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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

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


The burden of bipolar disorder

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.


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


Classification of mood disorders

Neel L Burton: Psychiatry, 2007, Blackwell publishing


Clinical course of

Mood disorders

Recurrent depression

Dysthymia

Bipolar depression

(bipolar I)

Cyclothymia

Dysthymia &

double depression

Neel L Burton: Psychiatry, 2007, Blackwell publishing


Epidemiology prevalence usa data
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)


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


Major depressive episode 1
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)


Major depressive episode 2
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


Dysthymic disorder 1
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


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


Comorbidity of affective disorders
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%


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


5 ht1 a promotor
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


Major depressive disorder biological model
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)




Response to stress in normal, major depression and PTSD stress

MDD

PTSD

Normal

DST:

DEX, 1mg,

cortisol >=0.5 ug/dl


憂鬱症之藥物治療 stress

  • 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



How SSRIs work to depression stress

Paul Harrison Lecture note of Psychiatry, 2006

Blackwell publishing.


Major depressive disorder therapy
Major depressive disorder: therapy stress

  • 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


Development of antidepressant from past to future
Development of antidepressant stressfrom 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


The five major regions of dysfunction in depressed brains stress

and Nu. Accumbens are underactivity

and HPA axis: overactivity


New concept of treatment in psychiatric disorders
New Concept of Treatment stress in Psychiatric Disorders:

  • TMS

    (transcranial magnetic stimulation)

  • VNS

    (vagnus nerve stimulation)

  • DBS

    (deep brain stimulation)


Repetitive transcranial stimulation rtms
Repetitive Transcranial stressStimulation (rTMS)

Time-varying electrical

current in a coil produces

Focal 2 tesla magnetic field

Passes unimpeded through skull induces current in neurons

Behavioral change


Biomarkers predicting rtms efficacy in medication resistant depression a 18f fdg pet study

Biomarkers predicting rTMS efficacy in Medication-Resistant Depression: a 18F-FDG PET study

Cheng-Ta Li/ Tung-Ping Su

980727


Hypotheses and aims
Hypotheses and Aims Depression:

  • 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


Results
Results Depression:



Treatment resistant mdd 20 vs nc 20
Treatment-Resistant MDD (20) vs. NC (20) Depression:

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


Treatment resistant mdd 20 vs nc 20 a cortico limbal dysregulation
Treatment-Resistant MDD (20) vs. NC (20) Depression: 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


Responder 13 vs non responder 7
Responder(13) Depression: 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


Less hypoactive in acc bilateral medial prefrontal gyrus
Less hypoactive in ACC, bilateral medial prefrontal gyrus Depression:

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


Less hyperactive in left hippocampus and fusiform gyrus
Less hyperactive in Depression: 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


Pre tx areas predicting treatment responses 50 decreases in hdrs
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


Summary
Summary decreases in HDRS)

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


Conclusions

Reduced risk decreases in HDRS)

factors

Medicated

Vulnerable 1st degree

relatives

Target on

Enhancing

CREB, BDNF

Antidepressants

rTMS

ECT

Balance NT and

Frontal-subcortical

circuits

Conclusions


Bipolar disorder

Bipolar disorder decreases in HDRS)

高潮

Mania

雙極性情感性障礙

低潮

Depression


Manic episode
Manic episode decreases in HDRS)

  • 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


Mixed episode and hypomanic episode
Mixed episode and hypomanic episode decreases in HDRS)

  • 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)


Bipolar mood disorders
Bipolar decreases in HDRS)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


The bipolar spectrum
The Bipolar Spectrum: decreases in HDRS)

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.


The bipolar spectrum weaker
The Bipolar Spectrum: Weaker decreases in HDRS)

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.


Proportion of major depressive disorder vs bipolar i and ii disorder
Proportion of Major Depressive Disorder vs Bipolar I and II Disorder

Zurich Strict Criteria

Zurich Broad Criteria

DSM-IV

0.55%

0.55%

0.55%

1.65%

5.30%

10.95%

20.72%

17.06%

11.41%

Major

Minor

Total

25.7%

49.5%

49.5%

Ratio of MDD vsBP I or BP II

9.4

2.9

1.0

Hypomania

Bipolar I (BP I)

Min BP

Bipolar II (BP II)

Major depressivedisorder (MDD)

Dysthymia

Mild depression

Angst J, et al. J Affect Disord.2003;73(1-2):133-146.


