Sheng-Yu Lee, MDDepartment of Psychiatry

NCKUH

週期性的表現情緒高昂或低落 主要包括躁期與鬱期的臨床表現

情緒失調 特定的冒險行為 衝動表現 人際關係障礙 憂鬱症狀

可能造成個人痛苦、家庭社會與職業上的重大損害

Significant Public Health Impact Suicide rate ~ 12% Annual U.S. cost > $45.2 B 1

6th leading cause of disability worldwide 2

90% recurrence rate (median number of episodes = 9)

50% recurrence within one year after 1st episode

1Kleinman L, et al. Pharmacoeconomics 2003;21(9):601-22

2Woods SW. J Clin Psych 2000;61(suppl 13):38-41.

Affective Disorder

Unipolar

depression

Bipolar

Mixed mood

Rapid cycling

TOP

DOWN

DSM-IV至少 2 週，至少 5 項1.憂鬱心情2.失去興趣3.體重、食慾改變4.失眠或嗜睡5.精神性激動或呆滯6.失去活力7.無價值感、罪惡感8.注意力減退9.死亡或自殺意念、 計畫

DSM-IV至少一週，心情異常亢奮、開闊、易怒 至少 3 項1.自大狂2.睡眠需求減少3.較多話4.思考跳躍5.注意力分散6.增加目的取向活動7.過分參與活動

DSM-IV至少 4 天，心情異常亢奮、開闊、易怒 至少 3 項1.自大狂2.睡眠需求減少3.較多話4.思考跳躍5.注意力分散6.增加目的取向活動7.過分參與活動

症狀較躁期輕 時間較短 ( 定義為四天以內 ) 可能表現

突然間話多 活動量增加 性慾增加 計畫增加 社交活動增加 突然想交朋友 超出預算或需要的購物

因表現常不離譜 , 過去常被忽略

DSM-IV至少 2 週，至少 5 項1.憂鬱心情2.失去興趣3.體重、食慾改變4.失眠或嗜睡5.精神性激動或呆滯6.失去活力7.無價值感、罪惡感8.注意力減退9.死亡或自殺意念、 計畫

DSM-IV至少 2 年，憂鬱心情佔大部分未一次消失 2 個月以上心情憂鬱時，至少 2 項1.食慾改變2.失眠或嗜睡3.活力低或疲憊4.低自尊5.專注力減退6.無望感

•less severe •longer lasting•unremitting

Alterating between major depression

and dysthymia , but not remitting

DSM-IV

• Single manic episode

• Most recent episode hypomanic

• Most recent episode manic

• Most recent episode mixed

• Most recent episode depressed

• Most recent episode unspecified

1 2 3 4

Mania recurs at least 4 times a year

1

2

3

4

Rapid switches from mania to depression and back

One full depressive episode +at least one hypomanic episode

1. Mood swings above and below normal mood

2. Less severe than mania & depression

Former US National Epidemiological Catchment Area (ECA) study : 1.3%

Recent analysis of ECA (Subsyndromal manic symptoms included) : 6.4% (Kessler, et al., 2005)

Zurich study (soft BP II included) : 11% (Angst, 1998)

第一型躁鬱症 : 2.4% (Rhimer & Angst, 2004)

第二型雙極症 : 3.9-11% (Angst et al. 2003)

Often misdiagnosed or undiagnosed: 35-60% have depression first¹ May have several depressive episodes

prior to manic episode² Many will not report mania/hypomania Lag between symptom onset and first

treatment with mood stabilizer³

¹Goodwin FK, Jamison KR. Manic-Depressive Illness 1990:56-73;NY: Oxford Univ Press

²Lish JD, et al. J Affect Disord. 1994;31:281-294.

³Goldberg JF, Ernst CL. J Clin Psych. 2002 Nov;63(11):985-91.

