Long-term integrative treatment of bipolar disorder.

The cytokine/metabokine (GDF15) GDF15 is gaining significant interest as a clinical biomarker given its associations with age and dramatic elevation in pregnancy and across disease states. It is a leading biomarker of aging—increasing by 100–150% on average per decade of life (, , , , ). In pregnancy, blood GDF15 is dramatically elevated, with increases up to 200-fold (), which in extreme cases causes excessive nausea and vomiting (i.e., hyperemesis gravidarum; (). GDF15 is also the most prominently elevated circulating protein across several medical conditions, including cancer, cardiovascular, kidney, Alzheimer’s, autoimmune, and rare mitochondrial diseases (, , , , , , , , , ). Beyond these cross-sectional disease associations, GDF15 also predicts the incidence of neurological, cardiac, metabolic, and psychiatric disorders over 1–2 decades, as well as all-cause mortality (, ). Together, these findings highlight the clinical and research importance of understanding the psychobiological factors that regulate GDF15 biology. In our recent preprint, we showed that GDF15 can be measured in human saliva as well as in blood, where it appears to dynamically respond to acute psychosocial stress (). A study of 70 healthy individuals showed that, much like cortisol and other stress mediators, salivary GDF15 increased by an average of ~43% within 5 minutes of psychosocial stress induction (i.e., a speech delivery task). Interestingly, the relative magnitude of plasma GDF15 response was blunted in people with mitochondrial disorders, though not in saliva. These individuals have OxPhos defects that trigger cellular energetic deficiency, contributing to systemically elevated baseline GDF15 levels (). People with psychiatric disorders (, , , , ) and comorbid mental-physical disorders (, , , ) also exhibit elevated blood GDF15. Furthermore, GDF15 has also been associated with psychosocial stressors in humans () and anxiety-related behaviors and physical restraint stress in mice (, ). Together, these new data suggest two things. First, salivary GDF15 may be an accessible marker of stress-reactivity and metabolic or mitochondrial health status. Second, mental and metabolic signaling pathways likely converge in the regulation of GDF15 signaling. Beyond acute laboratory stressors and clinical diagnoses, less is known about how GDF15 relates to sociodemographic, psychosocial, and health-related behaviors. Initial studies have investigated associations between circulating GDF15 levels and education, income, and poverty levels—finding that GDF15 was negatively correlated with years of education and household income (). Interestingly, the risk of all-cause mortality associated with GDF15 was lower in those below the poverty cutoff (, ). In some studies, GDF15 was also related to lifestyle habits, exhibiting negative correlations with healthy dietary patterns, but positive correlations with alcohol consumption and smoking (, , ).