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Pain and Depression: Pathophysiological aspect Zoran Grubič Institute of Pathophysiology Medical Faculty, University of Ljubljana, TOPICS Stress and depression neuroendocrine dysregulation excitotoxicity the role of BDNF (Brain derived neurothrophic factor) Depression and pain BDNF (Brain derived neurothrophic factor) Cytokine signalling Neuron – glia interactions 1 Progression of Depression –“Kindling” Phenomenon: Adverse Effects of Each Successive Episode Risk (odds ratio) 10 Likelihood of recent life stress precipitating depression Risk (odds ratio) of depression onset per month 8 Female participants only N=2,395 6 4 2 0 0 1 2 3 4 5 6 7–8 9–11 Number of previous depressive episodes Kendler KS, et al. Am J Psychiatry. 2000;157:1243–1251. Copyright © 2000 American Psychiatric Association. All rights reserved. Key brain areas involved in regulation of mood (A) Ventromedial prefrontal cortex (VMPFC)1 B4 Modulates pain and aggression, and sexual and eating behaviors Regulates autonomic and neuroendocrine response A4 (B) Lateral orbital prefrontal cortex (LOPFC)2 Activity is increased in depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and panic disorder Corrects and inhibits maladaptive, perseverative, and emotional responses (C) Dorsolateral prefrontal cortex (DLPFC)3 C4 Cognitive control, solving complex tasks, and manipulation of information in working memory Hypoactivity of DLPFC in depression has been associated with neuropsychological manifestation of depression 1. Öngür D, Price JL. Cereb Cortex. 2000;10(3):206-219. 2. Drevets WC. Annu Rev Med. 1998;49:341-361. 3. MacDonald AW III, et al. Science. 2000;288(5472):1835-1838. 4. Davidson RJ, et al. Annu Rev Psychol. 2002;53:545-574. Reprinted with permission from the Annual Review of Psychology. Key brain areas involved in regulation of mood (cont.) (A) Amygdala: regulates cortical arousal and neuroendocrine response to surprising and ambiguous stimuli1 Role in emotional learning and memory Activation of amygdala correlates with degree of depression2 Implicated in tendency to ruminate on negative memories2 (B) Hippocampus: has a role in episodic, A6 contextual learning and memory3,4 Rich in corticosteroid Regulatory feedback to hypothalamic-pituitaryadrenal axis Hippocampal dysfunction may be responsible for inappropriate emotional responses receptors5 1.Davidson RJ. Psychophysiology. 2003;40(5):655-665. 2.Drevets WC. Curr Opin Neurobiol. 2001;11(2):240-249. 3.Squire LR, Knowlton BJ. In: Gazzaniga MS, ed. The New Cognitive Neurosciences; 2000:765-779. B6 4. Fanselow MS. Behav Brain Res. 2000;110(1-2):73-81. 5. Reul JM, De Kloet ER. J Steroid Biochem. 1986;24(1):269-272. 6. Davidson RJ, et al. Annu Rev Psychol. 2002;53:545-574. Reprinted with permission from the Annual Review of Psychology. Neuronal circuits connecting the areas involved in depression Brain atrophy in depression? Atrophy of the Hippocampus in Depression1 Normal2 1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118. 2. Images courtesy of J Douglas Bremner, MD, Yale University. Depression2 Correlation between hippocampal volume and duration of untreated depression* Total Hippocampal Volume (mm3) 38 Female Outpatients With Recurrent Depression in Remission 6000 R2=.28 *P=.0006 N=38 5500 5000 4500 4000 3500 3000 0 1000 2000 3000 Days of Untreated Depression *Significant inverse relationship between total hippocampal volume and the length of time depression went untreated. Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518. 4000 Hippocampal dysfunction contributes to neuroendocrine dysregulation Hypothalamus Hippocampus + CRF Amygdala Pituitary ACTH Glucocorticoids Dexamethasone Nestler EJ, et al. Neuron. 2002;34(1):13-25. Hippocampus Adrenal cortex Cortisol levels in patients with depression predicted executive function and memory N=26 Patients with recurrent MDD, Mean HAM-D=21.4 Wisconsin Card Sorting Test (WCST) was used to evaluate executive function Saliva Cortisol (nmol/L) 60 50 40 30 20 10 0 0 1 2 3 4 5 6 Failure to Maintain Set Score Worse Performance Egeland J, et al. Acta Psychiatr Scand. 