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Depression: the brain, the mind, the family and work

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Conversations at The Royal public lecture series

By The Royal's Dr. Pierre Blier, MD, Ph.D
Endowed Chair and Director Mood Disorders Research
Institute of Mental Health Research
University of Ottawa, Ontario
Canada Research Chair, Psychopharmacology

Published in: Health & Medicine
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Depression: the brain, the mind, the family and work

  1. 1. Depression: the brain, the mind, the family, and work Pierre Blier, MD, Ph.D Endowed Chair and Director Mood Disorders Research Institute of Mental Health Research University of Ottawa, Ontario Canada Research Chair, Psychopharmacology
  2. 2. Global burden of diseases-World Health Organization DALYs: disability adjusted life years; WHO 2008 report
  3. 3. Global burden of diseases-World Health Organization DALYs: disability adjusted life years; WHO 2008 report
  4. 4. Global burden of diseases-World Health Organization +50% +30% DALYs: disability adjusted life years; WHO 2008 report
  5. 5. Mortality and severe mental illness  >15,000 patients with bipolar disorder diagnosis studied (Sweden)1  Standardized mortality ratio (all causes) in bipolar patients was 2.5 for males, 2.7 for females (values >1.0 indicate greater risk than general population)  Most frequent cause of death for bipolar patients • Cardiovascular disease: 31% • Suicide: 19% • Cancer: 14%  Patients with severe schizophrenia, bipolar disorder, and depression lose 25 or more years of life expectancy, with most of the premature deaths due to cardiovascular disease2, 3,4 1. Osby et al. Arch Gen Psychiatry 2001;58:844-850. 2. Angst et al. J Affect Disord 2002;68:167-181. 3. Newcomer and Hennekens. JAMA 2007;298:1794-1796. 4. Colton and Manderscheid. Prev Chronic Dis 2006;3:A42.
  6. 6. Depression worsens outcome of many medical conditions  Depression worsens morbidity and mortality after myocardial infarction1,2  Depression increases morbidity and mortality in patients with congestive heart failure3,4  Depression increases risk of mortality in patients in nursing homes5  Depression worsens morbidity post-stroke6  Depression may worsen outcomes of cancer, diabetes, AIDS, and other disorders7 1. Frasure-Smith N, et al. JAMA. 1993;270:1819-1825. 2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221227. 3. Jiang W, et al. Arch Intern Med. 2001;161:1849-1856. 4. Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205. 5. Rovner BW, et al. JAMA. 1991;265:993-996. 6. Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319. 7. Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl 1):80-84.
  7. 7. Depression Has an Impact on Mean Health Scores More Than Other Chronic Conditions “Depression had the largest effect on worsening mean health scores” 100 *p<0.0001 p<0.01 N=245,404 † 90.6 = No chronic condition 90 80 * 1 1 80 * 2 1 3 1 80 79 * 70 60 * 4 1 * 1 79 73 Depression only † † † 1 2 3 65 66 67 † 4 59 Conditions 1.Asthma 2.Angina 3.Arthritis 4.Diabetes 0 One Chronic Condition Depression + One Chronic Condition *Depressed respondents had lowest mean score among all chronic conditions (p<0.0001). † Depressed respondents with another chronic condition had lower mean health scores than respondents with the chronic condition alone (p<0.01). Moussavi et al. Lancet 2007;370(9590):851-58.
