1. 2011. 3. 25. 대한 중독정신의학회 춘계학술대회 건국대학교 충주병원 정신과 서정석 양극성 장애를 가진 알코올 의존

2. Contents Prevalence of each disorder and comorbidity Clinical Impact of comorbidity Clinical characteristics or risk factor Why high comorbidity ? Treatment summary

3. Prevalence of comorbidity

4. Lifetime prevalence of each disorder 외국 0 Lifetime prevalence(%) Bipolar I 1) 1.0 Bipolar II 1) 1.1 Alcohol abuse 2) 9.4 Alcohol dependence 2) 14.1 1. Merikangas et al, 2007; 2. Kessler et al, 1994  Alcohol use disorder 3)  life-time prevalence : 15.9%  female : 6.3%, male : 25.2%  기분장애 4)  전체 기분장애 : 4.0 ( 여자 :8.4, 남자 :6.2)  우울장애 : 3.6 ( 여자 : 7.6, 남자 : 5,6)  양극성 장애 : 0.4 ( 여자 0.3, 남자 : 0.3) 3. 보건복지부와 국립서울병원, 2001 4. 보건복지부. 정신질환역학조사, 2006

5. Overrepresentation of SUD and BD NCS lifetime diagnosis of alcohol dependence + co-occurring mania OR in men =12.03; OR in women = 5.3 (Kessler et al,1997) rates of BD are elevated 5 to 8 times in patients with SUD 1) prevalence rate of bipolar illness and concurrent substance use disorders: 21–58% (Brady and Lydiard, 1995) 4% – 65% compared with rates of 6% – 12% 2) in the general population (Brown et al, 2001) nearly 60% of patients hospitalized for manic or mixed episodes had a lifetime substance use disorder (Cassidy et al, 2001) 1. Kessler et al, 1997; 2. Kessler et al 1996

6. Lifetime prevalence of comorbid conditions Merikangas et al, 2007

7. Cerullo and Strakowski, 2007

8. Clinical Impact of comorbidity

9. Negative impact on clinical course and outcome higher rates of mixed or dysphoric mania, rapid cycling, increased symptom severity (Salloen et al, 2001; 2002) higher levels of novelty seeking, impulsivity, aggressivity, and suicidality (Frye and Salloun, 2006; Cardoso et al, 2008) Severer cognitive impairment (Levy. et al, 2007) earlier age of onset (Winokur et al, 1998) lower response to lithium (O’Connell et al, 1991;Sonne et al, 1994) less likely to achieve remission (Black et al, 1988) higher relapse rate (Tohen et al, 1990) non-compliance (Strakowski et al, 1998;Aagaard and Vestergaard, 1990) lower quality of life (Weiss et al, 2005) more psychiatric hospitalization (Hoblyn et al, 2009)

10. How much they drinks? N=30 of BP with alcohol abuse or dependence Alcohol Timeline Followback (TLFB) method 60% of alcohol patients had undiagnosed bipolar disorder. McKowen et al, 2005 Cf) 10 SD in alcoholism

11. Clinical characteristics or risk factor

12. Risk factor SUD + comorbid mood disorder than pure in women 1) less educated subjects unemployed those with parental psychiatric history, those with a childhood trauma. Associated variables between substance use disorders and past suicide attempt in BD-I 2) Aggression / impulsivity / hostility Variables associated with alcohol use disorders in BD-I 2) earlier age of onset of bipolar illness smoking physical/sexual abuse. Predominantly depressive episodes 3) 1) de Graaf et al, 2002; 2) Sublette et al, 2008; 3) Gonzalez-Pinto et al, 2010

13. BD first vs alcohol first more affective symptoms earlier onset of BD slower recovery of affective symptoms secondary SUD fewer days of euthymia more mood episodes more suicide attempts - Primary SUD (or alcohol first) is a less severe form of BD ? Cerullo and Strakowski, 2007

14. Why high comorbidity ?

15. Hypotheses of high comorbidity 1 Old explanation: so-called “ Berkson ’ s bias ” 1) Diagnostic dilemma “ excessive involvement in pleasurable activities that have a high potential for painful consequences ” (APA,1994), which could be interpreted to include substance abuse Insufficient diagnostic boundaries (Angst et al, 2006) Self-medication: less appropriate 1.Berkson, 1946

16. Hypotheses of high comorbidity 2 Genetic factor Twin study (Prescott et al, 2000) Dopamine receptor polymorphism : inconsistent Adoption study: substance abuse was more common in the biological relatives of bipolar adoptees than in controls’ relatives ( Ingraham and Wender, 1992) Family study: independent cause (Nurunberger et al, 2004) Causal relationship Substance could cause BD Mania as a predictor of the later onset of alcohol dependence (Kessler et al, 1997) Aroused affect and expansive temperament characteristics elevated risk behaviors and novelty seeking in patients with bipolar disorder (Hantouche e t al, 2003) high general prevalence of polysubstance dependence (Frye et al, 2003) Alcohol dependence is a symptom of bipolar disorder Strat and Gorwood. Medical Hypothesis, 2008

