The real pathology of Depression

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1 The real pathology of Depression Dr André F Joubert MB,ChB; M.Med(Psych); D.Med Cape Town, South Africa Copenhagen, Denmark

2 Depression hypothesis Joubert In preparation

3 Depression hypothesis Joubert In preparation

4 Depression hypothesis Joubert In preparation

5 Depression hypothesis Tryptophan depletion Joubert In preparation

6 Depression hypothesis Tryptophan depletion Joubert In preparation

7 Depression hypothesis Tryptophan depletion BDNF promoting Synaptogenesis leading to hippocampal volume & receptor increases Joubert In preparation

8 Antidepressant effects on plasma BDNF BDNF is hypothesised as being a key factor in neuroplasticity This study evaluated the pre- and post-treatment levels of BDNF in a group of depressed patients (n=20) and compared them with healthy controls (n=20) All were treated with escitalopram 10 mg/day over 6 weeks Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:

9 Anxiety and depression the controversy The links between depression and anxiety are complex and difficult to untangle Researchers, from as early as the 1920s, have been classified into two opposing groups 'Lumpers' 'Splitters' One disordertwo discrete disorders Van Praag 1960; Montgomery 1990

10 Cumulative age of onset curves of depressive and anxiety disorders Cumulative hazard rate (%) Anxiety Depression NCS data Age of onset (years) Wittchen et al. Psychol Med 1998

11 Proportion of individuals having one or more comorbid disorders Proportion of anxiety disorders that are pure, comorbid with one, two, and three or more other anxiety disorders Comorbid disorder OCD PTSD Phobia NOS Specific phobia SAnD Pure GAD Comorbid 1 Comorbid 2 Agoraphobia Comorbid 3+ Panic disorder Pure and comorbid (%) Wittchen et al. Psychol Med 1998

12 Comorbidity which disorder comes first? Which disorder comes first GAD or others? Comorbid disorder Drug disorder 21.4 Alcohol disorder 52.3 SAnD Simple phobia Agoraphobia 44.8 Prior to GAD Same year Secondary to GAD Panic disorder Dysthymia Major depression Lifetime proportions (%) Wittchen et al. Psychol Med 1998

13 Proportions (prevalence) of pure and depression-comorbid anxiety disorders among years old: baseline pure MD-comorbid Any Anxiety Separation Anx Specific Phobia Social Phobia Agoraphobia GAD Panic Disorder 19 2,2 13 5,1 2,2 1,3 0,8 2,5 0,3 1,9 1 0,3 0,1 0,2 0% 20% 40% 60% 80% 100% Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press

14 Anxiety Disorders 2 years later - How many are Pure, How many comorbid? Pure Comorbid major depression Any anxiety disorder 21,2 6,9 Separation anxiety 2,2 1,2 Specific phobia Social phobia Agoraphobia GAD Panic disorder 14,7 5,1 2,2 2,1 1 4,5 2,2 1 1,3 0,6 0% 20% 40% 60% 80% 100% Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press

15 5 years later - How many anxiety disorders are still pure and how many comorbid? Pure Comorbid MD Any anxiety 17,5 17,7 Separation anxiety 1,6 2,7 Specific phobia 14,3 10,9 Social phobia 4,4 5,3 Agoraphobia 1,7 2,7 GAD 1,5 3,2 Panic disorder 0,8 1,6 0% 20% 40% 60% 80% 100% Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press

16 Comorbidity Issues Independent symptoms Separate onset? Separately attributal functional impairment Joubert, In preparation

17 Separately attributable functional impairment Normal function GAD with impaired function GAD with Depression symptoms GAD Depression GAD with Major Depression

18 Comorbidity Issues Independent symptoms Separate onset? Separately attributal functional impairment If these are criteria are not met: Lumping of anxiety and depression Joubert, In preparation

as the 1920s, have been classified into two opposing groups 'Lumpers'

