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1 2008 년대한우울조울병학회하계연수교육 1 양극성장애의약물치료실제 조증 서울의대정신과학교실 안용민

Prescription in euphoric mania between 1994 and 2004 3

2 Prescription in euphoric mania between 1994 and German, Swiss, Austrian Hosp. Wolfsperger et al. 2007

3 4 조증에서치료약물변화원인 치료제측면 기존 mood stabilizer의제한점및인식변화새로운 Mood stabilizer의개발및도입 Atypical antipsychotics의개발과사용체계화된임상연구의증가와근거중심의치료강조치료목표의변화 질환측면 Bipolar disorder 의개념변화 Bipolar disorder 의다양한증상영역, 경과, 예후

4 조증에서치료약물변화원인 : 기존 mood stabilizer 의제한점및인식변화 5 기존 mood stabilizer 의인식변화 1950s-60s : Li introduced & popular 1980s-90s : CBZ, VPA introduced & popular, Li goes down 2000s : Li revival 기존 mood stabilizer 의제한점 Limited efficacy Mania: 3 주내에 >50% 호전될가능성 : 50% Depression : less effective than in mania Mixed/Rapid: less effective than in mania (esp. lithium) Non-sedative Delayed effect Side effects Li : thyroid, kidney, tremor, weight gain, G-I trouble, skin problems Valproate: weight gain, G-I trouble, hair loss CBZ: blood dyscrasia, drug interaction

5 조증에서치료약물변화원인 : AAPs 의개발과근거중심의치료 Placebo-controlled monotherapy trials with adequate a sample size Positive Negative / failed Lithium Lamictal Divalproex Gabapentin Olanzapine Topiramate Ziprasidone Aripiprazole Risperidone Seroquel 6 Placebo-controlled combination therapy trials with adequate a sample size Positive Negative / failed Lithium Lamotrigine Valproate Gabapentin Olanzapine Risperidone Haloperidol Seroquel a Power to detect a difference >0.8

6 조증에서치료약물변화원인 : 다양한증상영역 7 Manic Mood and Behavior Euphoria Grandiosity Pressured Speech Impulsivity Excessive Libido Recklessness Diminished Need for Sleep Psychotic symptoms Delusions Hallucinations Sensory Hyperactivity Mania Dysphoric or Negative Mood and Behavior Depression Anxiety Irritability Hostility Violence or suicide Cognitive symptoms Racing thoughts Distractibility Poor insight Disorganization Inattentiveness Confusion

7 조증에서치료약물변화원인 : 치료목표의변화 8 조증에서의치료목표 Control dangerous symptoms Suicide, agitation, psychosis Stabilize mood Control mania without provoking depression Treat all facets of mania including depressive, anxious, psychotic elements Restore pre-morbid functioning Avoid harming patient Overdose, severe toxicity, teratogenicity Compatibility with patient daily routines Enhance compliance through simple dosing avoid annoying side effects or cognitive dulling limit need for medical procedures SOURCE: 1999 research with 100+ psychiatric physicians

8 약물치료 algorithm, guideline 의변화 APA Guidelines Acute treatment Manic or mixed episode Depressive episode 1st line less severe: lithium or divalproex or antipsychotic 1st line severe: lithium + antipsychotic or divalproex + antipsychotic 1st line less severe: lithium or lamotrigine 1st line severe: lithium + antidepressant Maintenance treatment Lithium or divalproex APA 2002

9 약물치료 algorithm, guideline 의변화 10 TMA Total stage stage 7 stage 7 stage 4 Atypical antipsychotics Stage 5: add AAPs to MS(s) Stage 1: OZP Stage 2: OZP,RSP, QTP, ZPR Stage 1 : QTP, RSP, ZPR,ARP Stage 1b : OZP Mania 의구분 - Mixed or rapid - Euphoria -Euphoric M/m -mixed or dysphoric M/m - Psychotic M -Euphoric -Mixed Mood stabilizer - CBZ : 1 st stage for - OXC : 2 nd stage -OXC : 3 rd stage mixed/rapid KMAP Total stage Stage 5 Stage 3-4 Atypical antipsychotics Stage 1 (not monotherapy) Stage 1 : possible monotherapy except hypomania Mania의구분 Euphoric vs. Mixed/dysphoric vs. Psychotic Hypomanic vs. Euphoric vs. Mixed vs. Psychotic

10 Atypical Antipsychotics 관련 issues 11 Typical antipsychotics 에비하여우수한가? Atypical Antipsychotics는 Mood stabilizing effect가있는가? monotherapy가가능한가? Non-psychotic mania에서도사용할수있는가? Atypical Antipsychotics ( 병용 ) 치료의장점은? Treats psychotic symptoms Effective for High activity / agitation/ Violent behaviour Increased efficacy Rapid Efficacy for mania Broad efficacy (e.g. mixed, rapid cycling) Reduce depressive elements in mania Favorite cognitive effects Long-term efficacy : prevention of relapse