Patients without perceived and report to clinicians (Dunner and Tay,

1993)

Clinicians without asking directly (hypo)mania (Angst and Gamma, 2002)

40% of patients initially misdiagnosed and inappropriate

treatment (Ghaemi et al., 2002)

Overdiagnosis of major depression and schizo-affective

schizophrenia Missed treatment ： increased suicide risk, psychosocial suffering

and social resources utilization (McCombs et al., 2006)

Accurate diagnosis and appropriate treatment: BPII ≥ 12yrs BPI ≥

5yrs (Hirschfeld et al., 2003)

Highly awareness of BPII is necessary

complete suicide and psychiatric disorder

(~90%)

major depressive episode in particular (Zheng et al.,

1997)

suicide risk in UP v.s. BP: inconsistent findings

higher lethality, more aggression and impulsivity

in BP attempters (Rhimer and Kiss, 2002)

suicide attempt in BP: 25-50%, 15-20% die of

suicide

(Michaelis et al., 2003)

History of mania Family history of bipolar disorder Earlier age of onset¹ Multiple episodes Abrupt onset and termination of

depressive episodes Worsening with antidepressant

treatment²

¹Lish JD, et al. J Affect Disord. 1994 Aug;31(4):281-94.

²Ghaemi SN, et al. J Clin Psychiatry. 2000;61:804-808.

More depressive recurrences

Higher rates of substance use disorders

Greater degree of social disruption (marital, occupational)

Minor antisocial behavior (Angst et al., 2003)

Atypical features ? (Angst et al., 2002; Benazzi, 2003; Posternak and

Zimmerman, 2002)

BP family history (Merikangas et al., 2002)

Frequent “ups and downs” (Benazzi, 2004)

more likely to have a family history of bipolar disorder and to have earlier age of onset

Have you experienced sustained periods of feeling uncharacteristically energetic?

Have you had periods of not sleeping but not feeling tired?

Have you felt that your thoughts were racing and couldn't be slowed down?

Have you had periods where you were excessive in sexual interest, spending money, or taking unusual risks?

Onset: 15-25 years old, rare after 65y/o relapses and remissions. Manic episode: duration: 3-6months, 90% of individuals with one manic

episode have another within five years 90% of individuals with bipolar disorder

have at least one psychiatric hospitalization and 2/3 have two or more hospitalizations in their lifetime

Mixed Mania Simultaneous mania and depression May be > 40% prevalence of episodes*

Rapid Cycling > 4 episodes/year

Bipolar II Hypomania (< 4 days duration) alternating with

depression Secondary Mania

e.g., drugs, tumor, CVA, lupus, endocrine, infectious, Huntington’s, Wilson’s

*Akiskal HS, et al. J Affect Disord 2000 Sep;59 Suppl 1:S5-S30

All subtypes less responsive to Lithium

Impulse control disorder

Conduct disorder

migraine bulimiaThyroid disorders

Acute mania/mixed mania: 1st line: lithium or valproate or antipsychotic* 1st line severe: lithium or valproate + antipsychotic*

Acute depression: 1st line: lithium or lamotrigine 1st line severe: lithium + antidepressant

Maintenance lithium or valproate: Alternatives: lamotrigine, carbamazepine,

oxycarbazepine Atypical antipsychotics “may be considered”

*APA recommends atypical antipsychotics > typical antipsychotics

Lithium*Valproic AcidLamictal* (lamotrigine)Tegretol (carbamazepine)Trileptal (oxcarbazepine)Neurontin (gabapentin)Topamax (topiramate)Gabitril (tiagibine)Keppra (levetiracetam)

*FDA-approved

Advantages: 50+ years worldwide experience (FDA-approved 1970) effective in euphoric mania and hypomania inexpensive reduces suicide rate¹‚²

Disadvantages: slow onset ~ 14 days narrow therapeutic index non-response in > 50% (usually bipolar subtypes) frequent side effects (polyuria, tremor, GI symptoms)

and non-compliance discontinuation associated with high relapse rate³

¹Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52.

²Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73.

³Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.

Predictors of response to Lithium: euphoric mania good inter-episode functioning family history of Bipolar Disorder (and of

Lithium response¹) mania/depression/euthymia sequence

vs. depression/mania/euthymia²

¹Duffy A, et al. J Clin Psych. 2002 Dec;63(12):1171-8.

²Kleindienst N, Greil W. Neuropsychobiology. 2002;42 Suppl 1:2-10.