19 Anxiety and depression the controversy The links between depression and anxiety are complex and difficult to untangle Researchers, from as early as the 1920s, have been classified into two opposing groups 'Lumpers' 'Splitters' One disordertwo discrete disorders Van Praag 1960; Montgomery 1990

20 Comorbidity Terminology Co-morbidity : life-time vs co-occuring Co-occurrence : at the same time Consequential : unitary syndromes of consequence (Complication) Joubert In preparation

21 Degeneration hypothesis Psychological stress Serotonin Serotonin receptors Physical stress A/Inflamm IL1Ra IL4 IL10 IL13 TGFβ Inflamm IL1β IL2 IL6 IL12 IFNγ TNFα HPA Tryptophan IDO Myint and Kim, Medical Hypothesis, 2003 Kynurenine Quinolinate Neurodegeneration Kynurenate Neuroprotection Major Depression

22 Degeneration hypothesis Psychological stress Serotonin Serotonin receptors Physical stress A/Inflamm Inflamm Tryptophan IL1Ra IL4 IL10 IL13 TGFβ IL1β IL2 IL6 IL12 IFNγ TNFα IDO Kynurenine Quinolinate Kynurenate HPA Neurodegeneration Neuroprotection Myint and Kim, Medical Hypothesis, 2003 Major Depression

23 Cumulative age of onset curves of depressive and anxiety disorders Cumulative hazard rate (%) Anxiety Depression NCS data Age of onset (years) Wittchen et al. Psychol Med 1998

24 Time depressed and hippocampal volume Total hippocampal volume (mm 3 ) 5,800 5,300 4,800 4,300 3,800 3,300 2, ,000 1,500 2,000 2,500 3,000 3,500 4,000 Time depressed (days) Sheline et al. J Neurosci 1999; 19:

Antidepressants may help restore communication in depression Dendritic sprouting in hippocampal pyramidal neurons Depression Reduced Micrograph 1 Graphic representation 2 Post-treatment Increased

25 Antidepressants may help restore communication in depression Dendritic sprouting in hippocampal pyramidal neurons Depression Reduced Micrograph 1 Graphic representation 2 Post-treatment Increased Micrograph 1 Graphic representation 2 1. Manji HK, et al. Biol Psychiatry. 2003;53: Nestler EJ, et al. Neuron. 2002;34: Micrograph images reprinted with permission from Elsevier. Illustrations reprinted with permission from Cell Press

26 BDNF levels and HAM-D scores of depressed female patients and healthy female controls BDNF (ng/ml) ** Mean BDNF (ng/ml) Mean HAM-D score 45 *** HAM-D score Pre-treatment Post-treatment Healthy controls (n=20) Depressed patients (n=20) **p=0.002; ***p<0.001 (pre-treatment vs post-treatment; Wilcoxon signed ranks test) p=0.010 (pre-treatment vs healthy controls; Mann Whitney U-test) p=ns (post-treatment vs healthy control BDNF levels; Mann Whitney U-test) Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256

27 The real pathology of Depression Dr André F Joubert MB,ChB; M.Med(Psych); D.Med Cape Town, South Africa Copenhagen, Denmark

28 Real antidepressant effect Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants Luca Santarelli, Michael Saxe, Cornelius Gross, Alexandre Surget, Fortunato Battaglia, Stephanie Dulawa, Noelia Weisstaub, James Lee, Ronald Duman, Ottavio Arancio, Catherine Belzung, Rene Hen. Science, August 2003 Joubert In preparation

29 5 years later - How many anxiety disorders are still pure and how many comorbid? Pure Comorbid MD Any anxiety 17,5 17,7 Separation anxiety 1,6 2,7 Specific phobia 14,3 10,9 Social phobia 4,4 5,3 Agoraphobia 1,7 2,7 GAD 1,5 3,2 Panic disorder 0,8 1,6 0% 20% 40% 60% 80% 100% Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press

30 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain 2007 Kim et al. Prog Neuropsychopharmacol Biol Psychiatry Joubert, In preparation