17. Hypotheses of high comorbidity 3 Neurochemical abnormalities In lt. dorsolateral prefrontal cortex (DLPFC), lower glutamate concentration in alcoholic BD than non-alcoholic BD (Nery et al, 2010) reduced sensitivity to the dysphoric and adverse effects of ethanol (Schuckit and Smith, 1996). Multiple mechanism (Swendsen and Merikangas, 2000)

18. Mood disorder Hypercortisolemia Alcohol dependence stress Dysregulation in serotoninergic system Other mediator… Hypothesis:alcohol-HPA-5-HT-mood disorder Allostasis 서정석, 대한정신약물학회 구연발표, 2007

19. Hypothesis of overrepresentation 1. Substance abuse occurs as a symptom of bipolar disorder (-) 2. Substance abuse is an attempt by bipolar patients to self-medicate symptoms (-) 3. Substance abuse causes bipolar disorder (±) 4. BD causes substance abuse (±) Strakowski and DelBello, Clinical Psychology Review, 2000

20. Hypothesis of overrepresentation 1. Substance abuse occurs as a symptom of bipolar disorder (±) 2. Substance abuse is an attempt by bipolar patients to self-medicate symptoms (±) 3. Substance abuse causes bipolar disorder (±) 4. BD causes substance abuse (±) Strakowski and DelBello, Clinical Psychology Review, 2000

21. Treatment 1. Drugs 2. Treatment considerations

22. Ideal medication to relieve symptoms of the BPD to relieve withdrawal symptoms or drug craving so as to reduce drug use to prevent relapse to abuse after the withdrawal treatment to have low abuse liability and preferably be available in a formulation to require infrequent dosing to enhance medication adherence. to be well tolerated and have no or few side effects

23. Azorin et al, Neuropsychiatric Disease and Treatment, 2010

24. Cerullo and Strakowski, 2007

25. Medication strategies Mood stabilizer carbamazepine and valproate : some benefit ( Kosten and Kosten, 2004) effectiveness of valproate for maintenance (Salloum et al, 2005) Lithium poor response (O'Connell et al, 1991; Kusalic and Engelsmann, 1998) maybe useful in bipolar adolescents with a secondary SUD (Geller et al, 1998) lithium + divalproex : effective but greater adverse events (Salloum et al., 2005) Lamotrigine add-on or monotherapy: effective for BD + cocaine dependence (Brown et al, 2003) add-on: significant improvement in HAM-D, YMRS, BPRS and alcohol craving and CDT (Rubio et al, 2006)

26. Medication strategies Atypical antipsychotics Aripiprazole: Significant improvement (Brown et al, 2005) Quetiapine add-on no effect for BD + cocaine dependence (Broun et al,2002) no effect for BD + alcohol dependence (Stedman et al, 2010) effective for BD + alcohol+cocaine (Longotia et al, 2004) Quetiapine monotherapy : effective for type B drinker (Kampman et al, 2007) randomized, double-blind, placebo-controlled QTP add-on therapy in 115 outpatients for 12wks: no differences in primary outcomes (alcohol use or YMRS) (Brown et al, 2008) Natlrexone add-on therapy significant improvement in manic and depressive symptom severity, as well as alcohol use and craving (Brown et al, 2006) add-on therapy, randomized, double-blind, placebo-controlled (Brown et al, 2009) trends (p <.10) toward a greater decrease in drinking days (binary outcome), alcohol craving

27. Considerations in treatment Earlier implementing substance treatment program Increased aggression and impulsivity Alcohol abuse or excessive use of alcohol Gap between onset of bipolar symptoms and correct diagnosis of BD in alcoholism Alcohol problem screening in BD patients Relationship between 2 disorders Case 1: alcohol problem accompanied by mood episode Case 2: heavy alcohol drinking even in euthymic state 1) to treat the substance use disorder by ameliorating the bipolar disorder symptoms 2) to use medication (naltrexone) to directly decrease substance use

28. summary 두 질환의 공존은 매우 흔하다. 단독일 경우보다 공존할 경우 치료 결과나 예후가 좋지 못하다. 알코올 문제를 양극성 장애의 증상의 일부로 볼 것인지, 아니면 적극적인 치료가 필요한 공존 질환으로 볼 것인 가 ? valproate1 차 기분조절제이다. 그 외에 잠재적 이득이 있는 치료 약물을 선택한다.