Early-onset (age at onset <21) Disorder

-higher risks of drug abuse & alcohol abuse

-more rapid cycling and suicide attempts.

Lin Am J Psychiatry 2006; 163:240–246)


Patients with bipolar I disorder experienced mood symptoms nearly half of the time during a 12.8-year follow-up period.

  • Depressive symptoms were predominant

  • Depression was 3.5-fold more frequent than mania

  • 90% of patients had at least 1 week of depressive symptoms

  • Depression (but not mania) predicted greater future illness burden

Long-term Frequency of Depressive Symptoms (Percentage of Follow-up Weeks)

Mixed

13%

Weeks

With Symptoms

47%

Weeks

Without

Symptoms

53%

Manic/

Hypomanic

20%

Depressed

67%

Judd et al. Arch Gen Psychiatry. 2002;59:530-537.


Unipolar bipolar polarity conversion
Unipolar nearly half of the time during a 12.8-year follow-up period.Bipolar Polarity Conversion

74 initially unipolar, depressed, hospitalized, adolescent/young adult

patients followed for 15 years in the Chicago Follow-up Study

Adapted with permission from Goldberg JF et al. Am J Psychiatry. 2001;158:1265


Bipolar Unipolar nearly half of the time during a 12.8-year follow-up period.

History of mania or Yes No

hypomania (definitional)

Sex ratio Equal Women > men

Age at onset Teens,20s, and 30s 30s, 40s, 50s

Postpartum episodes More common Less common

Onset of episode Often abrupt More insidious

Number of episodes Numerous Fewer

Duration of episodes 3 to 6 months 3 to 12 months

Psychomotor activity

Sleep

Family history

Bipolar disorder High Low

Unipolar disorder High High

Pharmacological response

Antidepressants

Lithium carbonate Acute antidepressant effect Generally ineffective

Retardation > agitation > Hypersomnia > insomnia

Agitation > retardation > insomnia> Hypersomnia

Induce hypomania / mania

Induction of hypomania / mania is rare

Table 1.3

Differentiating characteristics of bipolar

and unipolar depressions


發病原因 nearly half of the time during a 12.8-year follow-up period.

  • 基因缺陷

  • 腦內神經化學物質分泌異常

  • 明顯的家族史(情感性疾病)

  • 其病程類似癲顯


Bipolar disorder etiology
Bipolar disorder: Etiology nearly half of the time during a 12.8-year follow-up period.

  • Genetic defect in MDP involves the circadian pacemaker or systems that modulate it (Goodwin and Jamison 1990)

    • cycle length with successive episodes

    • Increased sensitivity to light

    • Seasonal pattern (some bipolar)

    • Link between disturbed sleep and mood episodes

  • Kindling phenomenon (Post 1992)

    • “Episodes beget episodes”

    • Experience of affective episode (neurotransmitter and peptide alterations) --- memory trace -- predispose further episodes

    • Initiate long-term maintenance tx early in the course of illness


Stages of bipolar illness evolution
Stages of Bipolar Illness Evolution nearly half of the time during a 12.8-year follow-up period.


  • Neurotrophic factors nearly half of the time during a 12.8-year follow-up period. (CREB, BDNF, bcl2, MAP kinase) are targets of mood stabilisers

  • Atypical antipsychotics eg quetiapine modulate bcl 2, BDNF, and BAX

Manji, Bipolar Disord 2003 Wei J Neurosci Res 2003 Luo Brain Res 2004


29.2* nearly half of the time during a 12.8-year follow-up period.

* p< 0.001

† p< 0.05

6.4

2.2*

2.2*

1.7

2.0

1.6†

2.0*

1.6

1.3

1.3

1.3

1.4*

0.6

All Causes

Suicide

Other

Neoplasm

Cardio-

vascular

Cerebro-

vascular

Accidents

Living with bipolar disorderMortality ratios: treatment dramatically needed

Zurich Cohort, n=406

1959-1997

Untreated

Treated

Standardized values- Adapted from Angst, 2000


Thanks for nearly half of the time during a 12.8-year follow-up period.

Your

attention


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