Metabolic syndrome, inflammation and ill-health in depression. Brian Leonard, Emeritus Professor of Pharmacology, National University of Ireland, Galway. (Latin America,2018)

STRESS Early life trauma Dysfunctional genes Proinflammatory DEPRESSION platelet dysfunction cytokines HPA AXIS ACTIVITY Kynurenine metabolites -[Glucocorticoid receptor] +[Quinolinic acid,ROS etc] -[Insulin receptor] +[Subclin.hypothyroidism] -[Sex hormones] Metabolic consequences of depression.

Diseases associated with metabolic syndrome in depression. Heart disease [+] coronary artery disease myocardial infarction,atrial fibrillation, heart failure. Stroke[+] Diabetes, type 2 [+] Cancer [+] Bone density [-] “Depression as a systemic disease” Sotelo & Nemeroff,2017.

Pathological factors which underlie the metabolic syndrome in depression. Heart disease: [+] CRP, VEGF, beta-Thromboglobin. [+] IL-6, TNF-alpha. [-] IL-10. Cancer: [+] CRP, proinflammatory cytokines, Desynchronised cortisol rhythm. Diabetes-2 : Inflammatory changes, prolonged hypercorticolism, insulin insensitivity, glucocorticoid receptor insensitivity, impaired glucose metabolism. Stroke: Endothelial dysfunction,[+] platelet reactivity, fibrinogen dysregulation.

Consequences of metabolic syndrome. Hippocampal atrophy and thinning of prefrontal cortex. Decreased blood flow to frontal cortex IL-1 beta in pancreas causes islet inflammation leading to cell death. Insulin resistance causes reduction in glucose transport into brain. Cardiovascular disease and diabetes 2 increased. Toups & Trivedi,Neuropsychiat.2011.

Metabolic links between depression and Alzheimer’s disease. Insulin receptor hyposensitivity Reduced glucose transport into brain Mitochondrial dysfunction and brain energy deficit. Increased tryptophan-kynurenine pathway activity due to inflammation. Neurotoxic kynurenine metabolites and increased ROS damage neurons. Amino acid catabolism increased causing ammonia accumulation.

Changes in depression and the metabolic syndrome. Metabolic syndrome Depression Adiponectin [-] [-] Insulin/cortisol resistance [+] [+] IL-6 [+] [+] TNF alpha [+] [+] IL-1 [+] [+] CRP [+] [+] Leptin [+] [+] Toups & Trivedi,Neuropsychiat.2011.

Stress, depression and insulin resistance: links to the metabolic syndrome. Diabetes type 2 Inflammation Depression Hypercortisolaemia Stress INSULIN RESISTANCE [-] Brain insulin function [-] Glucose in frontal cortex and sub cortical areas [+] neurotoxicity,[-]neuroplasticity,[-]synaptic connections DEMENTIA

WHAT IS INSULIN DOING IN THE BRAIN? Approximately 25% of total body glucose is utilised by the brain; brain weighs only 2% of body weight!. Insulin receptors and insulin sensitive glucose transporters identified on neurons and astrocytes. Insulin is a neuropeptide critically important for neuroplasticity, neuromodulation and for neuronal growth and survival. Insulin regulates feeding behaviour ;insulin KO mice become obese. Insulin modulates normal emotional and cognitive functions. Intranasal insulin can improve verbal memory and selective attention in demented patients. Decreased glucose metabolism in late-life depressed patients in the posterior association cortex also found in patients with dementia. Smith et al. Neuropsychopharmac. 2007; Smith et al.Int.J.Geriat.Psychiat.2009;Ownby et al.Arch.Gen.Psychiat.2006.

Brain glucose metabolism and psychiatric disorders. In 18th century, Thomas Willis suggested that those suffering stressful life events or “long sorrow” were more likely to suffer from diabetes. 1897,Henry Maudesley observed that diabetes and “insanity” were often co-expressed in families. 1935,William Menninger described psychogenic diabetes and the “diabetic personality”. Depressed patients have approximately 60% higher risk of diabetes-2;diabetes patients more likely to suffer from depression. Enhancing brain glucose metabolism and insulin sensitivity improves symptoms of schizophrenia. Kaidanovich et al. The Scientist,2012.

