PSYCHO-NEURO-PSYCHO-NEURO-IMMUNOLOGYIMMUNOLOGY

DEPRESSIVE DISORDERS DEPRESSIVE DISORDERS SUCH AS MDD, PTSD, AND SUCH AS MDD, PTSD, AND

BIPOLAR CAN BE BIPOLAR CAN BE CHARACTERIZED AS CHARACTERIZED AS

CONDITIONS OF IMMUNE CONDITIONS OF IMMUNE ACTIVATIONACTIVATION

The Immunological Aspect to The Immunological Aspect to Psychiatric DisordersPsychiatric Disorders

► Innate immune response to pathogens Innate immune response to pathogens OR STRESS causes neuro-inflammation OR STRESS causes neuro-inflammation which in turn causes sickness behavior. which in turn causes sickness behavior.

►Sickness behavior’s symptoms are Sickness behavior’s symptoms are almost identical to symptoms of almost identical to symptoms of psychiatric disorders.psychiatric disorders.

►Research shows that Depression, PTSD, Research shows that Depression, PTSD, and Bipolar Disorder are linked to and Bipolar Disorder are linked to altered immune functionaltered immune function

Hypothalamic-Pituitary-Adrenal Hypothalamic-Pituitary-Adrenal AxisAxis

► TNF-α stimulates production of CRF TNF-α stimulates production of CRF (corticotropin releasing factor) causing the (corticotropin releasing factor) causing the pituitary gland to produce ACTHpituitary gland to produce ACTH

► ACTH causes the adrenal cortex to produce ACTH causes the adrenal cortex to produce Cortisol (or glucocorticoid).Cortisol (or glucocorticoid).

►   Glucocorticoid initiates metabolic effects, Glucocorticoid initiates metabolic effects, such as metabolizing glucose, that aim to such as metabolizing glucose, that aim to relieve affects of stressrelieve affects of stress

►   Glucocorticoids decrease levels of anti-Glucocorticoids decrease levels of anti-inflammatory cytokines when the stimuli or inflammatory cytokines when the stimuli or cause of inflammation goes away, as well as cause of inflammation goes away, as well as decreasing the CRF production in the decreasing the CRF production in the hypothalamus through negative feedback to hypothalamus through negative feedback to the hypothalamus and the pituitary.the hypothalamus and the pituitary.

Dysfunctional HPA AxisDysfunctional HPA Axis

► If the Glucocorticoids stimulated by TNFa If the Glucocorticoids stimulated by TNFa inhibit the production of the pro-inhibit the production of the pro-inflammatory cytokines and CRF, then inflammatory cytokines and CRF, then how do depressed patients have how do depressed patients have elevated circulating concentrations of elevated circulating concentrations of both cytokines and cortisol? both cytokines and cortisol?

► Raised levels of IL1 causes inhibition of Raised levels of IL1 causes inhibition of glucocorticoid response to glucocorticoid response to corticosterone thus the cytokines and corticosterone thus the cytokines and the cortisol continue to circulate and the cortisol continue to circulate and cause behavioral changes. cause behavioral changes.

IL-1IL-1ββ IL-6 IL-6► Causes inflammatory Causes inflammatory

responses such as responses such as cell proliferation, cell proliferation, differentiation, and differentiation, and apoptosisapoptosis

► Inhibits Inhibits glucocorticoid’s glucocorticoid’s reaction to the reaction to the negative feedback negative feedback

► Causes inflammatory Causes inflammatory pain hypersensitivitypain hypersensitivity

► Stress causes the Stress causes the release of release of neurotransmitter neurotransmitter Noradreniline which Noradreniline which stimulates the stimulates the astrocytes to release astrocytes to release IL6 in-vitro. IL6 in-vitro.

► IL6 has stimulatory IL6 has stimulatory affects on the HPA affects on the HPA axisaxis

► High IL6 and low High IL6 and low tryptophan in tryptophan in depressed patientsdepressed patients

Major Depressive DisorderMajor Depressive Disorder► Chronic stress Chronic stress IL-1IL-1ββ levels in levels in

hypothalamus raisedhypothalamus raised low levels of low levels of BDNFBDNF reduced cognitive performance reduced cognitive performance and memory functionand memory function

►HPA dysfunction: Chronic stressHPA dysfunction: Chronic stress continuous release of IL1continuous release of IL1 activated activated P38MAPK & jun-CkinaseP38MAPK & jun-Ckinase inhibition of inhibition of glucocorticoid response to glucocorticoid response to corticosteronecorticosterone chronically elevated chronically elevated levels of cortisol and pro-inflammatory levels of cortisol and pro-inflammatory cytokinescytokines depression. depression.

►Microglia: Stress causes elevated Microglia: Stress causes elevated glucocorticoid which can activate the glucocorticoid which can activate the microglia causing synthesis and microglia causing synthesis and secretion of neurotoxin proteins (such secretion of neurotoxin proteins (such as pro-inflammatory cytokines).as pro-inflammatory cytokines).