2005;112(6):434-441. 7 Excitotoxicity: excessive glutamatergic signalling Communications in the CNS Synaptic transmission - neurotransmitters Growth factors Activation and inactivation of neurons Excitotoxicity: excessive glutamatergic signalling Inhibitory neurotransmitter - GABA Serotonin (5-HT) and norepinephrine (NE) pathways Modulate balance between excitatory and inhibitory inputs in key brain areas Limbic System Prefrontal Cortex Amygdala Raphe Nuclei (5-HT source)1 Hippocampus Locus Coeruleus (NE source)1 Descending 5-HT pathways1 Descending NE pathways1 Based on: Cooper JR, et al. The Biochemical Basis of Neuropharmacology. 8th ed. New York: Oxford University Press; 2003. Communications in the CNS Synaptic transmission - neurotransmitters Growth factors Sympathetic ganglion without NGF 10 ng/ml NGF Neurotrophins – mode of action Neurotrophins – intracellular signaling Neurotrophins NGF (nerve growth factor) BDNF NT-3 (brain-derived neurotrophic factor – nevrotrofični dejavnik možganskega izvora) (neurotrophin-3) NT-4/5 (neurotrophins-4/5) The role of antidepressants and neurotrophic factors in the network hypothesis of depression: Rerouting aberrant patterns Nestler EJ, et al. Neuron. 2002;34(1):13-25. Reprinted with permission from Elsevier. Beyond synapse: Serotonin and norepinephrine aid BDNF synthesis (preclinical evidence) 1. Manji HK, et al. Biol Psychiatry. 2003;53(8):707-742. 2. Tsankova NM, et al. Nat Neurosci. 2006;9:519-525. Recurrent MDD and Suicidal Attempts May Be Associated with Lower BDNF Levels BDNF (pg/mL) 1800 1600 1400 1200 1000 800 600 400 Patients with MDD with or without SA 2000 *P<.001 1800 * * *P<.001 1600 BDNF (pg/mL) 2000 Patients with MDD with first episode or with recurrent episode 1400 1200 * 1000 800 600 400 200 200 100 100 First Recurrent Normal Without SA With SA Normal episode episode control control Plasma BDNF levels were measured in 77 patients with MDD and 95 normal controls BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder; SA=suicide attempt. Lee BH. J Affect Disord. 2007;101:239–244. Copyright © 2007, by permission from Elsevier. Monoamines Regulate BDNF Synthesis in Cultured Astrocytes in Rodents Astrocyte response to neurotransmitters† Increase in BDNF level (multiple of baseline) 6 5 4 4.7 Baseline Baseline NE1mM 1μM NE 5-HT1mM 1μM HT-5 DA 150μM DA 4 3 2 2.3 2.2 1.7 1 1 1 1.4 0 Cortical astrocytes Cerebellar astrocytes NE elevated BDNF levels 4-fold or more in cortical and cerebellum astrocytes; 5-HT and DA elevated levels roughly 2-fold †Cultured astrocytes incubated for 4 hours with monoamine neurotransmitters; 5-HT=serotonin; BDNF=brain-derived neurotrophic factor; DA=dopamine; NE=norepinephrine. Juric DM, et al. Brain Research. 2006;1108:54-62. Relationship Between Change in BDNF Levels, Duration of Treatment and Treatment Response in MDD Patients 2.0- BDNF changes versus days of improvement r = 0.65; P=.02 1.51.00.50- -0.50 2 4 6 Change in BDNF – effect size Change in BDNF – effect size BDNF changes versus depression improvement 2.0- r = 0.52; P=.01 1.5- 1.00.50-0.5- Cohen’s d for depression 0 20 40 60 Period of treatment (days) 80 Meta-regression based on 10 case control and 13 clinical trial studies assessing 1,504 subjects Study analyzed (weighted by inverse variance) BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder. Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11:1169–1180. Copyright © 2008 Cambridge University Press. Successful antidepressant treatment can be associated with BDNF increase 35 *P<.01 vs control or treated Plasma BDNF (ng/mL) 30 25 20 * 15 10 5 (n=50) (n=16) (n=17) 0 Control DepressedDepressed-Treated Treatment Naive Mixed group of antidepressants used for treatment. HAM-D17=27.810.2 and 18.811.4 for untreated and treated groups respectively. Shimizu E, et al. Biol Psychiatry. 