Brain glucose, depression and cognitive decline. Decrease in brain glucose in main cholinergic areas of the brain (basal forebrain, hippocampus) associated with memory dysfunction. Increased glutamate (NMDA) activity in depression linked to decrease in insulin and brain glucose. Fluoro-deoxyglucose studies show hypometabolism in cingulate gyrus; difference between treatment responders and non responders associated with insulin resistance. Nemeroff,J.clin.Psychiat.1989;Walker,Berrish &James,Clin.Endocrinol.1994;Small et al.Proc.Nat.acad. Sci.2000.

Depression, inflammation and neurotoxicity Why do neurons die prematurely? Depression Inflammatory changes [+]Tryptophan-kynurenine pathway [-] Astrocyte-neuron coupling with glucose metabolism. [+] Quinolinic acid neurotoxin [-]NAD+ synthesis [+] NMDA glutamate activation Mitochondrial damage Neuron apoptosis

The importance of the tryptophan-kynurenine pathway-1. Kynurenine shunt described by Lapin & Oxenkrug,1969. 30 studies (2008-2014),involving 7500 subjects, showed increase in kynurenine metabolites from the neurodegenerative pathway in depression. Stress, cortisol and inflammation activate liver tryptophan dioxygenase(TPO) and indoleamine dioxygenase(IDO) in periphery and brain;99% of dietary tryptophan is metabolised by TPO in the liver.

Possible mechanisms MD IL4 Tryptophan 5-HT Kynurenine Stress/ Infection IFN IDO TDO BDNF Cortisol MD K3MO Kynureninase 3-OH-KYN Quinolinate Anthranilic acid NAD Picolinate Kynurenine aminotransferase Kynurenate Energy Myint & Kim (2003) Myint et al (2007) 14

Kynurenine pathway in the brain (depressed patients) III (Steiner, Myint, Guillemin et al, paper under preparation) 15

Effect of inflammation on NAD+ and brain metabolism. Under physiological conditions, NAD+ is synthesised from quinolinic acid. Increased neurotoxic metabolites [above 1 uM] from the kynurenine pathway reduce NAD+ synthesis. Astrocyte viability compromised by reduction in NAD+ Increase in inflammatory cytokines, mitochondrial dysfunction and reduced NAD+ affects the energy balance in the brain resulting in increased neuronal death.

Inflammation, oxidative stress and endogenous neurotoxins: changes in depression Stress, genes and epigenetic trauma Depression Macrophage/microglia activation Tryptophan HPA axis Inflammation IDO Kynurenine Hypercortisolaemia n-3 fatty acids Oxidative stress (-) Neurotrophic factors Metabolites (hydroxynonenal, etc) 3-hydroxykynurenine Quinolinic acid Neurodegenerative changes IDO, indoleamine 2,3-dioxygenase 17

The resurgence of NAD+

Conclusion-1. Chronic low grade inflammation contributes to many of the principal pathophysiological aspects of depression. The microglia play a key role in this regard. Inflammation and stress induced activation of the tryptophan-kynurenine pathway plays an important role in the activation of glutamate pathways, oxidative stress and mitochondrial damage.

Conclusion-2. Metabolic changes in brain glucose due to reduced glucose transport and mitochondrial dysfunction contribute to neurodegenerative changes which may act as a prelude to dementia.

Stress, depression and the metabolic syndrome. Stress and depression (+) Energy intake (+)HPA axis (+) Adiposity GC resistance INFLAMMATION TDO & IDO activation IL6,IFN,TNF. (+)Tryp/ kynurenine, (-) serotonin Depression Insulin resistance (-) Glucose transport Stress & depression INFLAMMATION Insulin resistance