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Mood Disorders

Mood Disorders. Tung-Ping Tom Su, MD Department of Psychiatry National Yang-Ming University Veterans General Hospital-Taipei Sept. 28, 2010 (Yang-Ming IBS lecture). 憂鬱症之流行病學：. 美國重鬱症之病發率. Regier et al., 1988; Blazer et al., 1994. Sixth leading cause of disability worldwide

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Mood Disorders

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  1. Mood Disorders Tung-Ping Tom Su, MD Department of Psychiatry National Yang-Ming University Veterans General Hospital-Taipei Sept. 28, 2010 (Yang-Ming IBS lecture)

  2. 憂鬱症之流行病學： 美國重鬱症之病發率 Regier et al., 1988; Blazer et al., 1994

  3. Sixth leading cause of disability worldwide Higher risk of cardiovascular disease High economic costs ($45.2 billion in US in 1991) The Burden of Bipolar Disorder 6th Bipolar disorder 7th War 8th Violence 9th Schizophrenia DISABILITY Woods. J Clin Psychiatry. 2000;61(suppl 13):38-41; Ahrens et al. Can J Psychiatry. 1995;40:241-246; Wyatt and Henter. Soc Psychiatry Psychiatr Epidemiol. 1995;30:213-219.

  4. Prevalence of ‘treated depression’ Age by gender • Biological: • Genetic • predisposition • Horrmonal influences • Sociocultural: • Social pressure • Readiness to admit • depressive Sx • Diagnostic bias Neel L Burton: Psychiatry, 2007, Blackwell publishing

  5. Classification of mood disorders Neel L Burton: Psychiatry, 2007, Blackwell publishing

  6. Clinical course of Mood disorders Recurrent depression Dysthymia Bipolar depression (bipolar I) Cyclothymia Dysthymia & double depression Neel L Burton: Psychiatry, 2007, Blackwell publishing

  7. Epidemiology (prevalence): USA data • Major depressive d/o:M: 2.6 - 5.5%, F: 6 - 11.8% (Fava’96) • MDD higher in separated/divorced male, unemployed and medically ill pts. • Primary care: 4.8-9.2% (MDD) and 9 - 20% (all depressive d/o) • Dysthymia:3 - 4% (Keller 1996) • Bipolar d/o: • Lifetime risk & 6 month prevalence : 0.3-1.5% (nature: chronicity) • 1/3 of primary D met criteria for bipolar spectrum d/o and risk of bipolarity is higher in children and adolescent (32% and 20%) • Lifetime rate across culture: 0.3/100 (Taiwan) to 1.5/100 (N.Z)

  8. 憂鬱症之診斷標準 一、情緒：1)情緒低落(depression) 2)對任何事情 均沒樂趣(anhedonia) 3)人生乏味有自殺傾向 二、認知：4)自責愧疚 5)記憶力、注意力下降， 無法下決定 三、行為：6)整天不想動或是焦躁不安 7)疲倦乏力 四、身體：8)胃口或體重下降或上升 9)失眠或多眠

  9. Major depressive episode (1) • Occur in both major depression and bipolar d/o • Severity (mild, moderate and severe) without or with psychotic features • DSM-IV criteria: • More than 5 symptoms • Duration > 2 weeks • Significant impairment in functioning • Not related to medical illness, medications or substance abuse • Not accounted by bereavement (loss < 3 months)

  10. Major depressive episode (2) • Psychotic depression • Delusions and hallucinations (common: mood – congruent, Uncommon: mood - incongruent ) • Melancholia • Loss of pleasure, early morning awakening, diurnal variation, wt loss, excessiveguilt and agitation/retardation • Seasonal affective d/o (winter depression) • Hypersomnia, carbohydrate craving, overeating, weight gain and fatigue

  11. Dysthymic disorder (1) Chronic dysthymic d/o (DD) • Sx: depression and > 2 sxs of • Changes in appetite, sleep, energy, low self-esteem, distractibility, decision making and hopelessness • Sx never been free > 2 months at a time • No major depressive episode in the first 2 years • Dysthymic D vs. MDD: • cognitive & motivational vs. vegetative Sx, • 80% of dysthymia have lifetime MDD >= 2 years >=1 yr: children & adolescent MD MD Double depression

  12. 臨床憂鬱症之多型性型態 重鬱症 單極性 憂鬱症 慢性 輕鬱症 雙極性 憂鬱症 憂鬱症 憂鬱性 精神病 女性相關 憂鬱症 內科疾病 相關憂鬱症 精神疾病 共病憂鬱症 憂鬱性格 器質性 憂鬱症

