Mood Disorders

Tung-Ping Tom Su, MDTung-Ping Tom Su, MD

Department of PsychiatryDepartment of PsychiatryNational Yang-Ming UniversityNational Yang-Ming University

Veterans General Hospital-TaipeiVeterans General Hospital-Taipei

Sept. 28, 2010 (Yang-Ming IBS lecture)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

2.2

4.95.8

17.1

0

5

10

15

20

Epidemiologic CatchmentArea (ECA)

National ComorbiditySurvey (NCS)

Percentof Patients

point prevalence (30 day)

lifetime prevalence

The Burden of Bipolar DisorderThe 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)

• Sixth leading cause of disability worldwide

• Higher risk of cardiovascular disease

• High economic costs ($45.2 billion in US in 1991)

6th Bipolar disorder

7th War

8th Violence

9th Schizophrenia

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.

DIS

AB

ILIT

Y

Prevalence of Prevalence of ‘‘treated treated depression’depression’

Age by genderAge by gender

Neel L Burton: Psychiatry, 2007, Blackwell publishing

Biological:• Genetic predisposition • Horrmonal influencesSociocultural:• Social pressure• Readiness to admit depressive Sx• Diagnostic bias

Classification of mood disorders

Neel L Burton: Psychiatry, 2007, Blackwell publishing

Clinical course ofClinical course ofMood disordersMood disorders

Recurrent depression

Dysthymia

Bipolar depression (bipolar I)

Cyclothymia

Neel L Burton: Psychiatry, 2007, Blackwell publishing

Dysthymia & double depression

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)

• 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)

• Psychotic depression

– Delusions and hallucinations (common: mood – congruent,

Uncommon: mood - incongruent )

• Melancholia

– Loss of pleasure, early morning awakening, diurnal

variation, wt loss, excessive guilt and agitation/retardation

• Seasonal affective d/o (winter depression)

– Hypersomnia, carbohydrate craving, overeating, weight gain

and fatigue

Dysthymic disorder (1)

MD MD

• 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

Double depression

Chronic dysthymic d/o (DD)

>= 2 years>=1 yr: children& adolescent

臨床憂鬱症之多型性型態臨床憂鬱症之多型性型態

憂鬱症憂鬱性精神病

內科疾病相關憂鬱症

女性相關憂鬱症

重鬱症 單極性憂鬱症

雙極性憂鬱症

器質性憂鬱症

慢性輕鬱症

憂鬱性格精神疾病共病憂鬱症

Comorbidity of affective disorders

Affective disorders

Medical illness

Substance abuse Schizophrenia

Phobia, Panic d/o,

Personality d/o

OCD

25 – 50%

30 – 70%

50 – 60%

30 – 90%30 – 40%

Neurobiological model of the pathophysiology of major depression

Oxford Textbook of Psychiatry, 5th ed, 2006Oxford Textbook of Psychiatry, 5th ed, 2006

Adverse childhood experience

Current stress

HPA axis function

Genetic factors

Past depressive episode

Cortisol

NA function 5-HT function

Prefrontal cortex hippocampus

Depressive syndromeDepressive syndrome

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

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0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 1 2 3 4+

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s/l

s/s

Number stressful life events

Pro

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Caspi, A et al SCIENCE 301; 386 ff, JULY 18, 2003

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)

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

Hypercortisolemia in depression

Response to stress in normal, major depression and PTSD

MDDMDD

DST:DST:DEX, 1mg,DEX, 1mg,cortisol >=0.5 ug/dlcortisol >=0.5 ug/dl

PTSDPTSDNormalNormal

憂鬱症之藥物治療憂鬱症之藥物治療

•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

Serotonergic pathway

How SSRIs work to depression

Paul Harrison Lecture note of Psychiatry, 2006Blackwell publishing.

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

Development of antidepressantDevelopment of antidepressantfrom past to futurefrom past to future

1950

TCAs

1985

SSRIs:fluoxetinesertralineparoxetinecitalopramfluoxamine

1990

NDRI:bupropion

2000

SNRIs:venlafaxinemirtazapineduloxetineminacipran

2005

CRF antagonistSP antagonistAgomelatine

Targeting on CREB-BDNFsignalingcascade enzymes

The five major regions of dysfunction in depressed brains

and Nu. Accumbens are underactivity and HPA axis: overactivity

New Concept of Treatment New Concept of Treatment in Psychiatric Disorders: in Psychiatric Disorders:

• TMS TMS (transcranial magnetic stimulation)(transcranial magnetic stimulation)

• VNS VNS (vagnus nerve stimulation)(vagnus nerve stimulation)

