Background: Longitudinal research is critical for understanding the biological mechanisms
underlying the development of depression. Researchers recruit high-risk cohorts to understand
how risk is transmitted from one generation to the next. Biological measurements have been
incorporated into these longitudinal high-risk (LHR) studies in order to illuminate mechanistic
pathways.
Methods: To frame our review, we first present heritability estimates along the gene-byenvironment
continuum as a foundation. We then offer a Biomarkers of Intergenerational Risk
for Depression (BIRD) model to describe the multiple hits individuals at risk receive and to
allow for greater focus on the interactive effects of markers. BIRD allows for the known
multifinality of pathways towards depression and considers the context (i.e., environment) in
which these mechanisms emerge. Next, we review the extant LHR cohort studies that have
assessed central nervous system (electroencephalography (EEG), neuroimaging), endocrine
(hypothalamic-pituitary-adrenal axis (HPA)/cortisol), autonomic (startle, heart rate), genetic,
sleep, and birth characteristics.
Results: Results to date, in conjunction with the proposed model, point towards several
pathways of discovery in understanding mechanisms, providing clear direction for future
research examining potential endophenotypes.
Limitations: Our review is based on relatively narrow inclusion and exclusion criteria. As such,
many interesting studies were excluded, but this weakness is offset by strengths such as the
increased reliability of findings.
Conclusions: Blanket prevention programs are inefficient and plagued by low effect sizes due to
low rates of actual conversion to disorder. The inclusion of biomarkers of risk may lead to
enhanced program efficiency by targeting those with greatest ris