  13. Comorbidity of affective disorders Phobia, Panic d/o, Medical illness OCD 30 – 90% Affective disorders 30 – 40% Personality d/o 30 – 70% Substance abuse Schizophrenia 25 – 50% 50 – 60%

  14. Neurobiological model of the pathophysiology of major depression Adverse childhood experience Current stress HPA axis function Cortisol Genetic factors NA function 5-HT function Prefrontal cortex hippocampus Past depressive episode Depressive syndrome Oxford Textbook of Psychiatry, 5th ed, 2006

  15. 生活壓力事件與5-HT1A promotor多型性基因型態之相互影響憂鬱症 Probability of MDE Number stressful life events Caspi, A et al SCIENCE 301; 386 ff, JULY 18, 2003

  16. Major depressive disorder: biological model • Stronger genetic basis: • Monozygote > dizygote (bipolar > MDD) (Gershon 1990) • Unipolar and bipolar may coexist in a twinship • Risk of major affective d/o: one bipolar parent: 29.5%, two parents with affective d/o with one bipolar: 74% • Biochemical (neurotransmitters): • 5-HT, NE, DA (uptake inhibition) • Receptor sensitivity: beta-adrenergic receptor downregulation • Neuroendocrinology: • HPA axis: cortisol releasing factor (CRF) overdrive • HPT axis: blunted TSH response to TRH, T3 augmentation • REM latency(< 65 min):marker (endogenous depression)

  17. Hypothalamo-pituitary-adrenal axis (HPA) system during acute stress

  18. Hypercortisolemia in depression

  19. Response to stress in normal, major depression and PTSD MDD PTSD Normal DST: DEX, 1mg, cortisol >=0.5 ug/dl

  20. 憂鬱症之藥物治療 • 從輕至重度憂鬱症均有效 • 有效率 60-80% • 治療目標為症狀緩解、功能恢復及預防再發

  21. Serotonergic pathway

  22. How SSRIs work to depression Paul Harrison Lecture note of Psychiatry, 2006 Blackwell publishing.

  23. Major depressive disorder: therapy • Remission (6M-1 yr) & recovery (>1yr), relapse (6M-1yr) and recurrence (>1 yr) • Psychotherapy • supportive, brief psychodynamic , interpersonal psychotherapy (IPT) and cognitive therapy (CT), cognitive-behavior therapy (CBT) • Antidepressant drug therapy • Acute therapy- at least 6-9 months • Maintanence therapy: more than 1-2 years (full dose, more protective against recurrence) • Light therapy: seasonal affective d/o • Exercise:mild to moderate depression

  24. Development of antidepressantfrom past to future 1950 1985 1990 2000 2005 TCAs SSRIs: fluoxetine sertraline paroxetine citalopram fluoxamine CRF antagonist SP antagonist Agomelatine Targeting on CREB-BDNF signaling cascade enzymes NDRI: bupropion SNRIs: venlafaxine mirtazapine duloxetine minacipran

  25. The five major regions of dysfunction in depressed brains and Nu. Accumbens are underactivity and HPA axis: overactivity

  26. New Concept of Treatment in Psychiatric Disorders: • TMS (transcranial magnetic stimulation) • VNS (vagnus nerve stimulation) • DBS (deep brain stimulation)

  27. Repetitive Transcranial Stimulation (rTMS) Time-varying electrical current in a coil produces Focal 2 tesla magnetic field Passes unimpeded through skull induces current in neurons Behavioral change

  28. Biomarkers predicting rTMS efficacy in Medication-Resistant Depression: a 18F-FDG PET study Cheng-Ta Li/ Tung-Ping Su 980727

  29. Hypotheses and Aims • Responders are different from non-responders in resting brain metabolism • Differences may account for core antidepressant mechanism of rTMS • Pre-rTMS regional brain glucose uptake in DLPFC, ACC, hippocampus and brainstem may • Predict rTMS effectiveness in medicated MRD patients. • Underlying pathophysiology of MRD is different from other depressives ? • Compare with previous hypothesis of depression

  30. Results

  31. Study design for rTMS in treatment refractory depressed

  32. Treatment-Resistant MDD (20) vs. NC (20) NC > MDD NC < MDD • Global variance across scans: removed by analysis of covariance (ANCOVA) • Btw-gp comparison: ANCOVA, Controlling for age and gender • Cluster level, controlled p <0.001