Advantages: extensive experience (FDA-approved for epilepsy

1983; for bipolar mania 1995) rapid onset (1-4 days) loading dose strategy¹ well-tolerated:

20 mgs/kg 77% moderate to marked response

effective in Bipolar subtypes effective for psychotic symptoms² plasma levels (50-125 mcg/ml) less cognitive impairment than lithium³

¹McElroy SL, Keck PE. Neuropsychobiol. 1993;27(3):146-9.

²McElroy SL, et al. J Clin Psych. 1996 Apr;57(4):142-6.

³Zajecka J, et al. J Clin Psych. 1996 Aug;57(8):356-9.

Disadvantages: sedation transient hair loss weight gain tremor GI upset dose-related thrombocytopenia rare hepatotoxicity, pancreatitis possible Polycystic Ovarian Syndrome plasma level monitoring

FDA-approved for maintenance treatment of Bipolar I Disorder

Black box warning for serious rash (includes Stevens-Johnson Syndrome and toxic epidermal necrolysis)

Slow titration necessary Interaction with other AEDs

(especially valproic acid and carbamazepine)

Stevens-Johnson syndrome 死亡率達 3~15% 在台灣地區，預估每年每百萬人會有八人發生 SJS ，相較

於歐美地區每年每百萬人的二至三人，往往淪為無法解決的醫療糾紛。

在長庚醫院治療的 SJS 患者中，有 26% 的病例是由Tegretol 所引起，這個情形也不同於歐美各國主要是由磺胺劑所造成。

鐘文宏說：「這可能與種族體質有關，也可能是台灣在藥物的使用上較不謹慎。」

長庚醫院便與中研院生醫所合作，於基因型鑑定核心設施實驗室展開了尋找基因標記的研究。

Utilization Effective in bipolar mania, in

maintenance treatment for preventing manic recurrence

Less study in bipolar depression Second-line mood stabilizer

Side effects Bone marrow suppression Notable induction of CYP450 3A4 Sedation Fetal toxicity, such as neural tube

defects

Monitoring Blood counts

Clozaril (clozapine) Risperdal* (risperidone) Zyprexa* (olanzapine) Seroquel* (quetiapine) Geodon* (ziprasidone) Abilify* (aripiprazole)

*FDA-approved

Comparable efficacy on positive symptom Better efficacy for improving cognitive and

affective (“negative”) symptoms Less risk of extrapyramidal symptoms

D1 D2

5HT2A

5HT1A

A1

A2

H1

M

ClozapineClozapineOlanzapineOlanzapine

RisperidoneRisperidone

D1 D2

5HT2A

5HT1A

A1

A2

H1

QuetiapineQuetiapine

ZiprasidoneZiprasidoneD2

D1

5HT2A

5HT1A

A1

HaloperidolHaloperidol

Receptor:Receptor:

AA1, 2 1, 2 = a= a11, a, a22 adrenergicadrenergic

DD1,21,2 = dopamine = dopamine

HH11 = histamine = histamine

5HT5HT1A, 2A1A, 2A = serotonin = serotonin

M = muscarinicM = muscarinicGoldstein 1999Goldstein 1999

D2 antagonist/partial agonist 1. Block dopamine hyperactivity2. reduce psychotic symptoms in mania

5HT2A antagonist

1. Reduce glutamate hyperactivity2. Reduce non-psychotic manic and depressed symptoms

High 5HT2:DA blockade (aripiprazole: unique mechanism)

5HT-2a antagonism: Mesolimbic: does not reverse

antipsychotic action at D2 receptors Nigrostriatal: reverses enough D2

blockade to EPS Mesocortical: DA enough to improve

cognition

Receptor actions that improve mood and cognition: 5HT2a antagonism (CLZ/RIS/OLZ/QTP/ZIP/ARI)

5HT2c antagonism (RIS/OLZ/ZIP)

5HT1a agonism (CLZ/QTP/ZIP/ARI)

5HT/NE reuptake blockade (ZIP)

Proper dosing:

Drug Initial launch Current

Risperidone 16 mgs 4-8 mgs

Olanzapine 10 mgs 15-20 mgs

Quetiapine 200-300 mgs 600-800 mgs

Ziprasidone 40-80 mgs 120-160 mgs

Aripiprazole 20-30 mgs 5-10 mgs

Young Mania Rating Scale items*: Elevated mood Increased motor activity Sexual interest Sleep Irritability Speech Language Content Disruptive/aggressive behavior Appearance Insight

