Depression, inflammation and dementia; can antidepressants help? Brian E. Leonard, Emeritus Professor of Pharmacology, National University of Ireland, Galway.

INFLAMMATION AND DEPRESSION: What is the evidence?

Evidence for inflammatory biomarkers in depression Acute phase proteins increased haptoglobin, alpha 1-antitrypsin, complement C3c and C41 C-reactive protein increased2 Following cytokines reported to be increased TNFα, IFNγ , IL-1α, IL-1β, IL-6, IL-8, IL-12, TGF-β3 Chemokines increased MCP-1, eotaxin4 Soluble receptors Soluble IL-6 receptor (sIL-6R)5 Other markers myeloperoxidase (MPO)6 prostaglandin E27 1Song et al 1994; 2Howren et al 2009 3Debnath et al 2011; 4Simon et al 2008 5Maes et al 1995; 6Vaccarino et al 2008 7Calabrese et al 1986 IFN, interferon; MCP-1, monocyte chemotactic protein 1; TGF, transforming growth factor

Inflammatory biomarkers in the brain. IL-1 beta raised in CSF [Levine et al.1999] Following cytokines raised in the prefrontal cortex: IL-1 alpha and beta,IL-2, IL-3,IL-8, IL-9, IL-12,IL-18, TNF-alpha. [ Shelton et al. 2010].

Chronic inflammation a major factor in the pathology of depression ‘Depression is an illness with very real and dangerous physical concomitants’ Patients with chronic depression have increased rates of mortality due to heart disease, complications of diabetes, cancers and autoimmune diseases In all these conditions, chronic low-grade inflammation plays a significant role Glassman & Shapiro 1998

What do antidepressants do to inflammation?

Are therapeutic effects of antidepressants due to a reduction in inflammation?. CORRELATION IS NOT CAUSATION! Symptoms of depression are complex, only some of which may be inflammation related. Is inflammation associated “sickness behaviour” and depression part of a continuum or biologically distinct aspects? Do antidepressants target both phases of depression or are they selective for depression?

ANTI-INFLAMMATORY PROFILE OF ANTIDEPRESSANTS BASED MAINLY ON EXPERIMENTAL STUDIES. INCREASE IL-10 Antioxidant eNOS Action of ANTIDEPRESSANTS DECREASE MPO IL-6 IL-1 TNF NO iNOS NF-kB PGE2 Caspase 3 HClO3 Inflammatory Glutamate Inflammation Apoptosis oxidant cytokines activation In depression, gene polymorphisms determined for COX2,MPO,iNOS and inflammatory cytokines. [Galecki et al,J.Affect.Dis.2012]

Possible sites of anti-inflammatory action of antidepressants Genetic and epigenetic factors Dysfunctional neurotransmitter networks Antidepressants Stressors (+) CRF Monoamines (NA, DA, 5-HT) (+) (+) Neuropeptides (BDNF) (-) Antidepressants Amino acids (glutamate, GABA) (-) NFκB Neuronal apoptosis Microglia TNF Map kinase IL-6 JAK/STAT Oxidative stress (-) Antidepressants BDNF, brain-derived neurotrophic factor; CRF, corticotrophin-releasing factor; DA, dopamine; 5-HT, serotonin; JAK/STAT, janus kinase/signal transducer and activator of transcription

Effect of antidepressants on serum inflammatory cytokines. TNF-alpha: 13 studies (n=438)-no overall effect! IL-6 : 13 studies (n=274)-no overall effect! IL-1beta : 6 studies (n=115)-significant decrease, mainly due to SSRI’s. [Meta-analysis by Hannestad et al. Neuropsychopharm.36,2452 (2011)

EFFECTS OF VENLAFAXINE ON PRO-INFLAMMATORY MARKERS OF DEPRESSION. HAM-D SCORES week 0 26.2+/- 1.0 week 8 10.9 +/-2.0 (P<0.01) PRO-INFLAMMATORY CYTOKINES P values 0.02-0.05 vs controls TNF-alpha (pg/ml) Controls 17.3+/- 1.2 week 0 - 31.6+/-5.4 week 8 - 23.9+/- 4.2 IL-1-beta 5.4+/-0.8 11.9+/-2.4 13.0+/- 3.7 MCP-1 132+/-23 205+/-19 199+/-24 CRP (ug/ml) 2.1+/-0.2 *3.2+/-0.8 *2.1+/-0.5 Note: CRP values in patients unchanged! Conclusion: despite the reduction in the HAM-D scores after 8 weeks of treatment with venlafaxine, the pro-inflammatory cytokine levels were largely unchanged! Piletz et al. World J.Biol.Psychiat.(2008).

BUT ARE ANTIDEPRESSANTS ANTI-INFLAMMATORY DRUGS? THE JURY IS STILL OUT AND IF IS NOT, AND INFLAMMATION IS A MAJOR FACTOR IN THE PSYCHOPATHOLOGY OF DEPRESSION, PERHAPS THE FUTURE FOR EFFECTIVE ANTIDEPRESSANTS LIES IN INFLAMMATION RESEARCH.

Chronic depression and the link to dementia.