Brain cytokine (IL-1) levels 8 7 6 pg/ml protein 5 4 3 2 1 0 Normal mouse +

injection of water Dementia mouse + peripheral infection Brain Cell Death 1

31 Brain cytokine (IL-1) levels pg/ml protein Normal mouse + injection of water Normal mouse + peripheral infection Dementia mouse + injection of water Dementia mouse + peripheral infection Brain Cell Death 1 1x 5x 10x Combrinck et al. Neuroscience 2002; Cunningham et al. J Neurosci 2005

32 The Spectrum of Symptoms in Alzheimer s Disease Mood symptoms Depression Apathy Social Withdrawal Anxiety Agitation Body symptoms Malaise Fatigue Somnolence Decreased Appetite Sleep disturbance Memory symptoms Concentration Executive function Short term memory Psychomotor speed

33 The Spectrum of Sickness Behaviour Mood symptoms Depression Apathy Social Withdrawal Anxiety Agitation Body symptoms Malaise Fatigue Somnolence Decreased Appetite Sleep disturbance Fever Memory symptoms Concentration Executive function Short term memory Psychomotor speed

34 Hypothesis In Alzheimer s disease systemic inflammation leads to an exaggerated brain cytokine response (with more sickness behaviour) causing the death of brain cells and increased cognitive decline Evidence Animal models Clinical studies anecdotal observations the effects of systemic inflammation on clinical progression in Alzheimer s Disease cohorts

35 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002 Joubert, In preparation

36 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002 Hypersecretion of cortisol reduces synaptogenesis Tripathi and Verma, Biochem Mol Biol 2003 Accumulation of neurotoxic factors in depression and Alzheimer s Disease similar Hock et al. Eur Neurol 1998 Joubert, In preparation

37 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002 Hypersecretion of cortisol reduces synaptogenesis Tripathi and Verma, Biochem Mol Biol 2003 Accumulation of neurotoxic factors in depression and Alzheimer s Disease similar Hock et al. Eur Neurol 1998 Chronic 5HT dysfunction increases the synthesis of ß-amyloid 2004 Steurenburg et al. Neuro Endocrinol Lett Joubert, In preparation

38 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002 Hypersecretion of cortisol reduces synaptogenesis Tripathi and Verma, Biochem Mol Biol 2003 Accumulation of neurotoxic factors in depression and Alzheimer s Disease similar Hock et al. Eur Neurol 1998 Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett 2004 Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007 Joubert, In preparation

39 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002 Hypersecretion of cortisol reduces synaptogenesis Tripathi and Verma, Biochem Mol Biol 2003 Accumulation of neurotoxic factors in depression and Alzheimer s Disease similar Hock et al. Eur Neurol 1998 Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett 2004 Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007 Each depr episode increases dementia risk by 13% Kessing 2004 Joubert, In preparation

40 Risk of dementia increases with the number of depression episodes N Hazard ratio (95 % CI) 1 episode (ref.) 2 episodes episodes episodes > 5 episodes Episodes ( ) Kessing and Andersen, J Neurol, Neurosurg, Psychiatry, 2004.

41 The Great Depression When the facts change, I change my mind. What do you do, sir? John Maynard Keynes Lost Prophets: An Insider's History of the Modern Economists (1994) Alfred L. Malabre

42 Anxiety is.. Prevalent Predictable Preventable Predisposes other psychiatric disorders Promises substance abuse Anxiety is the (psychiatry s) new Black

43 Depression hypothesis Tryptophan depletion BDNF promoting Synaptogenesis leading to hippocampal volume and receptor increase Joubert In preparation

44 Degeneration hypothesis Psychological stress Serotonin Serotonin receptors Physical stress A/Inflamm IL1Ra IL4 IL10 IL13 TGFβ Inflamm IL1β IL2 IL6 IL12 IFNγ TNFα HPA Tryptophan IDO Kynurenine Quinolinate Neurodegeneration Myint and Kim, Medical Hypothesis, 2003 Kynurenate Neuroprotection Major Depression

