There is a fundamental lack of knowledge about the biological mechanisms underlying peripartum mood disorders, that combined with the lack of appropriate models hinders prevention and treatment. The goals of this proposal are therefore to define biological processes that cause peripartum depression and to find measurable outcomes that can be used to determine who is at risk of developing it. The central hypothesis is that women with a deficient activity of a key enzyme in the kynurenine pathway will develop depression and suicidality in response to pregnancy. During pregnancy, the kynurenine pathway in the placenta breaks down tryptophan, releasing metabolites into the blood that have subsequent effects on the brain as they affect glutamate neurotransmission. The hypothesis has its origin in strong preliminary data, showing that in depressed individuals with suicidal thoughts the levels of kynurenine-metabolites are dysregulated and neuroinflammation occurs, and a similar tendency in depressed pregnant women. The rationale for this research is that the proposed biological mechanism opens the way for pharmacological interventions, targeting kynurenine pathway enzymes, as well as for the development of biomarkers for peripartum depression and suicidality. In this proposal, levels and activity of the key kynurenine pathway enzyme and its downstream metabolites will be determined in placenta, blood, and monocytes from women during pregnancy and in the post-partum. Participants will be enrolled from a community-based population attending an ob/gyn clinic, as well as from a unique clinical program specializing in the treatment of suicidal women and their infants in the post-partum period, both in Grand Rapids, MI. Placentas will be collected at delivery. All study participants will be carefully diagnosed and assessed for psychiatric symptoms of depression and suicidality as well as risk-factors. Monocytes and placental trophoblasts will be cultured and the supernatant- and blood levels will be analyzed for kynurenine metabolites using Gas-Chromatography Mass-Spectrometry. The results will be validated in two co-horts of biobanked plasma and placenta tissue, respectively, from separate geographical locations. This study will determine whether peripartum depression is a distinct subtype of depression, with a pathophysiology similar to cytokine-induced depression. The findings can lead to the identification of new therapeutic targets and biomarkers for peripartum depression and suicidality.
During pregnancy, the placenta releases substances into the blood stream that can enter the brain and activate nerve cells that use the neurochemical glutamate to communicate. This project will determine whether women with altered levels of these substances are the ones developing depression and suicidal thoughts in pregnancy and the post-partum period. Identifying vulnerable women by biomarkers will improve screening and treatment options for depression in this critical period, benefitting both the affected women and their infants, thus the proposal is highly relevant to the missions of NIMH and NICHD.
| Bryleva, Elena Y; Brundin, Lena (2017) Kynurenine pathway metabolites and suicidality. Neuropharmacology 112:324-330 |
| Gould, T D; Georgiou, P; Brenner, L A et al. (2017) Animal models to improve our understanding and treatment of suicidal behavior. Transl Psychiatry 7:e1092 |
| Thirtamara-Rajamani, Keerthi; Li, Peipei; Escobar Galvis, Martha L et al. (2017) Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease? J Parkinsons Dis 7:577-587 |
| Brundin, Lena; Bryleva, Elena Y; Thirtamara Rajamani, Keerthi (2017) Role of Inflammation in Suicide: From Mechanisms to Treatment. Neuropsychopharmacology 42:271-283 |
| Brundin, L; Sellgren, C M; Lim, C K et al. (2016) An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation. Transl Psychiatry 6:e865 |
| Brundin, Lena C; Grit, Jamie (2016) Ascertaining Whether Suicides Are Caused by Infections. JAMA Psychiatry 73:895-6 |
| Coccaro, Emil F; Lee, Royce; Fanning, Jennifer R et al. (2016) Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects. Psychoneuroendocrinology 71:189-96 |
| Brundin, L; Erhardt, S; Bryleva, E Y et al. (2015) The role of inflammation in suicidal behaviour. Acta Psychiatr Scand 132:192-203 |