Major depression and the progression to Alzheimer’s disease. Study by Rapp et al. Arch,Gen.Psychiat. 63,161,2006. Postmortem brains from AD patients with a life-time history of depression showed a markedly higher plaque density and tangle formation in the hippocampi than AD patients who had not been chronically depressed. Those with AD + depression showed a more rapid cognitive decline than those with depression alone. Hippocampal shrinking more pronounced in the AD+depression group. Possible link: in depression, reduction in serotonin prevents the conversion of amyloidogenic amyloid precursor protein to the soluble, non-amyloidgenic form

Importance of early treatment: impact on neuroprogression MDD vulnerability (e.g. genetics, cell damage) Psychosocial and physical stressors Neuroprogression é Vulnerability for further episodes and treatment resistance Major depressive episode Inflammation Damage to cellular components Induction of apoptosis Inhibited neuronal growth and survival Oxidative and nitrosative stress Epigenetic changes Mitochondrial dysfunction Neurotrophic disturbance Cognitive and functional decline and é structural abnormalities HPA axis dysregulation Moylan et al 2012

Neurodegeneration in depression-evidence. Reduced volume of gray matter in hippocampus ( Sheline et al. Am.J.Psychiat.2003) Decreased hippocampal neuropil (Stockmeier et al. Biol. Psychiat.2003) Loss of prefrontal cortical astroglia and neurons (Rajkowska et al. Biol. Psychiat.1999). Reduced amygdala volume. 16

How do endogenous neurotoxins contribute to neurodegeneration? 1.Inflammatory cytokines increase the activity of the tryptophan-kynurenine pathway via indoleamine dioxygenase. This also results in a reduction in serotonin synthesis from tryptophan. 2.In depression, this results in the synthesis of the neurotoxic glutamate agonist quinolinic acid.

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)

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

Link between chronic depression in the elderly and dementia Chronic low grade inflammation Neurotoxins from TRP-KYN pathway Hypercortisolaemia Chronic depression Decreased neuroprotection (-) BDNF Increased neuronal apoptosis/ decreased neurogenesis Oxidative stress Metabolic syndrome? Accelerated ageing Dementia TRP-KYN, tryptophan-kynurenine

Are anti-inflammatory drugs potential antidepressants?

Can an aspirin a day keep Alzheimer’s away? Rotterdam epidemiological study of ageing(2001): 7000 subjects studied and showed that chronic use (> 2years) of NSAID’s was associated with a significant reduction in Alzheimer’s; 4 other studies have shown similar results. Possible mechansms: cyclooxygenase (COX) and peroxisome proliferative activated receptor gamma (PPARg) control inflammatory genes. COX inhibition reduces synthesis of beta amyloid (Ab) by inhibiting gamma secretase (amyloidogenic), increasing alpha secretase (non amyloidogenic) and decreasing alpha-1 chymotrypsin (converts amyloid pecursor to Ab). 22

Are NSAID’s potential antidepressants? The elevation of proinflammatory cytokines in the serum, brain and CSF of depressed patients suggests that selective COX 2 inhibitors (celecoxib) or non-selective inhibitors (aspirin) might have antidepressant properties. These drugs have been studied in retrospective cohort studies (5),randomised controlled trials (4) and case controlled studies (1). Results variable! Positive effects-4; No effect-3; Detrimental effect-3 [possibly due to neuronal damage caused by chronic inhibition of COX2].

Future directions in inflammation research in the search for novel antidepressants as immune regulators?

Non-monoamine directed anti-inflammatory antidepressants. Adenosine, A2, agonists. PDE 4 inhibitors [eg.rolipram]. Beta-2 adrenoceptor agonists [salbutamol] NF-kB inhibitors [aspirin type]. Glucocorticoid agonists/ antagonists [mifepristone]. Indoleamine dioxygenase (IDO) inhibitors Antagonists of kynurenine-quinolinic acid pathway [eg.6-chlorotryptophan].

MINOCYCLINE as a potentialanti-inflammatory antidepressant. Experimental and clinical evidence, the tetracycline antibiotic minocycline which has anti-inflammatory, anti-oxidant, anti-apoptotic properties and modulates glutamate and monoamine function, has potential antidepressant effects.

CONCLUSION: Linking inflammation and depression with dementia!

Main interconnections between inflammation, oxidative stress and endogenous neurotoxins that contribute to neurodegenerative changes in depression. Stress, genes and epigenetic trauma DEPRESSION Macrophage/microglia activation TRP HPA AXIS INFLAMMATION IDO KYN HYPERCORTISOLAEMIA n-3 fatty acids OXIDATIVE STRESS (-) Neurotrophic factors metabolites 30HKYN [hydroxynonenol etc.] QA NEURODEGENERATIVE CHANGES

IS THIS THE END OF A BEAUTIFUL HYPOTHESIS? The great tragedy of science: the slaying of a beautiful hypothesis by an ugly fact! Thomas Huxley (1825-1895) 29

Sickness behaviour and depression :two separate phases or a continuum-1.? Sickness behaviour due to infection, injury etc. is protective and associated with lethargy, social isolation, anorexia, energy conservation, altered sleep pattern. TNF alpha and IL-6 contribute to these symptoms that are not primarily reduced by antidepressants. Depression defined by mood state, changes in cognitive function, feelings of guilt, suicidal thoughts etc. These symptoms usually respond to antidepressant treatment and are associated with an increase in oxidative stress, the neurodegenerative arm of the tryptophan- kynurenine pathway etc.

Sickness behaviour, inflammation and depression-2. Thus fatigue, anergia, increased irritability etc., but not guilt or suicidal thoughts, associated with sickness behaviour that can occur in medical (eg. CHD) and psychiatric disorders and is associated with increased inflammatory markers (IL-6,CRP,IL-1ra) but probably not with depression [Steptoe et al.Psychol.Med.33,667,2003;Jansky et al.Brain Behav. Immun.19,555,2005].

Is Depression a chronic form of Sickness Behaviour ?. When sickness behaviour becomes chronic due to: Genetic, epigenetic factors +adverse environmental risk factors. Chronic low grade inflammation. Activation of endogenous neurotoxins. Increased oxidative and nitrosative stress. Defects on central monoamine transmission. Increased neuronal apoptosis etc. etc.