45 Degeneration hypothesis Psychological stress Serotonin Serotonin receptors Physical stress A/Inflamm IL1Ra IL4 IL10 IL13 TGFβ Inflamm IL1β IL2 IL6 IL12 IFNγ TNFα HPA Tryptophan IDO Myint and Kim, Medical Hypothesis, 2003 Kynurenine 3-HK Quinolinate QA Neurodegeneration Kynurenate KA Neuroprotection Major Depression

46 5HT depletion during recovery from depression and anxiety 100% Relapse rates after TD 50% 5HT dependent recovery Recovery due to other factors Growth factors Neurogenesis NA / DA BDNF SSRI Treatment Well Months Nutt, Inst Mag, 2006

47 Time depressed and hippocampal volume 5,800 Total hippocampal volume (mm 3 ) 5,300 4,800 4,300 3,800 3,300 2, ,000 1,500 2,000 2,500 3,000 3,500 4,000 Time depressed (days) Sheline et al. J Neurosci 1999; 19:

2 1. Manji HK, et al. Biol Psychiatry. 2003;53:707-742. 2. Nestler EJ, et al. Neuron. 2002;34:13-25.

48 Antidepressants and neuroplasticity Dendritic arborization in hippocampal pyramidal neurons Depression Reduced Micrograph 1 Graphic representation 2 Post-treatment Increased Micrograph 1 Graphic representation 2 1. Manji HK, et al. Biol Psychiatry. 2003;53: Nestler EJ, et al. Neuron. 2002;34: Micrograph images reprinted with permission from Elsevier. Illustrations reprinted with permission from Cell Press

49 Antidepressant effects on plasma BDNF BDNF is hypothesised as being a key factor in neuroplasticity This study evaluated the pre- and post-treatment levels of BDNF in a group of depressed patients (n=20) and compared them with healthy controls (n=20) All were treated with escitalopram 10 mg/day over 6 weeks Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:

50 DSM-5 proposal The person was exposed to the following event(s): death or threatened death, actual or threatened serious physical injury actual or threatened sexual violation in one or more of the following ways:

51 DSM-5 proposal In one or more of the following ways: 1.Experiencing the event(s) him/herself 2.Witnessing the event(s) as they occurred to others 3.Learning that the event(s) occurred to a close relative or close friend 4.Experiencing repeated or extreme exposure to aversive details of the event(s) (e.g first responders to body parts; police officers repeatedly exposed to details of child abuse)

Primary diagnosis major depression Primary diagnosis minor depression Primary diagnosis anxiety Results 36% also

52 Depression and anxiety the Zürich study Study The perception of depression and anxiety as separate illnesses disregards the evidence from epidemiological studies The Zürich study is one of the main sources of data in this area Primary diagnosis major depression Primary diagnosis minor depression Primary diagnosis anxiety Results 36% also suffer from anxiety disorders 60% also suffer from anxiety disorders 49% also suffer from major or minor depression Angst et al. 1990

5% (6.5%) Anxiety (total): 10.2% Depression (total): 12.

53 ICD-10 anxiety and depression Patients affected by anxiety Patients affected by depression 5.6% (5.0%) 4.6% (1.3%) 7.5% (6.5%) Anxiety (total): 10.2% Depression (total): 12.1% (+ subthreshold anxiety) (+ subthreshold depression) Sartorius et al. 1996

Overlap and discrimination of GAD and depression GAD Depression Anticipatory anxiety Nervous tension Muscular tension Restlessness Tension pains Physiological arousal Fatigue Dysphoria

54 Overlap and discrimination of GAD and depression GAD Depression Anticipatory anxiety Nervous tension Muscular tension Restlessness Tension pains Physiological arousal Fatigue Dysphoria Irritability Sleep disturbance Appetite disturbance Sensitivity (criticism) Apathy Retardation Withdrawal Loss of interest Morning depression Poor concentration Self confidence Hopelessness Nutt et al. 2002

55 Cumulative age of onset curves of depressive and anxiety disorders Cumulative hazard rate (%) Anxiety Depression NCS data Age of onset (years) Wittchen et al. Psychol Med 1998