MDDMDD► TNFα: stimulation of HPA (hypothalamic-TNFα: stimulation of HPA (hypothalamic-

pituitary-adrenal axis) to release CRF pituitary-adrenal axis) to release CRF (corticotropin-releasing factor).(corticotropin-releasing factor).

► Activation of NFkβ Translocates to Activation of NFkβ Translocates to the nucleus and mediates the transcription of the nucleus and mediates the transcription of pro-inflammatory cytokines such as TNFa, IL6, pro-inflammatory cytokines such as TNFa, IL6, and IL1β.and IL1β.

► IDO enzyme in microglia degrades tryptophan IDO enzyme in microglia degrades tryptophan into kynurenine using metabolite called into kynurenine using metabolite called quinolic acid which is a neurotoxin and quinolic acid which is a neurotoxin and contributes to depression. contributes to depression.

► Clinical: Subjects getting treated for auto-Clinical: Subjects getting treated for auto-immune disorders by using cytokine inhibiting immune disorders by using cytokine inhibiting chemicals show significant decrease in chemicals show significant decrease in depression. There is a speculation that depression. There is a speculation that depression is secondary to the chronic state of depression is secondary to the chronic state of primary infection.primary infection.

PTSDPTSD► Pro-inflammatory cytokines upregulated in Pro-inflammatory cytokines upregulated in

hippocampus amygdala and hypothalamus hippocampus amygdala and hypothalamus fallowing physical or psychological stressfallowing physical or psychological stress

► Overexpression of IL-1Overexpression of IL-1ββ cytokine disrupts memory cytokine disrupts memory formation and consolidationformation and consolidation

► HPA activation HPA activation elevated IL-6 in serum even elevated IL-6 in serum even months after incidentmonths after incident

► TNFTNFαα and and IL-1IL-1ββ chronically elevated. Humans have chronically elevated. Humans have sensitivity in IL-1sensitivity in IL-1ββ pathway allowing the pathway allowing the possibility for PTSD. IL-1possibility for PTSD. IL-1ββ inhibits the hippocampal inhibits the hippocampal volume which is decreased in PTSD. It is not volume which is decreased in PTSD. It is not known whether the volume being small is a risk known whether the volume being small is a risk factor to getting the disease, or if is a symptom factor to getting the disease, or if is a symptom that will go away when the patient recovers.that will go away when the patient recovers.

Bipolar DisorderBipolar Disorder► Disturbances in circadian function, dopaminergic Disturbances in circadian function, dopaminergic

activity corticol synchrony.activity corticol synchrony.► Lithium (drug that alleviates symtoms of bi-polar Lithium (drug that alleviates symtoms of bi-polar

disorder) acts upon the GSK3disorder) acts upon the GSK3ββ gene. Other gene. Other medicines promote antioxidant response in medicines promote antioxidant response in astrocytes protecting the cells from activated astrocytes protecting the cells from activated microglia. microglia.

► IL-1IL-1ββ highest in bi-polar patients who recently highest in bi-polar patients who recently had a manic episode. This suggests that the had a manic episode. This suggests that the inflammatory tone may vary depending on the inflammatory tone may vary depending on the whether the patient is manic or depressive. whether the patient is manic or depressive.

► Receptor expressed in myeloid cells-1 (TREM1), Receptor expressed in myeloid cells-1 (TREM1), and its transcription factors, are triggered by pro-and its transcription factors, are triggered by pro-inflammatory genes.inflammatory genes.

► Polymorphism in the P2X7 gene, also linked with Polymorphism in the P2X7 gene, also linked with depression, has been linked to bi-polar severity depression, has been linked to bi-polar severity and specific symptoms of the disease.and specific symptoms of the disease.

Raised levels of IL-1Raised levels of IL-1ββ and TNF and TNFαα in Bipolar and Depressed in Bipolar and Depressed

patientspatients

New Treatment OpportunitiesNew Treatment Opportunities

► Target pro-inflammatory cytokines and their Target pro-inflammatory cytokines and their receptors directly or via down or upstream receptors directly or via down or upstream pathways. There are no small molecule pathways. There are no small molecule inhibitors for these receptors, therefore we inhibitors for these receptors, therefore we rely on antibodies and other biologics such as rely on antibodies and other biologics such as TNFTNFαα inhibiting protein, and IL-6 antibodies, inhibiting protein, and IL-6 antibodies, which are being developed now. The difficulty which are being developed now. The difficulty with these are that they may not efficiently with these are that they may not efficiently enter the brain. enter the brain.

► Up and downstream effectors of cytokine Up and downstream effectors of cytokine activity seem to reverse the biochemical activity seem to reverse the biochemical effects of inflammation in animals, teaching us effects of inflammation in animals, teaching us that we can likely treat central diseases that we can likely treat central diseases through peripheral pathways. through peripheral pathways.