11 Atypical Antipsychotics 관련 issues Monotherapy 가가능한가? 12 Controlled study for comparison between AAP and Placebo Drugs Studies N number mg/d Weeks Results Olanzapine Tohen et al 1999 OZP (n=70) vs PLA (n=69) vs (p=0.02) Tohen et al 2000 OZP (n=55) vs PLA (n=60) vs (p<0.001) Tohen et al 2002 OZP(n=229) vs PLA (n=115) +Li/DVP vs (p=0.003) Risperidone Hirschfeld et al RSP (n=134) vs. PLA (n=125) vs (p=0.02) 2004 Khanna et al 2005 RSP (n=146) vs. PLA (n=144) vs (p<0.001) Sachs et al 2002 RSP(n=52) or HAL (n=53) or PLA (n=51) +Li/DVP vs vs Yatham et al 2003 RSP(n=75) or PLA(n=76) + Li/DVP/CBZ vs (p=0.089) Quetiapine Jones & Huizar 2005 QTP(n=209) vs. PLA (n=198) vs (p<0.001) Yatham et al 2004 QTP(n=197) vs. PLA(n=205) , vs (p<0.05) Li/DVP DelBello et al 2002 QTP(n=1 5) vs. PLA(n=15) + DVP QTP > PLA (p=0.03) Ziprasidone Keck et al 2003 ZIP (n-131) vs. PLA(n=66) vs (p<0.005) Weisler et al 2003 ZIP(n=101) vs. PLA (n=103) +Li ZP>PLA (p,0.05) Aripiprazole Keck et al 2003 ARP(n=130) vs.pla(n=132) vs (p=0.002) Keck et al 2003 ARP(n=135) vs. PLA(n=137) vs (p<0.001)

12 Atypical Antipsychotics 관련 issues Monotherapy 가가능한가? 13 Controlled study for comparison between AAP and Placebo Adopted from review by Vieta E (2005)

13 Atypical Antipsychotics 관련 issues Nonpsychotic Mania 에서사용가능한가? 14 OZP Study I three weeks 0 OZP Study II four weeks 0 With psychosis Without psychosis (n=56) (n=51) (n=63) (n=76) YMRS Mean Change(LOCF) p= p=0.41 Psychotic Non-psychotic P<0.05 Risperidone Placebo P<0.001 Hirschfeld et al 2002

14 Olanzapine demonstrated a statistically significant improvement compared to placebo on all YMRS items except (11) insight. Pooled data from: Tohen M et al. Am J Psychiatry. 1999;156(5): Tohen M et al. Arch Gen Psychiatry. 2000;57(9): Atypical Antipsychotics 관련 issues Nonpsychotic Mania 에서사용가능한가? Mean YMRS Item Change (LOCF) Baseline to Endpoint Improvement ** * 1. Elevated mood 2. Increased motor activity/energy 3. Sexual interest 4. Sleep 5. Irritability * ** * 6. Speech (rate and amount) ** 7. Language/thought disorder 8. Abnormal thought content 9. Disruptive/aggressive behavior 10. Appearance 11. Insight * * * * *p<.05 **p<.01 OLZ (n=122) PBO (n=124)

15 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : Increased efficacy 16 Combination of AP + MS vs. MS only Adopted from review by Vieta E (2005)

16 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : Increased efficacy 17 Increased remission rate : clinical significance Patients in remission a at Day 21 (LOCF) [%] % P< % 0 Lithium / divalproex + Seroquel (n=185) Lithium / divalproex + placebo (n=185) Data from a combined analysis of two randomized trials a Remission defined as YMRS total score <12 Mullen & Paulsson 2003

17 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : Increased efficacy 18 Olanzapine Cotherapy vs MS Monotherapy YMRS Item Change (LOCF, Week 6) OLZ cotherapy (n=220) Li + /VPA -2.5monotherapy (n=114) * Scale Legend: 1. Elevated mood Irritability 9. Disruptive/aggressive behavior 2. Increased motor activity/energy 6. Speech 10. Appearance 3. Sexual interest 7. Language/thought disorder 11. Insight 4. Sleep 8. Content Olanzapine cotherapy demonstrated a statistically significant improvement compared to monotherapy on the YMRS items of (5) irritability, (6) speech, (7) language/thought disorder, and (9) disruptive/aggressive behavior. Tohen M et al. Arch Gen Psychiatry. 2002;59(1): * * ** *p<.025 **p=.002

18 Improvement from Baseline in YMRS Total Score (LOCF) Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : Rapid efficacy * *p=.031 **p=.019 p=.028 Divalproex (n=123) Olanzapine (n=125) * *p <0.05 Days ** * Lithium / divalproex + Seroquel (n=185) Lithium / divalproex + placebo (n=185) * Olanzapine vs. Divalproex (Tohen et al. 2002) 19 QTP + MS vs. MS only (Mullen & Paulsson et al. 2003)

19 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : hostility, violence, agitation 에대한효과 20 Olanzapine in Mania: PANSS hostility component of 4 items Percent Improvement from Baseline in PANSS Hostility Score % P=0.01-9% Olanzapine Placebo *In the four-week study II, the olanzapine group had superior LOCF improvement from baseline hostility (p=.01) on PANSS Hostility Component of four items: Excitement, Hostility, Uncooperativeness, Poor Impulse Control