  8. 8. DEPRES-STUDY 78,463 ADULTS I I 5,414 (6.9%) MAJOR DEPRESSIVES 100% 31% 28% 24% 5% NO CONSULTATION NO DRUG TREATMENT NON-ANTIDEPRESSANT DRUG INADEQUATE DOSE OF AN ANTIDEPRESSANT DRUG 12% ADEQUATE DOSE OF AN ANTIDEPRESSANT DRUG INT. CLIN. PSYCHOPHARMACOL. 12 : 19, 1997
  9. 9. Only one patient in three fully recovers after a first medication trial Antidepressant Effects After 6-8 Weeks Partial Response 33% Full Remission 33% 33% No response Kennedy et al, Human Psychopharmacology 2001
  10. 10. Residual Symptoms Following Acute Remission of Depression Percentage of Subjects 50 Threshold 38% 40 30 Subthreshold 44% 28% 20 10 0 Mood Diminished Weight Sleep PsychoDisturbance motor Pleasure or Interest Fatigue Guilt Concentration Symptoms of Depression Nierenberg AA, Keefe BR, Leslie VC, et al. J Clin Psychiatry. 1999(Apr);60(4):221-225 © 2009 Canadian Psychiatric Association. All rights reserved. (N=215) Suicidal Ideation
  11. 11. The many faces of major depression DSM-IV criteria 35 y.o. female + Depressed mood + Hypersomnia + Increased appetite/weight + Psychomotor retardation + No energy + Suicidal ideation 70 y.o. male - Marked loss of interest/pleasure - Insomnia - Decreased appetite/weight - Psychomotor agitation - Impaired concentration/decision - Inappropriate guilt
  12. 12. Evidence of Hippocampal Atrophy and Loss in MDD Patients  Compared to controls, patients with depression had smaller hippocampal volumes1 Images reprinted with permission of JD Bremner. 1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118. 2. Sheline YI, et al. J Neurosci. 1999;19:5034-5043. 3. Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93:3908-3913. 4. Sheline YI, et al. Am J Psychiatry. 2003;160:1516-1518.  Decreased hippocampal volume may be related to the duration of depression2-4
  13. 13. Hippocampal Volumes Are Decreased In Depressed Patients with Multiple Episodes (ME)but Not In The First Episode (FE) 4000 Control FE Control 3500 3500 3000 3000 2500 2500 2000 2000 1500 1500 1000 FE 1000 Right Left 3500 3500 3000 3000 2500 2500 2000 2000 1500 1500 1000 1000 Control MacQueen et al, PNAS, 2003 ME Control ME
  14. 14. Alteration of Brain Volume in Depression Phillips et al, J Clin Psychiiatry 2012
  15. 15. Antidepressants and Neurotrophic Factors May Help Restore Communication in Depression Normal Nestler EJ, et al. Neuron. 2002;34(1):13-25. Depressed Treated Reprinted with permission from Elsevier.
  16. 16. Functional Overlap Between Aminergic Systems: Features of Depression NE 5-HT Energy Interest Anxiety Irritability Impulsivity Mood, emotion, cognitive function Motivation Drive Dopamine Sex Appetite Aggression
  17. 17. Functional connectivity 5-HT2A for NE neurons 5-HT2C for DA neurons
  18. 18. LOCUS COERULEUS 5-H T (+) 5-HT (-) RAPHE α2 (-) SSRI? 5-HT α 1 α2 (-) 1 α T 1A -H 5 (-) POSTSYNAPTIC NEURON (-) 5-HT β1 (+) α 2 (-) α 2 1A HT 5-
  19. 19. SSRIs decrease NE transmission (Szabo and Blier, 2000; Kawahara et al, 2007) Normal : Norepinephrine (NE) Long-term treatment with a SSRI Amygdala Locus coeruleus 9 2 * 1 0 90 Cont 54 Citalopram Fmoles/sample Spikes/sec 3 6 3 0 * Cont Citalopram
  20. 20. Reciprocal interactions between monoaminergic neurons DOPAMINE D2 (-) ? (-) 5-HT 2A 5-HT1A (-) 5-HT α ) 1(+ NE α 1 (+) -) α2 (