56 Proportion of individuals having one or more comorbid disorders Proportion of anxiety disorders that are pure, comorbid with one, two, and three or more other anxiety disorders Comorbid disorder OCD PTSD Phobia NOS Specific phobia SAnD Pure GAD Comorbid 1 Comorbid 2 Agoraphobia Comorbid 3+ Panic disorder Pure and comorbid (%) Wittchen et al. Psychol Med 1998

57 Comorbidity which disorder comes first? Which disorder comes first GAD or others? Comorbid disorder Drug disorder 21.4 Alcohol disorder 52.3 SAnD Simple phobia Agoraphobia 44.8 Prior to GAD Same year Secondary to GAD Panic disorder Dysthymia Major depression Lifetime proportions (%) Wittchen et al. Psychol Med 1998

58 Separately attributable functional impairment Normal function GAD with impaired function GAD with Depression symptoms GAD Depression GAD with Major Depression

59 Comorbidity Issues Independent symptoms Separate onset? Separately attributal functional impairment If these are criteria are not met: Lumping of anxiety and depression Joubert, In preparation

60 Comorbidity Terminology Co-morbidity : life-time vs co-occuring Co-occurrence : at the same time Consequential : unitary syndromes of consequence (Complication) Joubert In preparation

61 Untreated anxiety leads to depression Chronic stress model Hypersecretion of cortisol blocks proteien synthesis - leading to decreased synaptogenesis (neuroplasticity) Tripathi and Verma, Biochem Mol Biol 2003 Hypercortisolemia blocks glucose activity in the brain Wittchen s epidemiological data Tripathi and Verma, Biochem Mol Biol 2003 Wittchen et al. Arch Gen Psychiatry In press Joubert, In preparation

62 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Joubert, In preparation

63 8, Brain cytokine (IL-1) levels 6, pg/ml protein 4, 2, 0, Normal mouse + injection of water Normal mouse + peripheral Dementia mouse + injection infection of water Dementia mouse + peripheral infection Brain Cell Death 1 1x 5x 10x Combrinck et al. Neuroscience 2002; Cunningham et al. J Neurosci 2005

64 The Spectrum of Symptoms in Alzheimer s Disease Mood symptoms Depression Apathy Social Withdrawal Anxiety Agitation Body symptoms Malaise Fatigue Somnolence Decreased Appetite Sleep disturbance Memory symptoms Concentration Executive function Short term memory Psychomotor speed

65 The Spectrum of Sickness Behaviour Mood symptoms Depression Apathy Social Withdrawal Anxiety Agitation Body symptoms Malaise Fatigue Somnolence Decreased Appetite Sleep disturbance Fever Memory symptoms Concentration Executive function Short term memory Psychomotor speed

66 Untreated depression leads to dementia Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry 2007 Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002 Hypersecretion of cortisol reduces synaptogenesis Tripathi and Verma, Biochem Mol Biol 2003 Accumulation of neurotoxic factors in depression and Alzheimer s Disease similar Hock et al. Eur Neurol 1998 Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett 2004 Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007 Each depr episode increases dementia risk by 13% Kessing 2004 Joubert, In preparation

67 Risk of dementia increases with the number of depression episodes N Hazard ratio (95 % CI) 1 episode (ref.) 2 episodes episodes episodes > 5 episodes Episodes ( ) Kessing and Andersen, J Neurol, Neurosurg, Psychiatry, 2004.

68 The real pathology of Depression Dr André F Joubert MB,ChB; M.Med(Psych); D.Med Cape Town, South Africa Copenhagen, Denmark

PSYCHIATRIC CO-MORBIDITY STEVE SUGDEN MD MPH

PSYCHIATRIC CO-MORBIDITY STEVE SUGDEN MD MPH OVERVIEW: PSYCHIATRIC DISORDERS Mood Disorders Anxiety Disorders Psychotic Disorders Personality Disorders PTSD Eating Disorders EXAMPLE What is the diagnosis?