• DBS DBS (deep brain stimulation)(deep brain stimulation)

Repetitive Transcranial Repetitive Transcranial Stimulation (rTMS)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

Biomarkers predicting rTMS efficacy in Medication-Resistant Depression:

a 18F-FDG PET studyCheng-Ta Li/ Tung-Ping Su

980727

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

Results

Study design for rTMS in treatment refractory depressed

Treatment-Resistant MDD (20) vs. NC (20)

NC < MDDNC > 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

• MDDBil DLPFCBil OFCBil Med. PFC Bil Ant. Insula - IFAAnterior CingulumMiddle Cingulum

Bil AmygdalaBil Putamen/GP Bil InsulaHippo/ParahipRaphe nu. Cerebellum

Responder(13) vs. Non-Responder(7)• Responders

Bil DLPFC (BA 9) Bil OFC Bil Med. PFC (BA 6d)Anterior CingulumMiddle Cingulum

Bil Uncus/FusiformBil Srtiatum Bil InsulaHippo/ParahipRaphe nu. Cerebellum

•Voxel level, k=300, uncontrolled p <0.05

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

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

Pre-tx areas predicting treatment responses (≥50% decreases in HDRS)

•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

ACC Left fusiform/hippocamcal gyri

Summary• 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/Fusiform activities

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

Responder Non-Responder

Conclusions

Medicated Vulnerable 1st degree

relatives

Target on Enhancing

CREB, BDNF

Balance NT and Frontal-subcortical

circuits

Reduced riskfactors

AntidepressantsrTMSECT

Bipolar disorder雙極性情感性障礙

高潮Mania

低潮

Depression

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

Mixed episode and hypomanic episode

• Mixed episode:– Criteria are met both for manic and depressive episode

– 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 DisordersBipolar 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:Bipolar I

4 DaysBipolar II

Bipolar NOS

“Bipolar III” Antidepressant-related hypomania

Adapted from Akiskal HS, Pinto O. Psychiatr Clin North Am. 1999;22:517-534.

< 4 Days

1 week

The Bipolar Spectrum: WeakerThe 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.

Proportion of Major Depressive Disorder vs Proportion of Major Depressive Disorder vs Bipolar I and II DisorderBipolar I and II Disorder

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

49.5%

2.9

Zurich Strict Criteria

25.7%TotalRatio of MDD vsBP I or BP II

9.4

DSM-IV

49.5%

1.0

Zurich Broad Criteria

Bipolar I (BP I)Bipolar II (BP II)Major depressivedisorder (MDD)

HypomaniaMin BPDysthymiaMild depression

5.30%

17.06%

1.65%

20.72% 10.95%

11.41%

0.55%0.55% 0.55%

Major

Minor

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

Early-onset (age at onset <21)

-higher risks of drug abuse & alcohol abuse

-more rapid cycling and suicide attempts.

Manic/Hypomanic

20%

Mixed13%

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

Depressed67%

Weeks With

Symptoms47%

Weeks Without

Symptoms53%

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

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

UnipolarBipolar Polarity Conversion74 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

Differentiating characteristics of bipolar and unipolar depressions

Table 1.3

Bipolar Unipolar

History of mania or Yes Nohypomania (definitional) Sex ratio Equal Women > menAge at onset Teens, 20s, and 30s 30s, 40s, 50sPostpartum episodes More common Less commonOnset of episode Often abrupt More insidiousNumber of episodes Numerous FewerDuration of episodes 3 to 6 months 3 to 12 monthsPsychomotor activity SleepFamily history Bipolar disorder High Low Unipolar disorder High HighPharmacological 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

發病原因

•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

• Genetic defect in MDP involves the circadian pacemaker or systems that modulate it (Goodwin and Jamison 1990)(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)(Post 1992)

– ““Episodes beget episodes”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

Neurotrophic Neurotrophic factorsfactors (CREB, BDNF, bcl2, MAP kinase) are targets targets of mood stabilisersmood stabilisers

Atypical antipsychotics eg quetiapine modulate bcl 2, bcl 2, BDNF,BDNF, and BAXBAX

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

Neoplasm Cardio-vascular

Cerebro-vascular

Accidents Suicide Other All Causes

29.2*

6.4

1.4* 0.62.2* 1.7 1.6† 1.3 1.6 2.0 2.0* 1.3 2.2* 1.3

* p< 0.001 † p< 0.05

Zurich Cohort, n=4061959-1997

Untreated

Treated

Standardized values- Adapted from Angst, 2000

Living with bipolar disorderMortality ratios: treatment dramatically needed

Thanks for Your attention