  21. 21. Inhibitory Effect of Escitalopram (X 14 days) on VTA Dopamine Neuronal Firing Control (11 cells/6 rats) 10 Escitalopram (22 cells/5 rats) 9 8 7 6 5 * * * 3 * 4 2 1 0 Rate (Hz) Bursts/10 sec Spikes/Bursts % Spikes Occurring in Bursts (x10) Dremencov et al, J Psychiat Neurosci 2009
  22. 22. Reciprocal interactions between monoaminergic neurons DOPAMINE D2 (-) (-) 5-HT 2C (-) 5-HT 2A 5-HT1A (-) 5-HT α1 NE α 1 (+) -) α2 (
  23. 23. Atypical Antipsychotic Medication: Meta-analysis of Response Rates Odds Ratios of Response Rates With Atypical and Placebo Trials Nested by Drug Olanzapine trials Shelton 2001 Shelton II 2005 Corya 2006 Thase 2006 Thase II 2006 OR (Fixed) 95% CI Subtotal 1.83 [1.18, 2.82]; Z=2.71, p=0.007 Subtotal 1.61 [1.24, 2.09]; Z=3.56, p=0.0004 Subtotal Quetiapine trials 1.39 [1.05, 1.84]; Z=2.30, p=0.02 Subtotal Risperidone trials Mahmoud 2007 Keitner 2009 Reeves 2008 2.07 [1.58, 2.72]; Z=5.28, p=0.00001 Khullar 2006 Mattingly 2006 McIntyre 2006 Earley 2007 El-Khalili 2008 Aripiprazole studies Berman 2007 Marcus 2008 Berman 2008 1.69 [1.46, 1.95]; Z = 7.00, p< 0.00001 Test for overall effect: 0.1 0.2 0.5 1 Favors Control Nelson JC and Papakostas GI Am J Psychiatry, 2009 2 5 10 Favors Treatment Double-blind, placebo-controlled add on trials
  24. 24. Acute Study Design Depressed Patients With Unipolar Major Depression Washout + Screening Day Day 0 -7 Day 7 Day 14 Day 21 Day 42 Fluoxetine 20 + Placebo Fluoxetine 20 + Mirtazapine 30 Venlafaxine 75 Venlafaxine 150 Venlafaxine 225 + + + Mirtazapine 30 Mirtazapine 30 Mirtazapine 30 Bupropion 150 + Mirtazapine 30 Blier et al, Am J Psychiat 167:281-8,2010
  25. 25. Effectiveness of drug combinations Fluoxetine (n = 28) HAMD 17 scores (+ SEM) 25 Fluoxetine + Mirtazapine (n = 25) Bupropion + Mirtazapine (n = 26) Venlafaxine + Mirtazapine (n = 26) 20 15 10 * 5 0 1 4 7 10 14 21 28 35 42 Day of treatment * P = 0.011 when comparing the combination groups with fluoxetine Blier et al, Am J Psychiat 167:281-8,2010
  26. 26. Remitters Hamilton-17 Depression Score ≤ 7 Fluoxetine (7/28) 25% Fluoxetine + mirtazapine (13/25) 52%* Bupropion + mirtazapine (12/26) 46% Venlafaxine + mirtazapine (15/26) 58%* Blier et al, Am J Psychiat 167:281-8,2010
  27. 27. Actual Dropouts Treatment groups Causes Fluoxetine Fluoxetine Bupropion Venlafaxine + Mirtazap + Mirtazap + Mirtazap Adverse events XX X X Lack of efficacy XX X X Lost to follow up X X XX XXX 4/26 (15%) 3/26 (12%) Protocol violation Total: 16/105 (15%) X 5/28 (18%) 4/25 (16%)
  28. 28. Remission rates in monotherapy vs combination from treatment initiation Patients (%) achieving remission 100 75 50 25 49 45 SSRI Mirtazapine SSRI 20-30 mg 0.0 21 30 mg 20-30 mg* Blier et al, Eur Neuropsychopharmacol 2009 Blier et al, Am J Psychiat 2010; * Paroxetine 20-30, Fluoxetine 20 25 25 Bupropion Venlafaxine 150 mg 225 mg + Mirtazapine 30 mg
  29. 29. Remitters Hamilton-17 Depression Score ≤ 7 (N=88) Dropouts* 1 site Escitalopram (mean: 35 mg/day) 42% 3/31 Bupropion 28% 6/28 52% 3/29 (mean: 375 mg/day) Combination (mean: 33/380) *Mean dropout rate: 13%
  30. 30. Antidepressants modulate interconnected signaling cascades (-) (-) Adapted from: Charney DS, et al. Science STKE. 2004;225 re5:1-10. (-)
