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The Neurobiology of Depression (Dr Imran Waheed)


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A lecture delivered in the West Midlands by Dr Imran Waheed, Consultant Psychiatrist, on The Neurobiology of Depression. For further information visit

Published in: Health & Medicine
  • A presentation of really highest Quality. In Pain-Centers the term algogene Depression is often used, so I strongly subscribe for the relationship of pain and mood,especially most patients suffering from chronic pain decrease in pain Sensation when they are treated with antidepressents.
    Another Observation strengthens the Connection of cortisol, hippocampal shrinking and mood. A volumetric examination of elder men, wich paticipated im World War II, shomed loss of volume for those, who were for a Long period of time in direct combat with the enemy, a prolonged fearful experience with no possibility to Change it by oneself.(published by spritzer). Wouldn`t it be interesting to find a connection to the psychosis by corticoid application, sometimes seen. To me the cortisol receptor seems to be crucial in this process.
    Could you mail me that interesting ppt.
    With king regards
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  • Sirk, Please mail me the mail id is
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The Neurobiology of Depression (Dr Imran Waheed)

  2. 2. Presentation Outline Context Monoamine hypothesis HPA Axis HPT Axis Growth hormone Structural and functional changes The role of neurotrophic factors The relationship between pain and depression The role of antidepressants
  3. 3. Major Depressive Disorder may have Systemic ConsequencesAdapted from Musselman DL, et al. Arch Gen Psychiatry 1998;55(7):580-592.
  4. 4. Complex Biological Factors Neurotransmitter systems Hormonal axes Genetics Structural and functional changes in brain circuits Neurotrophic factors Complex intersection between neurotransmitters, hormones and regions of the brain controlling sleep, motivation, empathy and emotion, etc.
  5. 5. Monoamine Hypothesis Posits that depression is caused by reduced monoamine function in the brain Iproniazid and imipramine had antidepressant effect and later shown to enhance central 5-HT and NA transmission. Reserpine depletes monoamine stores and produces depressive symptoms. ADs increase monoamine transmission e.g. SSRIs inhibit reuptake, MAOIs inhibit degradation However, cause of depression is more complex than central reduced monoamine function MAOIs and SSRIs cause immediate increase in monoamines yet do not immediately alleviate symptoms
  6. 6. HPA Axis
  7. 7. HPA Axis HPA axis overactivity is one of the best replicated findings in the neurobiology of depression Fifty percent of depressed patients exhibit nonsuppression of cortisol secretion after administration of the dexamethasone ; appears that glucocorticoid receptors may become dysfunctional in depression. IV administration of exogenous CRF causes depressed patients to exhibit a blunted ACTH response compared with that in healthy subjects; likely to be due to downregulation of CRF receptors in the pituitary, secondary to persistent increased CRF secretion. Hypercortisolaemia is associated with neurotoxicity and reduced hippocampal neurogenesis.
  8. 8. HPA Axis in Depression
  9. 9. Lack of HPA Normalization May Predict Relapse in Remitted Patients with MDD (Dex/CRH Neuroendocrine Test)  38 remitted patients with MDD followed up for 12 months 250 Prolonged remission (N=20) Depressive relapse (N=12) Cortisol (nmol/L) 200 Control (N=24) 150 * 100 50 *P=.029 compared with control 0 2:45 3:00 3:30 3:45 4:00 4:15 4:30 Time (PM)Dex/CRH=dexamethasone/corticotropin-releasing hormone; MDD=major depressive disorder.Aubry JM, et al. J Psychiatr Res. 2007;41:290–294.
  10. 10. HPT Axis Blunting of the circadian rhythm of thyroid hormone secretion, with the absence of the normal nocturnal peak of thyroid-stimulating hormone (TSH) secretion. Some depressed patients demonstrate elevated CSF TRH concentrations. The hypersecretion of TRH may lead to downregulation of TRH receptors on thyrotropic cells of the anterior pituitary, which accounts for the widely documented blunted TSH response to exogenous TRH (this is somewhat diagnostically nonspecific because it is often observed in manic and alcoholic patients as well.)
  11. 11. Growth Hormone Growth hormone (GH) is secreted by the anterior pituitary and plays a pivotal role in enhancing somatic growth; its secretion is stress responsive. Depressed patients demonstrate a blunting of the diurnal rhythm of GH secretion, especially the nighttime peak. This blunting may be due to the interrupted sleep that accompanies depression. A blunted GH response to provocative stimuli, such as clonidine use, stress, and hypoglycemia, has also been noted in depressed patients.