*Possible Score = 0-60

FDA-approved for acute mania (2000) and bipolar maintenance (2004)

First-line treatment for mania per APA 2002 Practice Guidelines (along with lithium & divalproex)

Superior to placebo¹ Equivalent to lithium² Superior efficacy (vs. placebo) as add-on

to lithium or valproate ³ Superior to depakine4

1. Tohen M, et al. Am J Psych. 1999 May;156(5):702-9.

2. Berk M, et al. Int Clin Psychopharmacol. 1999 Nov;14(6):339-43.

3. Tohen M, et al. Arch Gen Psych. 2002 Jan;59(1):62-9.

4. Tohen M, et al. Am J Psych. 2003 Jul;160(7):1263-71.

FDA-approved for acute mania (2003)

Superior to placebo (equivalent to haloperidol) as add-on to mood stabilizer (lithium or divalproex)¹

Equivalent to lithium or haloperidol monotherapy²

¹Sachs, et al. Am J Psych 2002 Jul;159(7):1146-54

²Segal J, et al. Clin Neuropharm 1998 May-Jun;21(3):176-80

FDA-approved for acute mania up to 12 weeks (2004)

2 monotherapy and 2 adjunct therapy studies completed*

Superior efficacy on YMRS, PANSS, CGI (including Response and Remission rates on YMRS) for 3 of 4 studies

*Data on file, AstraZeneca Pharmaceuticals LP, Wilmington, DEPresented at 16th Annual U.S. Psychiatric & Mental Health Congress. Nov 6-9, 2003. Orlando, FL

No clinically significant changes observed on ECG parameters (including QTc)

No clinically significant changes in glucose levels (random test) from baseline to endpoint

No other laboratory abnormalities occurred

No clinically significant change observed in blood pressure (including orthostatic)

No difference from placebo in EPS or prolactin levels

No difference from placebo in withdrawal due to adverse events

FDA-approved for mania August 2004 3-week, double-blind, randomized trial

(DSM-IV mania/mixed mania) N = 210 Ziprasidone 40-80 mgs B.I.D. vs. placebo Outcome: SADS (MRS), PANSS, CGI-I, CGI-

S, GAF Ziprasidone superior from day 2 on all

primary and most secondary efficacy measures

Keck PE, et al. Am J Psych. 2003 Apr; 160(4):741-8.

FDA-approved for mania October 2004 3-week, multi-center, double-blind,

randomized trial (acute mania/mixed mania) N=262 aripiprazole 30 mgs vs. placebo Outcome: YMRS change from baseline and

response rate ( > 50%) aripiprazole superior from day 4:

YMRS (-8.2 vs. –3.4) YMRS response (40% vs. 19%) Similar discontinuation rate, weight, prolactin,

QTc

Keck PE, et al. Am J Psych. 2003 Sep; 160(9):1651-8.

Quetiapine

Olanzapine

Aripiprazole

Olanzapine

DRUG WEIGHT GAIN DIABETES RISK

WORSENING LIPID PROFILE

CLOZAPINE +++ + +

OLANZAPINE +++ + +

RISPERIDONE ++ D D

QUETIAPINE ++ D D

ARIPIPRAZOLE +/– – –

ZIPRASIDONE +/– – –

(+) = increase; (–) = no effect; D = discrepant results

Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes.

Diabetes Care. 2004 Feb. 27(2):596-601.

New Onset DM DKA/Coma Deaths

Clozapine 242 80 25

Olanzapine 225 100 23

Risperidone 131 36 5

Quetiapine° 69 21 11

Ziprasidone 1 1 0

Aripiprazole ? ? ?

*Data from MedWatch and Koller et al. Am J Med. 2001;111:716-23/ Koller et al. Pharmaotherapy. 2002;22:841-52.

°J Clin Psychiatry 2004;65:857-863

Literature reports through July 2003 and post-marketing surveillance date through August 2002

Drug: EPS: Weight Gain:

Sedation: Prolactin:

Aripiprazole 0/+ 0 0 0Clozapine 0 +++++ +++++ 0

Olanzapine ++ ++++ ++ ++

Quetiapine 0 ++ +++ 0Risperidone +++ +++ + +++Ziprasidone ++ 0 + +

“Negative” symptom benefits Cognitive benefits Decreased dysphoria Improved compliance Lower risk for tardive dyskinesia

Tandon R, Jibson MD. Annals Clin Psychiatry 2002;14(2):123-9.