  31. 31. Rapid Antidepressant of Ketamine (iv) Zarate et al. Arch Gen Psychiat 63: 856-63, 2006
  32. 32. Rapid Antidepressant of Ketamine (iv) Zarate et al. Arch Gen Psychiat 63: 856-63, 2006
  33. 33. Attenuation of suicidal ideation by ketamine Price et al, Biol Psychiat 66:522-6,2009
  34. 34. Our experience with ketamine  Monitoring of pulse, EKG, blood pressure, and EKG, and O2 saturation  230 infusions in 16 patients taking antidepressants  6 remitters, 5 responders, 5 non-responders  Duration of action: starting from 60 minutes to 12 hours, for a total time of 24 hours to 3 weeks  0.5 mg/kg, iv/40 min > 0.2 mg/kg, iv/bolus  Marked anti-suicidal ideation effect  No evidence of neurotoxicity or dependence * Blier, Zigman & Blier, Biological Psychiatry 2013
  35. 35. A case of remission  37 y.o. female, married, 4 kids, works as teacher  Physical History: not contributory  Psychiatric History • 2 episodes of depression • Paroxetine 30 mg w/ response Zigman & Blier, J Clin Psychopharmacol 2013
  36. 36. Current episode  Relapse in Dec 2009, no trigger  Feb 2010 – Venlafaxine up to 300 mg, no response  Nov 2010 - Started NIH study, MADRS 39 • Up to Escitalopram 40 mg + bupropion XL 450 mg  Mar 2011 – End of phase 1 (12 weeks), MADRS 36  Mar 2011 – Suicide attempt by overdose
  37. 37. Current Episode  Mar -> Sept 2011 • Trials of Duloxetine + Quetiapine XR, Duloxetine + Aripiprazole, Duloxetine + Risperidone • Persistent moderate to severe depressive symptoms  Oct 2011 • Lithium added to Duloxetine + Risperidone • “I feel better than I have in 2 years”  Nov 2011 – Feb 2012 • Relapsed after 1 month • Lithium restarted, Duloxetine switched to Moclobemide • Persistent moderate depressive symptoms
  38. 38. Current Episode  Feb 2012 – • Lithium tapered to discontinuation because of loss of benefits  Patient presents to office 2 weeks later in severe distress, intense suicidal ideation, MADRS 48  Offered admission + ECT or trial of ketamine
  39. 39. Ketamine infusion #1  Given 0.5 mg / kg ketamine over 40 min  Reported feeling “numb”, “dopy” and “as if floating”  No psychotic symptoms  Subjectively: Pre Post (60min) Dysphoria 10/10 3/10 Anxiety 8/10 0/10 Suicidal ideation 9/10 0/10
  40. 40. Ketamine infusion # 2  Relapsed after 2 weeks  Given 0.5 mg / kg ketamine over 40 min  Subjectively: Pre Post (60min) Dysphoria 10/10 1/10 Anxiety 7/10 0/10 Suicidal ideation 3/10 0/10
  41. 41. Follow up and Medications  Patient had a third ketamine infusion with the same response as the first two  Sustained remission in the Fall of 2012 • Nortriptyline 125 mg/day • Lithium 600 mg/day • Vyvanse 20 mg/day  Partial relapse in January 2013 • Nortriptyline switched to Anafranil 75 mg/day • Return to normal within a few days
  42. 42. Take home messages  We all have a role to play in decreasing the stigma of depression to get people in treatment  Depression must be treated aggressively because it worsens all other medical disorders and shrinks the brain  In most cases, depression does not take months to bring to remission because there are efficacious treatments  There are new treatments on the horizon

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