2003;54(1):70-75. Depression: Multiple Core and Associated Symptoms Emotional symptoms Feelings of guilt Suicidal Lack of interest Sadness Associated symptoms Physical symptoms Lack of energy Decreased concentration Change in appetite Brooding Obsessive rumination Irritability Excessive worry over physical health Change in sleep Pain Change in psychomotor skills Tearfulness American Psychiatric Association (APA). DSM-IV-TR; 2000:352,356. Anxiety or phobias What is the Prevalence of Associated Painful Symptoms in Patients with Depression? Depressed patients Studies addressed both depression and painful symptoms, including: Headaches MDD without painful symptoms 35% MDD with painful symptoms 65% Back pain Neck pain Extremity/joint pain Chest pain Pelvic pain Mean prevalence data from 14 studies focusing on painful symptoms in patients with depression Abdominal pain General pain Prevalence was not influenced by psychiatric versus primary care settings MDD=major depressive disorder. Bair MJ, et al. Arch Intern Med. 2003;163:2433–2445. % Patients (depressed at baseline) achieving endpoint recovery Painful Symptoms Decrease the Chance of Recovery in Depressed Patients 3-year longitudinal study of adults aged 55–85 80 70 60 50 40 30 20 10 0 47% 9% N=102 MDD only N=119 MDD and painful symptoms The close association between painful symptoms and depression emphasizes the need for progressive treatment strategies MDD=major depressive disorder. Geerlings SW, et al. Soc Psychiatry Psychiatr Epidemiol. 2002;37:23–30. Patients achieving remission (9-Week studies) (%) Improving Painful Symptoms in MDD Increases Chances of Remission 60 100 *P<.001 2 pooled studies 50 * 40 36% 30 18% 20 10 n=77 0 50% improvement in painful physical symptoms n=49 50% improvement in painful physical symptoms Remission=HAMD-17 total score 7 Painful physical symptom improvement measured by the Visual Analog Scale (VAS) overall pain score Fava M, et al. J Clin Psychiatry. 2004;65:521–530. Multiple Types of Pain1 The Good Noxious A. Nociceptive pain peripheral stimuli Brain B. Inflammatory pain Inflammation Brain The Bad C. Neuropathic pain Brain Peripheral nerve damage Multiple mechanisms D. Non-inflammatory/ non-neuropathic pain Brain No known tissue or nerve damage Patients may experience multiple pain states simultaneously2 Abnormal central processing 1. Figures adapted from: Woolf CJ. Ann Intern Med. 2004;140:441–451. Copyright © 2004, by permission from American College of Physicians. 2. Chong MS, Bajwa ZH. J Pain Symptom Manage. 2003;25:S4–S11. Questions Which are the brain areas that may play a role in both MDD and Pain ? Are there any characterisitc changes in these common areas in MDD patients with pain symptoms? Which pathophysiolgical mechanisms can explain these changes at the cellular and molecular level? Questions Which are the brain areas that may play a role in both MDD and Pain ? Are there any characterisitc changes in these common areas in MDD patients with pain symptoms? Which pathophysiolgical mechanisms can explain these changes at the cellular and molecular level? Some Key Areas of the Brain that May Play a Role in Both MDD and Pain Prefrontal cortex Insular cortex Anterior cingulate cortex Hippocampus Amygdala Brain image courtesy of ATI. Questions Which are brain areas that may play a role in both MDD and Pain ? Are there any characterisitc changes in these common areas in MDD patients with pain symptoms? Which pathophysiolgical mechanisms can explain these changes at the cellular and molecular level? Kako razložiti v okviru teh mehanizmov delovanje antidepresivov pri obnovi nevrobiološkega stanja ? Key Replicated Brain Imaging Findings Most brain imaging studies have shown abnormalities in these key areas: amygdala, hippocampus, prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex1–3 Many studies have found prefrontal cortical hypoactivity4 and limbic hyperactivity4 More recent studies have focused on network relationships (limbic, prefrontal) and dynamic changes over time2,4–6 There is great heterogeneity among patients; scanning is not predictive or individually diagnostic 1. Sheline YI. Biol Psychiatry. 2000;48:791–800. 2. Sheline YI. Biol Psychiatry. 2003;54:338–352. 3. Nestler EJ, et al. Neuron. 2002;34:13–25. 4. Mayberg HS. Br Med Bull. 2003;65:193–207. 5. Fales CL, et al. Biol Psychiatry. 2008;63:377–384. 6. Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209. Patients With Pain May Experience Gray Matter Atrophy N=26 Areas in red indicate a composite of regions where gray matter density was reduced in chronic back pain (CBP) patients compared with controls A slice of the right anterior thalamus at the peak of decreased thalamic gray matter Patients with CBP had 5–11% less whole-brain gray matter, equivalent to 10–20 years of normal aging Images copyright 2006 by the Society for Neuroscience. Apkarian AV, et al. J Neurosci. 2004;24:10410–10415. Copyright © 2004 Society for Neuroscience. Mood Alters Pain-Evoked Activity in Limbic structures AI=anterior insular region; dACC=dorsal anterior cingulate cortex; DLPFC=dorsolateral prefrontal cortex; PAG=periaqueductal gray; R=right; rACC=right anterior cingulate cortex. Strigo IA, et al. Arch Gen Psychiatry. 2008;65:1275–1284. Copyright © 2008 American Medical Association. All rights reserved. The Amygdala as a Primary Modulator: Emotions and Stress Effects Amygdala Response to Pain (Hypothetical Model) Amygdala Negative Emotion Chronic stress, depression, anxiety Positive Emotion music, pleasant odors, etc. + – Increases amygdala activity Inhibits amygdala activity Pain Modified from: Neugebauer V, et al. Neuroscientist. 2004;10:221–234. Brain image courtesy of ATI. Questions Which are brain areas that may play a role in both MDD and Pain ? Are there any characterisitc changes in these areas in MDD patients with pain symptoms? Which pathophysiolgical mechanisms can explain these changes at the cellular and molecular level? Pathophysiolgical mechanisms to explain changes in MDD and Pain at the cellular and molecular level? BDNF (Brain derived neurothrophic factor) Cytokine signalling Neuron – glia interactions Pathophysiolgical mechanisms to explain changes in MDD and Pain at the cellular and molecular level? BDNF (Brain derived neurothrophic factor) Cytokine signalling Neuron – glia interactions Stress and Pain Lower BDNF in Rats BDNF levels (Pg BDNF mRNA/ng -actin mRNA) Changes in hippocampal BDNF synthesis Stress Pain *P<.05 compared with control 8 6 6 4 4 * * 2 Control n=12 n=12 Acute Chronic stress stress (45 minutes) (10 days) * * * n=7 n=7 n=12 * 2 n=12 0 *P<.05 compared with control 8 n=12 n=12 0 Control 2:45 h 24 h 10-day CFA (chronic) Formalin (acute) BDNF=brain-derived neurotrophic factor; CFA=complete Freund’s adjuvant. Duric V, et al. Neuroscience. 2005;133:999–1006. Copyright © 2005, by permission from Elsevier. 6h Pathophysiolgical mechanisms to explain changes in MDD and Pain at the cellular and molecular level? BDNF (Brain derived neurothrophic factor) Cytokine signalling Neuron – glia interactions Beyond the Brain: Similar Dysregulation of HPA Axis and Cytokines Stress and Depression1,2 Pain3 red=inhibitory pathways to hypothalamus–pituitary–adrenal (HPA) axis; green=stimulatory pathways to HPA axis Adapted from: 1. Raison CL, et al. Trends in Immunol. 2006;27:24–23. 2. Nestler EJ, et al. Neuron. 2002;34:13–25. 3. Blackburn-Munro G, et al. J Neuroendocrinol. 2001;13:1009–1023. Copyright © 2001, by permission of Blackwell Publishing Ltd. 4. Maletic V, et al. Int J Clin Pract. 2007;61:2030–2040. Copyright © 2007, by permission of Blackwell Publishing Ltd. Psychiatric Symptoms Commonly Associated with Inflammatory Cytokines1–3 Fatigue Aches and pains Depressed mood and anhedonia Difficulty concentrating Anxiety and irritability Sleep, appetite, and libido disturbances 1. Raison CL, et al. CNS Drugs. 2005;19:105–123. 2. Dantzer R, et al. Nat Rev Neurosci. 2008;9:46–56. 3. Kim YK, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044–1053. Cytokine signalling Inflammatory Cytokines May Interfere With BDNF Signaling 1.2 *P=.05 Relative levels 1.0 0.8 Primary culture of rat cerebral cortical neurons * 0.6 * 0.4 0.2 0 BDNF BDNF BDNF IL-1 (5 ng/mL) IL-1 (20 ng/mL) BDNF=brain-derived neurotrophic factor; IL=interleukin. Tong L. Neurobiol Aging. 