20 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : hostility, violence, agitation 에대한효과 21 Seroquel : improvement in aggression and hostility -6-5 Seroquel (n=208) Placebo (n=195) -4.8 Mean change in PANSS activation subscale score from baseline (LOCF) *** -1.4 *** Day 21 Day 84 Jones & Huizar 2003 ***p<0.001 vs placebo Mean baseline PANSS activation subscale score: Seroquel 16.0; placebo 15.8 Data from a combined analysis of two randomized trials

21 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : Mixed, rapid cycling 에대한효과 22 0 mixed patients OLZ + MS n=121 MS only n=54 Treat with OZP Rapid cyclers n=24 Not rapid cyclers, n=30 Mean Change p< No difference Tohen et al. 2002

22 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : Comorbid depressive symptoms 호전 23 Mean Change in HAM-D (LOCF) Baseline to Endpoint (Week 3) Baseline: p=ns Olanzapine (n=123) Divalproex (n=123) Baseline: Mean Change in HAM-D from Baseline to Endpoint (Week 6) * *p<.001 OLZ + Li + /VPA (n=220) PBO + Li + /VPA (n=114) Tohen M et al. Am J Psychiatry. 2002;159(6): Tohen M et al. Arch Gen Psychiatry. 2002;59(1):62-69.

23 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : 조증후우울증발생억제효과 24 Probability of Not Switching to Depression Olanzapine co-therapy (n=51) Monotherapy (n=48) p= Time to Switching to Depression (weeks) Tohen et al. 2002

24 Atypical Antipsychotics 관련 issues : ( 병용 ) 치료의장점 : 인지기능장애개선효과 25 Mean Change in PANSS Cognitive Score PANSS Cognitive Component Olanzapine (n=129) Placebo (n=125) Significant improvement in PANSS Cognitive component score relative to placebo (p<.001) Conceptual disorganization Difficulty in abstract thinking Stereotypic thinking Tension Mannerisms Poor attention Poor judgment and insight Pooled results from placebo controlled studies. Data on file, Eli Lilly and Company.

25 Atypical Antipsychotics 관련 issues : 약물간의효과차이가있는가? 26 Polled Trial Drug Effects (random-effects model) Perlis et al Dotted line on the left indicates the pooled difference from placebo among all monotherapy and combination trials

26 Atypical Antipsychotics 관련 issues : 약물간의효과차이가있는가? 27 Monotherapy efficacy in Responders (50% improvements) Dotted line on the right indicates the mean OR. Perlis et al. 2006

27 AAPs 와 MS 의선택기준은? 28 Mania Mixed Rapid Cycling Depression Prophylaxis Lithium yes?? Probable Probable Carbamazepine yes Yes Probable? Probable Valproate yes yes Yes? probable yes efficacy based on at least one double-blind monotherapy study in a phase of bipolar illness Probable appreciable open evidence of efficacy in monotherapy? minimal open data supporting efficacy

28 AAPs 와 MS 의선택기준은? 29 Good response to Lithium 기분장애의가족력 euphoric mania(60-80%) dysphoric or mixed mania(20%) 약물순응도 ( ), 자살위험성 (-) 조증삽화가 3회미만 정신병적양상 (-) 과거의좋은반응 삽화순서 : M-D-I Poor response to Lithium Dysphoric mania & mixed state Psychotic mania Depression-maniaresolution (DMI) 순서 Past manic episodes > 11, or depressive episodes >4 History of rapid cycling Substance abuse Better response to AC & AP

29 Ideal Combination : Bipolar Treatment Paradigm 30 Anxiolytic Additional Mood Stabilizer Antipsychotic Antidepressant Foundational Mood Stabilizer

30 Rationale for ideal combination therapy 31 Different modes of action Non-additive side-effect profiles Enhanced efficacy with no increased toxicity Improved outcome compared with monotherapy Patients showing poor response to monotherapy may benefit from combination treatment

31 Novel antipsychotics and novel AEDs have complementary actions in bipolar disorder Novel antipsychotics D2 antagonists (with fewer EPS) NA α2 receptor blockade (linked to moodmodifying effects) 5-HT2 receptor blockade (linked to lower EPS and mood-modifying effects) B I P O L A R Novel AEDs Block Na + channels Increase GABA function Alter glutamate function

32 TIMA, Adapted from: Suppes, JCP 2005;66:

33 KMAP-BP 2006: Acute Mania 34 Hypomanic Euphoric Mixed Psychotic Li/DVP (Li/DVP) + AAP AAP DVP+AAP (DVP/Li) + AAP Li + DVP Li + DVP + AAP DVP + (Li/CBZ/LTG) + AAP DVP + Li + AAP change AAP ECT or benzodiazepine at any stage Avoid CLZ + CBZ change AAP to AAP(including CLZ) or CAP or change MS to CBZ or other anticonvulsant or add another MS

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