  12. 12. Functional and Structural Changes Associated with MDD
  13. 13. Areas of the Brain Implicated in Depression Prefrontal cortex2 Insular cortex1 Anterior cingulate cortex3Hippocampus5 Nucleus accumbens4 Amygdala21. Kennedy SE, et al. Arch Gen Psychiatry. 2006;63:1199–1208. 2. Drevets WC. Curr Opin Neurobiol. 2001;11:240–249.3. Whittle S, et al. Neurosci Biobehav Rev. 2006;30:511–525. 4. Schlaepfer TE, et al. Neuropsychopharmacology.2008;33:368–377. 5. Gaughran F, et al. Brain Res Bull. 2006;70:221–227.
  14. 14. Decreased Activity in DLPFC and dACC in Patients with MDDAreas of increased activation in patients with MDD at rest (red) anddecreased activation (blue) compared with controlsIncreased activity: lateral orbital prefrontal cortex, ventromedial prefrontal cortex,amygdala, thalamus, caudateDecreased activity: dorsolateral prefrontal cortex (DLPFC), insula, pregenual and dorsalanterior cingulate cortex (dACC), superior temporal gyrusFitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.
  15. 15. Hippocampal Volume Decreases as Number of Days Depressed Increases 6000 Total Hippocampal Volume ( mm3) R2=0.28; p=.0006 5500 N=38 5000 4500 4000 3500 3000 2500 0 1000 2000 3000 4000 Days of Untreated DepressionSheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.
  16. 16. Brain Atrophy in Depression Atrophy of the Hippocampus in Depression Normal DepressionBremner JD, et al. Am J Psychiatry 2000;157(1):115-118.Reprinted with permission from JD Bremner.
  17. 17. Patients with MDD May Have Smaller Medial Orbitofrontal Cortices than Controls 800 *P=.02 vs comparison by ANOVA Orbitofrontal cortical (gyrus rectus) 700 Comparison subjects (N=20) 600 Major depression (N=15) volume (mm3) 500 MOFC 400 * 300 200 100 Image reprinted with permission from Elsevier 0  Patients with MDD had 32% smaller MOFC (VMPFC) than controlsANOVA=analysis of variance; MOFC=medial orbitofrontal cortices; VMPFC=ventromedial prefrontal cortex.Bremner JD, et al. Biol Psychiatry. 2002;51:273–279.
  18. 18. Decline in Gray Matter Volume in MDD Patients Compared to Healthy Controls 3-year prospective study comparing 38 patients with 30 healthy controls Significant decline in gray matter density was noted in hippocampus, amygdala, anterior cingulate cortex, and dorsomedial prefrontal cortex Threshold was set at P<.001Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165.
  19. 19. 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 diagnostic1. 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.
  20. 20. Neurotrophic factors Volumetric decreases in the hippocampus and other forebrain regions in depressed patients have supported hypothesis for depression involving decrements in neurotrophic factors. Main focus has been BDNF Support for the „BDNF hypothesis‟ has come from a literature showing that several forms of stress reduce BDNF-mediated signalling in the hippocampus, whereas chronic treatment with antidepressants increases BDNF-mediated signalling.
  21. 21. The Role of Brain-Derived Neurotrophic Factor Brain-derived neurotrophic factor (BDNF) and other neurotrophic factors are involved in cell health or growth as well as cell apoptosis (death) in an activity- dependent manner Neurotrophins such as BDNF may be critical for growth and function of the nervous system,1 as well as for learning and memory2 BDNF is expressed throughout the brain in neurons and glia3  Monoamine neurons such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), as well as γ-aminobutyric acid (GABA) and glutamate neurons  Monoamines may be involved in the regulation of the synthesis and release of BDNF Downregulation of neurotrophins may occur in depression,1-2 anxiety,4 and pain5 Treatment of MDD may restore BDNF function1,2,6-71. Castren E, et al. Curr Opin Pharmacol. 2006;6:1–4. 2. Duman RS, et al. Biol Psychiatry. 2006;59:1116–1127.3. Charney DS, et al. Sci STKE. 2004;225:1–10. 4. Chen B, et al. Science. 2006;314:140–143. 5. Duric V, et al. Neuroscience.2005;133:999–1006. 6. Ivy AS, et al. Pharmacol Biochem Behav. 2003;75:81–88. 7. Gervasoni N, et al.Neuropsychobiology. 2005;51:234–238.
