| Reverse translation research agenda for circadian-based mood disorders | |
| Reverse translation strategies | Specific research studies |
| 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). | |
Hickie et al.
Hickie et al. BMC Medicine 2013 11:125 doi:10.1186/1741-7015-11-125