2008;29:1380–1393. Copyright © 2008, by permission from Elsevier. Pathophysiolgical mechanisms to explain changes in MDD and Pain at the cellular and molecular level? BDNF (Brain derived neurothrophic factor) Cytokine signalling Neuron – glia interactions Altered Neuron–Glia Communication May Contribute to MDD Maletic V, Raison C. 2008, Frontiers in Bioscience, in press. Image used with permission from V. Maletic. Glial Changes in the Prefrontal Cortex of a Depressed Patient Glial immunoreactivity in the prefrontal cortex1 Control (27 years old) MDD (32 years old) Reduction in glial cell density and number is the most prominent feature of cell pathology in depression1–4 Images courtesy of Bentham Science Publishers. 1. Rajkowska G, et al. CNS Neurol Disord Drug Targets. 2007;6:219–233. Copyright © 2007 Bentham Science Publishing Ltd. 2. Rajkowska G, et al. Biol Psychiatry. 1999;45:1085–1098. 3. Ongür D, et al. Proc Natl Acad Sci USA. 1998;95:13290– 13295. 4. Si X, et al. Neuropsychopharmacol. 2004;29:2088–2096. Conclusions 2 Depression is reflected in the structural and functional changes in the brain. Morphological changes have been observed in the areas which are responsible for the impaired functions of depressed patients and which can be caused by stress (neuroendocrine dysfunction and excitotoxicity). Depression can be improved by modifying neurochemical signalling in the affected areas. 5-HT in NA are responsible for the balance between excitatory 1 (glutamatergic) and inhibitory (GABAergic) activities in the prefontal cortex and limbic system Activation of NA and/or 5-HT pathways increases BDNF level and in this way improves structural damage in depressed patients. 3 N effect Conclusions Pain is a serious problem of depressed patients and must be approached as a part of the treatment. Emotional symptoms and pain might have a common pathophysiological background - brain areas involved in both emotional reactions and pain processing are damaged. Structural changes in these areas are likely to be a consequence of insufficient neurotrophic effects (BDNF) due to neuroendocrine impairment, proinflammatory factors and some other factors. There is accumulating evidence that the actions of antidepressives acting at the level of NA and 5-HT transmitter systems can be explained in the terms of improved and restored neuroprotection, neuroplasticity and neurogenesis. Hippokampus – Šempeter v Savinjski dolini NEVROBIOLOGIJA DEPRESIJE prof. dr. Zoran Grubič, dr. med., Medicinska fakulteta Ljubljana, Oddelek za patofiziologijo Antidepressants Modulate Complex, Interconnected Signaling Cascades 5-HT NE synaptogenesis PKA neuroplasticity cell survival CaMK BDNF CREB neurogenesis 5-HT=serotonin; BDNF=brain-derived neurotrophic factor; CaMK=calcium-calmodulin-dependent kinase; CREB=cAMP response element binding protein; NE=norepinephrine; PKA=protein kinase A. Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge UP: New York, NY; 2008. Copyright permission granted by Neuroscience Education Institute. Serotonin and Norepinephrine: Modulation of Mood and Pain Perception1–3 Limbic System Raphe nuclei (5-HT source) Prefrontal cortex Locus coeruleus (NE source) Amygdala Descending 5-HT pathways Hippocampus Descending NE pathways Ascending pain pathways 5-HT=serotonin; NE=norepinephrine. Adapted from: 1. Bymaster FP, et al. Curr Pharm Des. 2005;11:1475–1493. 2. Fields H. Nat Rev Neurosci. 2004;5:565–575. 3. Fields HL, et al. Annu Rev Neurosci. 1991;14:219–245. Synaptic transmission in the CNS Common Symptoms of Neuropathic Pain • burning • numbness • shooting pain • pins and needles • electric shock-like pain • sensitivity to touch or cold • tingling • a crushing sensation • a deep, aching pain • swelling along with temperature changes • skin discoloration Key Replicated Brain Imaging Findings Most brain imaging studies have shown abnormalities in these key areas: amygdala, hippocampus, prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex1–3 Many studies have found prefrontal cortical hypoactivity at baseline improved after treatment4 Many studies have found limbic hyperactivity (especially cingulate) at baseline normalized after treatment4 More recent studies have focused on network relationships (limbic, prefrontal) and dynamic changes over time2,4–6 There is great heterogeneity among patients; scanning is not predictive or individually diagnostic 1. Sheline YI. Biol Psychiatry. 