Loss of libido Anorgasmia/Ejaculation difficulty Amenorrhea Gynecomastia Galactorrhea Osteoporosis

*DA blockade in tubero-infundibular tract

Appropriate use and effectiveness is controversial

Antidepressant-induced mania in 20-40% with all antidepressant classes (TCAs > others)¹‚²

Increased risk of switching³: Previous antidepressant-induced mania Bipolar family history Exposure to multiple antidepressant

trials¹Stoll AL, et al. Am J Psych 1994 Nov;151(1):1642-45

²Calabrese JR, et al. Eur Neuropsychopharm 1999 Aug;9 Suppl 4:S109-12

³Goldberg JF, et al. Bipolar Disord 2003 Dec;5(6):407-20

Conflicting evidence for efficacy against depressive relapse: Protective?:

Altshuler L, et al¹ (retrospective, 39 pts, 1 year): 35% relapse rate with antidepressant continuation 68% relapse rate with antidepressant discontinuation

Altshuler L, et al² (prospective, 84 pts, 1 year): 36% relapse rate with antidepressant continuation 70% relapse rate with antidepressant discontinuation

¹Altshuler L, et al. J Clin Psychiatry. 2001;62:612-16.

²Altshuler L, et al. Am J Psychiatry. 2003;160:1252-62.

No benefit?: Frankle WG, et al¹ (retrospective, 50 pts, 30

weeks): No difference in length of depressive episode

regardless of antidepressant status Ghaemi S, et al² (open, randomized 33 pts, 1

year): Relapse rate 50% within 20 weeks regardless of

antidepressant status

¹Frankle WG, et al. Psychol Med. 2002 Nov;32:1417-23.

²Ghaemi S, et al. San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2003.

Antidepressants can be safe and effective* Review of 12 randomized, controlled

trials in Bipolar Depression (1,088 patients):

Antidepressants more effective than placebo Switch rate 3.8% for antidepressants and

4.7% for placebo Tricyclics had 10% switch rate vs. 3.2% for

all other antidepressants

*Gijsman HJ, et al. Am J Psychiatry 2004; 161:1537-1547.

Recommendations for Bipolar depression*: Augment mood stabilizer with

antidepressant, unless: “ultra-rapid” cycler (>4 episodes/week) History of antidepressant-induced cycle

acceleration History of multiple episodes antidepressant-

induced mania despite mood stabilizer treatment Continue maintenance antidepressant if

stable for 2 months

*Post RM. Current Psychiatry. 2004 July. 3(7):40-49.

Electroconvulsive treatment¹‚²: superior to pharmacotherapy bilateral ECT superior to unilateral ECT psychotic depression predicts better response effective in depressed and manic phases > 300 case reports of ECT during pregnancy

Phototherapy (bright light treatment) Benefit as monotherapy³ or augmentation4

especially if seasonal component Sleep deprivation5

improvement in 40-60% (may last weeks) some risk of hypo-mania

¹UK ECT Review Group. Lancet. 2003 Mar 8;361(9360):799-808; ²Kho KH, et al. J ECT. 2003 Sep;19(3):139-47; ³Levitt AJ, et al. J Affect Disord. 2002 Sep;71(1-3):243-8; 4Loving RT, et al. Depress Anxiety. 2002;16(1):1-3; 5Giedke H, Schwarzler F. Sleep Med Rev. 2002 Oct;6(5):361-77.

Psychotherapy issues: acceptance of illness effect of illness on relationships effect on employment enhance compliance (>50% non-

compliance: M>F, white>non-white, combination therapy>monotherapy, substance abusers)*

identify precipitants to mood episodes manage/reduce stress

*Keck PE, et al. Psychopharm Bull 1997;33(1):87-91

Bipolar disorder: Significant public health impact Highly recurrent Must look to find

Usually presents in depressed phase Subtypes exist and are less lithium-responsive First-line treatment:

Mood stabilizers Atypical antipsychotics

Thank you!!