  22. 22. Recurrent Depression and Suicidal Attempts May Be Associated with Lower BDNF Levels Patients with MDD with first Patients with MDD with episode or with recurrent episode or without SA 2000 2000 *P<.001 * *P<.001 1800 1800 * 1600 1600 1400 1400BDNF (pg/mL) BDNF (pg/mL) 1200 1200 * 1000 1000 800 800 600 600 400 400 200 200 100 100 Normal First Recurrent Normal Without SA With SA control episode episode 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.
  23. 23. Successful Antidepressant Treatment can be Associated With BDNF Increase 35 *P<.01 30 vs control or treated Plasma BDNF (ng/mL) 25 20 * 15 SD + 11.4 SD + 9.6 SD + 12.3 10 5 0 Control Depressed- Depressed-Treated Treatment Naïve (n=17) (n=50) (n=16)• Mixed group of antidepressants used for treatment.• HAM-D17=27.8 10.2 and 18.8 11.4 for untreated and treated groups respectively p=.024. Adapted from Fig 1; Shimizu E, et al. Biol Psychiatry 2003;54(1):70-75.
  24. 24. Depression and Pain
  25. 25. Physical Symptoms in Psychiatric Patients Psychiatric Healthy Symptom Patients % Subjects % Tiredness, lack of energy 85 40 Headache, head pains 64 48 Dizziness or faintness 60 14 Feeling of weakness in parts of body 57 23 Muscle pains, aches, rheumatism 53 27 Stomach pains 51 20 Chest pains 46 14Data from Kellner R, Sheffield BF. The one-week prevalence of symptoms in neurotic patients and normals. Am J Psychiatry 1973;130:102–105
  26. 26. Prevalence of Associated Painful Symptoms in Patients with Depression Depressed patients  Studies addressed both depression and painful symptoms, including:  Headaches MDD MDD with without painful  Back pain painful symptoms symptoms  Neck pain 65% 35%  Extremity/joint pain  Chest pain  Pelvic pain  Abdominal pain Mean prevalence data from 14 studies focusing on painful symptoms  General pain in patients with depression Prevalence was not influenced by psychiatric versus primary care settingsMDD=major depressive disorder.Bair MJ, et al. Arch Intern Med. 2003;163:2433–2445.
  27. 27. Some Key Areas of the Brain that May Play a Role in Both MDD and Pain Prefrontal cortexInsularcortex Anterior cingulate cortexHippocampus Amygdala
  28. 28. Depression & Pain: Similar Dysregulation Stress and Depression1,2 Pain3red=inhibitory pathways to hypothalamus–pituitary–adrenal (HPA) axis; green=stimulatory pathways to HPA axisAdapted from: 1. Raison, 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.
  29. 29. The Role of Antidepressants
  30. 30. Are Antidepressants Neuroprotective? Animal studies show that antidepressants can induce neurogenesis Out of 38 women with depression, those who had spent the least time on antidepressants had greater shrinkage of the hippocampus More evidence from human studies is needed
  31. 31. HPA Axis and Treatments Laboratory animal studies show that antidepressants and ECT alter glucocorticoid receptors, enhancing the binding of glucocorticoids to these receptors. Interestingly, this effect of antidepressants on glucocorticoid receptors takes 2 weeks, about the same duration of time needed for antidepressants to begin improving depressive symptoms. Persistent nonsuppression in the DST as well as persistent elevation of CSF CRF concentrations despite symptomatic improvement of depressive symptoms with treatment, is associated with risk for early relapse.
  32. 32. Antidepressant Use can be Associated with Normalization in Brain ActivityAreas of increased activation in patients with MDD after antidepressant treatment (red)and decreased activation (blue) compared with baseline.Increased activity: DLPFC, dACC, posterior cingulateDecreased activity: sgACC, VMPFC, amygdala, hippocampus, insulaACC=anterior cingulate cortex; DLPFC=dorso-lateral prefrontal cortex; VMPFC=ventromedial prefrontal cortex.Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.
  33. 33. Relationship Between Change in BDNF Levels, Duration of Treatment and Treatment Response in MDD Patients BDNF changes versus BDNF changes versus depression improvement days of improvementChange in BDNF – effect size Change in BDNF – effect size 2.0- r = 0.65; P=.02 2.0- r = 0.52; P=.01 1.5- 1.5- 1.0- 1.0- 0.5- 0.5- 0- 0- -0.5- -0.5- 0 2 4 6 0 20 40 60 80 Cohen‟s d for depression Period of treatment (days)  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.
  34. 34. Conclusion Depression is more complex than just a “chemical imbalance” Good evidence that there is interplay between neurotransmitters, hormones, immunological factors, structural deficits, etc. Pain is a common symptom in depression Some evidence of link between depression and pain Depression may be neurotoxic – therefore important to diagnose early and treat „aggressively‟