2000;48:791–800. 2. Sheline YI. Biol Psychiatry. 2003;54:338–352. 3. Nestler EJ, et al. Neuron. 2002;34:13–25. 4. Mayberg HS. Br Med Bull. 2003;65:193–207. 5. Fales CL, et al. Biol Psychiatry. 2008;63:377–384. 6. Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209. Antidepressant Use can be Associated with Normalization in Brain Activity Areas of increased activation in patients with MDD after antidepressant treatment (red) and decreased activation (blue) compared with baseline. Increased activity: DLPFC, dACC, posterior cingulate Decreased activity: sgACC, VMPFC, amygdala, hippocampus, insula ACC=anterior cingulate cortex; DLPFC=dorso-lateral prefrontal cortex; VMPFC=ventromedial prefrontal cortex. Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695. Copyright © 2008, by permission of John Wiley & Sons, Inc. Patients with Chronic Back Pain Gray matter density is reduced in patients with CLBP compared with controls and degree of reduction is related to duration of symptoms CLBP=chronic low back pain; nuCBP=neuropathic chronic back pain. Apkarian AV, et al. J Neurosci. 2004;24:10410–10415. Copyright © 2004 Society for Neuroscience. Neuroplasticity in Peripheral Pain Transmission: Peripheral Sensitization Voltage-gated sodium channels Several neurochemicals may be released following tissue injury (inflammatory soup), leading to peripheral sensitization Na+ PKA Erk1/2 Cytokine receptor IL-1 IL-6 TrkA B1/2 MOR PKC TRPV1 EP COX-2 TNF Ca2+ NGF BK PGE2 AA IL-1 Tissue injury Mast cell Macrophage AA=arachidonic acid; BK=bradykinin; COX-2=cyclooxygenase-2; EP=prostaglandin E receptor; Erk1/2=extracellular signal-regulated kinases; IL=interleukin; MOR=m opioid receptor; NGF=nerve growth factor; PGE2=prostaglandin E2; PKC, PKA=protein kinases C, A; TNF-=tumor necrosis factorα; TrkA=neurotrophic tyrosine kinase A receptor; TRPV1=transient receptor potential vanilloid 1. Woolf CJ. Ann Intern Med. 2004;140:441–451. Copyright © 2004, by permission from American College of Physicians. Baron R. Nat Clin Pract Neurol. 2006;2:95–106. Inflammatory Cytokine Potentiation of Pain May be Mediated by Glia TNF IL-6 IL-1 IL-1 TNF Sciatic nerve Dorsal IL-6 Glia Pathogen Phagocytic immune cell Hyperalgesia Dorsal horn Dorsal horn Gray matter Ventral Ventral horn horn White matter Ventral IL=interleukin; TNF=tumor necrosis factor. Wieseler-Frank J, et al. Brain Behav Immun. 2005;19:104–111. Copyright © 2005, by permission from Elsevier. Major depressive disorder: The consequences MDD can have emotional, cognitive, behavioral, and physical manifestations1,2,4 MDD is associated with metabolic changes in the prefrontal cortex and limbic system2,3 Structural changes in the hippocampus and prefrontal cortex often accompany MDD1 Compromised neuroendocrine regulation in MDD can lead to widespread systemic consequences1,3 MDD may be associated with diminished neurotrophic support, resulting in impaired neuroplasticity, neurogenesis, and cellular resilience3 Cerebral areas affected by MDD have significant noradrenergic 3 and innervation 1. Sheline YI.serotonergic Biol Psychiatry. 2000;48(8):791-800. 2. Drevets WC. Annu Rev Med. 1998;49:341-361. 3. Manji HK, et al. Nat Med. 2001;7(5):541-547. 4. APA. DSM-IV-TR; 2000. 1968: First growth factor discovered (NGF) Rita Levi-Montalcini; Nobel prize 1986 Major depressive disorder may have systemic consequences 2. The adrenal gland releases excessive amounts of catecholamines and cortisol 3. Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and can contribute to ventricular arrhythmias ACTH 1. Hypothalamus stimulates the pituitary gland to release excessive ACTH, continuously driving the adrenal gland 4. Increase in catecholamines causes platelet activation; increase in cytokines and interleukins may also contribute to atherosclerosis and eventual hypertension 5. Cortisol antagonizes insulin and contributes to dyslipidemia, type 2 diabetes, and obesity; increases in cortisol also suppress the immune system Adapted from: Musselman DL, et al. Arch Gen Psychiatry. 1998;55(7):580-592.