Pathophysiology of depression-the importance of inflammation! Montevideo lecture, 2018.

What happens to the brain in depression and how can antidepressants help? 2

What causes depression? A primary deficit in monoamine function. A primary deficit in excitatory amino acid function. Decrease in neurotrophin synthesis; impaired neuronal plasticity. A change in the neuroglia/oligodendroglia support for the neuronal networks that cause neuronal dysfunction. Impaired capacity of the brain to recycle neurotoxins caused by chronic inflammation. Any combination or none of these !! 3 3

What happens to the brain in depression? The importance of brain plasticity! The following structural changes in the brain occur: 1] Decreased clustering of neurons; reduced neuron size. 2] Reduced density of glial cells, particularly astrocytes. 3] Decreased cortical thickness and size of neurons in pyrimidal cells in prefrontal cortex, anterior cingulate cortex and hippocampus. 4] Reduced density of dendritic spines and branching in prefrontal cortex and hippocampus. 4

Damaged neuronal networks in depression! Abnormal neuronal networks in cortical-limbic regions due to genetic, developmental factors and stress. Structural changes in discrete brain regions [hippocampus, frontal cortex] associated with endocrine and immune induced apoptosis. Current antidepressants enhance neurotrophin synthesis {BDNF etc} but alone do not produce stable changes in neuronal plasticity. Antidepressants do permit activity-dependent environmental signals to “retrain” the aberrant networks thereby optimising antidepressant response. Thus antidepressants+ psychotherapies, social contact, exercise etc. essential for optimal treatment of depression. Castren et al. CNS Drugs 24,1172,2010. 5 5

Dendritic atrophy in depression Atrophic “depressed” “Treated” 6 6 6

Endocrine changes in depression-1. Disturbances of the HPA axis lead to:- Hypercortisolaemia and dexamethasone non-suppression (DST test). Impaired DST test predicts recurrence and chronicity of depression. Impaired TRH test common in depression. Levels of sex hormones (loss of libido) and growth hormone (tissue repair decreased) lower in chronic depression. 7 7 7

New Antidepressant Targets Depression and Cortisol Cognitive changes and ¯Hippocampal volume Steroid toxicity Growth factors Glucocorticoid antagonists X Hypothalamus ­Cortisol stress Defective in depression CRF AVP CRF antagonists V3 antagonists Pituitary ACTH 8 8

WHERE DOES INFLAMMATION COME INTO THE EXPLANATION ? Why is the brain “inflamed”?

Central nervous system Antigen Presenting cell CYTOKINE NETWORK Peripheral immune system Central nervous system Antigen Presenting cell ( Macrophage ) Astrocyte IFN- TNF- IL-1 IL-6 IFN- IL-6 NK cells B-lymphocyte IL-1 IL-6 TNF- T-lymphocyte GM-CSF G-CSF TNF- IL-1 IL-2 Plasma cell T-helper 1 T-helper 2 Antibody Microglia IL-2 IFN- IL-4 IL-10 IL-6 10

Clinical 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 TNF-α, IFN-γ , 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 1997; 6Vaccarino et al 2008 7Calabrese et al 1986 IFN, interferon; MCP-1, monocyte chemotactic protein 1 TGF, transforming growth factor 11 11

Depression is characterised by aberrations in related pathways Inflammatory pathways Neuroprogressive pathways Immune pathways IL-1, IL-6, TNF-α interferon-γ neopterin Depression Damage to mitochondria and mitochondrial DNA Oxidative and nitrosative stress Lower levels of key antioxidants lipid peroxidation DNA, protein and mitochondrial damage reduced ATP production coenzyme Q10, zinc, vitamin E, glutathione IL, interleukin; TNF, tumour necrosis factor Maes et al 2012 12 12 12

Immune changes in major depression. Macrophage theory of Smith [1991]suggested that the major symptoms of depression [ anhedonia, sleep disturbance, anorexia, cognitive dysfunction, loss of libido etc.] were the result of chronic low grade inflammation. Evidence: increase in pro-inflammatory cytokines [IL-1 and 6,interferon gamma, tumour necrosis factor alpha etc] and a reduction in anti-inflammatory cytokines [ IL-4,IL-10,IL-13 etc] in depressed patients. : pro-inflammatory cytokines, such as interferon alpha, used therapeutically [ eg.in hepatitis and MS] cause severe depressive symptoms in about 40% of otherwise non-depressed patients.

Immune changes in depression-1. Depression as an inflammatory disorder:- Over 40 different immune markers ( most of them inflammatory markers!) related to depression (Zorrilla et al,2000) Increased peripheral and central pro-inflammatory cytokines associated with depression (IL-1, IL-6, TNF,IFN). Rise in acute phase proteins. Epidemiological studies show increase in inflammatory diseases [ such as rheumatoid arthritis, psoriasis and autoimmune diseases] in patients with depression.

The macrophage theory of depression-2. Depression-like symptoms are initiated by LPS, bacterial and viral infections. These include: anhedonia, anorexia, lethargy, sleep disturbance, loss of libido, memory deficit, cognitive dysfunction). Effective antidepressant treatment reduces these changes. 15

16

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. 17

Are current antidepressants anti-inflammatory agents? Antidepressants enhance noradrenergic and serotonergic function that attenuate inflammation. Reduce pro-inflammatory cytokines [interferon gamma, tumour necrosis factor alpha, interleukin-6 etc] and increase anti-inflammatory cytokines [IL-4,IL-10,IL-13]. Increase release of IL-1 receptor antagonist. Reduce Nuclear Factor kappa-beta (NF-kB), thereby reducing inflammatory signals. Sensitize glucocorticoid receptors to inhibitory feed-back thereby reducing hypercortisolaemia in depressed patients.

Inflammatory mechanisms in neurodegeneration. The increase in IDO lies at the interface between chronic inflammatory disease and depression [Dantzer et al. Nat.Rev.Neurosci.9,46-56,2008]. Increase in IDO activity positively correlated with severity of depression [Capuron et al. Mol.Psychiat.7,468-473,2002]. “Knock-out” mice lacking IDO do not show depression -like behaviour following an immune challenge with BCG vaccine..

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)

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

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

Conclusion. Currently available antidepressants [NRI’s, SSRI’s, SNRI’s, RIMA’s etc.] modulate the inflammatory cascade indirectly, possibly by increasing intracellular cAMP. A new generation of antidepressants may act more directly on the inflammatory cascade (for example, by inhibiting NF-kB).

Genetic factors Childhood trauma Depression Hypercortisolaemia Pro-inflammatory cytokines Induction of IDO Increase in Quinolinic acid in microglia Neuronal apoptosis Reduced neuronal repair Astrocyte apoptosis [reduced bcl-2 and BDNF] Impaired neural function DEMENTIA STRESS 25

Thank you for listening! ANY QUESTIONS?

Changes in neuroprotective ratio before and after treatment Depressed Treated Controls (N=58) (N=40) (N=189) Neuroprotective ratio (KA:KYN) 14.08* 14.01* 19.36 HDRS score 27.2 7.6 *** Conclusion: Despite effective treatment and the reduction in inflammatory cytokines, the neurodegenerative changes remain! A-M.Myint et al.J.Affect.Dis.2006.

Neuroprotective ratio in first episode depressed patients. Patients on admission: 12.43 (3.01) Patients on discharge: 15.24 (4.98)* *P<0.044 Controls 19.36 (5.97) 28

Kynurenine pathway (depressed patients) II (Myint , Schwarz, Riedel, unpublished new data)