  33. Treatment-Resistant MDD (20) vs. NC (20) A cortico-limbal dysregulation MDD Bil DLPFC Bil OFC Bil Med. PFC Bil Ant. Insula - IFA Anterior Cingulum Middle Cingulum Bil Amygdala Bil Putamen/GP Bil Insula Hippo/Parahip Raphe nu. Cerebellum

  34. Responder(13) vs.Non-Responder(7) • Voxel level, k=300, uncontrolled p <0.05 Responders Bil DLPFC (BA 9) Bil OFC Bil Med. PFC (BA 6d) Anterior Cingulum Middle Cingulum Bil Uncus/Fusiform Bil Srtiatum Bil Insula Hippo/Parahip Raphe nu. Cerebellum

  35. Less hypoactive in ACC, bilateral medial prefrontal gyrus Responder > N-R • Global variance across scans: removed by analysis of covariance (ANCOVA) • Btw-gp comparison: ANCOVA, Controlling for age and gender • Using NC vs. MDD mask • Cluster level, k=2000,uncontrolled p <0.05

  36. Less hyperactive in left hippocampus and fusiform gyrus Responder < N-R • Global variance across scans: removed by analysis of covariance (ANCOVA) • Btw-gp comparison: ANCOVA, Controlling for age and gender • Using MDD vs NC mask • Cluster level, k=1000,uncontrolled p <0.10

  37. Pre-tx areas predicting treatment responses (≥50% decreases in HDRS) ACC Left fusiform/hippocamcal gyri • Higher pre-tx metabolism in ACC • Cluster level, k=1000, uncontrolled, • p = 0.089 (trend-significance) • Lower pre-tx metabolism in Left fusiform/hippo/parahippocamcal gyri • Cluster level, k=1000, uncontrolled, • p = 0.004

  38. Summary Non-Responder Responder • Medicated M-R MDD patients vs. normal subjects • Lower metabolism in both L and R DLPFC • Also in the status of limbic-cortical dysregulation • Patients who responded well to rTMS • Not that severe in limbic-corticol dysregulation • Higher pre-tx ACC and lower left Hippocampal/Fusiformactivities could predict rTMS responses • rTMS mechanism: stimulate L DLPFC • By reverse metabolism of L DLPFC activities only ? • Might have an effect of normalizing limbal-cortical dysregulation

  39. Reduced risk factors Medicated Vulnerable 1st degree relatives Target on Enhancing CREB, BDNF Antidepressants rTMS ECT Balance NT and Frontal-subcortical circuits Conclusions

  40. Bipolar disorder 高潮 Mania 雙極性情感性障礙 低潮 Depression

  41. Manic episode • Duration: > 4 days - elevated or expansive or irritabe mood • > 3 sxs or > 4 sxs (if the mood is only irritable) • Grandiosity • Pressured speech (hypertalkative) • Flight of ideas (thoughts are racing) • Distractibility • Decreased need for sleep • Hyperactivity (goal-directed) or agitation • +++ involvement in pleasure activities (spending money, sexual indiscretions and foolish business investment) • Marked impairment in social activities or occupational functioning and interpersonal relationships

  42. Mixed episode and hypomanic episode • Mixed episode: • Criteria are met both for manic anddepressiveepisode • Duration: everyday for > one - week period • Hypomanic episode: • The criteria is the same as mania • Disturbance in mood and change in functioning - present • The episode is not severe enough to cause +++ impairment in functioning and no psychotic features • Psychotic mania (mood - congruent and incongruent)

  43. Bipolar Mood Disorders • Bipolar I • Defined by mania=mood elevation with impairment • Bipolar II • Defined by major depression PLUS hypomania=mood elevation, no impairment • Bipolar spectrum • Defined by major depression PLUS minor mood elevation (mild and/or brief) • Unipolar depression

  44. The Bipolar Spectrum: Bipolar I  1 week Bipolar II  4 Days Bipolar NOS < 4 Days “Bipolar III” Antidepressant-related hypomania Adapted from Akiskal HS, Pinto O. Psychiatr Clin North Am. 1999;22:517-534.

  45. The Bipolar Spectrum: Weaker Hyperthymic “Bipolar IV” Depressive Mixed State “IV ½” Recurrent “Unipolar” Depression “Bipolar V” Adapted from Akiskal HS, Pinto O. Psychiatr Clin North Am. 1999;22:517-534. Akiskal HS, et al. J Affective Disorders. 2006;96:197-205.

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