1. Alcohol and Co-Occurring Psychiatric Disorders Kathleen Brady, M.D., Ph.D. Medical University of South Carolina

2. Overview Prevalence Prevalence Relationship between psychiatric and alcohol use disorders Relationship between psychiatric and alcohol use disorders Differential Diagnosis Differential Diagnosis Course of Illness Course of Illness Treatment Treatment

3. Specific Disorders of Focus Mood Disorders Mood Disorders Anxiety Disorders Anxiety Disorders Schizophrenia Schizophrenia Attention Deficit Hyperactivity Disorder Attention Deficit Hyperactivity Disorder

4. 12-Month Odds of AUD and Mood/Anxiety Grant et al., 2004 Arch Gen Psychiatry

5. Substance-induced Substance-induced Self-medication Self-medication Common etiology Common etiology –Common risk factors –Common neurobiology Alcohol Use Disorders and Psychiatric Disorders: Etiologic Connections

6. Diagnostic Confusion Chronic alcohol use and withdrawal can mimic symptoms of many psychiatric disorders Chronic alcohol use and withdrawal can mimic symptoms of many psychiatric disorders –Acute intoxication - mood symptoms –Withdrawal - anxiety and mood symptoms –Chronic use - delirium, cognitive changes

7. Complex Relationship Relationship not unidirectional Relationship not unidirectional –Alcohol Use Disorders (AUD) increase risk for the development of psychiatric disorders - ? adolescent use particularly problematic –Some psychiatric disorders increase risk for development of AUD –Certain environmental conditions predispose to both AUD and psychiatric disorders –? Shared genetic risk

8. Yale Family Study Alcohol + anxiety increased risk for both Alcohol + anxiety increased risk for both Alcohol only = no increased anxiety Alcohol only = no increased anxiety Anxiety only = increased alcohol Anxiety only = increased alcohol Gender influence Gender influence Shared etiologic factors: Shared etiologic factors: –Genetic factors predisposing to both –Environmental risk factors Merikangas KR, et al. Psychol Med. 1998; 28:773-788.

9. Two pathways for comorbidity suggested: Social anxiety disorder (SAD) Social anxiety disorder (SAD) –Transmitted independently –Precedes onset alcoholism –? Self medication Panic disorder Panic disorder –Shared diathesis –Nonsystematic order of onset –? Manifestations of underlying risk Merikangas KR, et al. Psychol Med. 1998;28:773-788. Familial Aggregation of Alcoholism and Anxiety Disorders

10. Abuse positively associated with a number of disorders Abuse positively associated with a number of disorders Strongest relationship with alcohol/drug use Strongest relationship with alcohol/drug use More severe abuse increases risk More severe abuse increases risk Not explained by background/familial factors Not explained by background/familial factors Kendler KS, et al. Arch Gen Psychiatry. 2000;57:953-959. Childhood Sexual Abuse and Psychiatric Disorders in Women

11. Screening and Assessment Many screening tools available Many screening tools available Diagnostic assessment requires more time/expertise Diagnostic assessment requires more time/expertise Every individual with a psychiatric disorder should be screened for substance use Every individual with a psychiatric disorder should be screened for substance use Every individual with a substance use disorder should be screened for psychiatric disorder Every individual with a substance use disorder should be screened for psychiatric disorder

12. Diagnostic Difficulties Diagnose if: Symptoms clearly began before the onset of substance use disorder Symptoms clearly began before the onset of substance use disorder Symptoms persist during sustained periods of abstinence Symptoms persist during sustained periods of abstinence Shorter period of abstinence may be necessary to accurately diagnose some disorders Shorter period of abstinence may be necessary to accurately diagnose some disorders

13. General Principles of Differential Diagnosis Order of onset Order of onset Periods of abstinence Periods of abstinence Substance-induced symptoms abate relatively quickly Substance-induced symptoms abate relatively quickly Non-overlapping symptoms Non-overlapping symptoms Family history positive Family history positive

14. APA Treatment Guidelines When possible, delay treatment by 1-4 weeks to allow for the identification of transient substance-induced symptoms When possible, delay treatment by 1-4 weeks to allow for the identification of transient substance-induced symptoms Earlier treatment if: Earlier treatment if: –Severe symptoms –Symptoms precede substance use/prior episodes –Family history positive

15. Careful screening/diagnostic evaluation Careful screening/diagnostic evaluation Address psychiatric and AUD problems at same time Address psychiatric and AUD problems at same time Use medication with least abuse potential and least toxicity should relapse occur Use medication with least abuse potential and least toxicity should relapse occur Maximize the use of non-pharmacologic treatment Maximize the use of non-pharmacologic treatment General Principles in the Treatment of Comorbidity

16. Benzodiazepines Use beyond detoxification is controversial Use beyond detoxification is controversial Not absolute contraindication Not absolute contraindication Difference in abuse potential within class: Difference in abuse potential within class: –Diazepam/alprazolam greater than clonazepam/oxazepam

17. Important to maximize non-pharmacologic strategies Important to maximize non-pharmacologic strategies Cognitive-behavioral therapies efficacious in AUD’s and many psychiatric disorders Cognitive-behavioral therapies efficacious in AUD’s and many psychiatric disorders  Enhance self-efficacy  Decrease helplessness/dependency  Enhance coping strategies Psychotherapy

18. Synergy Between Pharmacotherapy and Psychotherapy 95 methadone-maintained subjects 95 methadone-maintained subjects No main effect of sertraline No main effect of sertraline Significant impact of sertraline on depression in individuals with less adversity in environment Significant impact of sertraline on depression in individuals with less adversity in environment Carpenter, K. M., et al., 2004. Drug Alcohol Depend, 74(2), 123-134.

19. MOOD DISORDERS

20. Depressive Disorders Depressive Disorders –Most common co-morbidity –Reflects prevalence in general population –Odds ratio approximately 2.0 Bipolar Disorder Bipolar Disorder –Less prevalent in general population, but higher percentage of BPAD have SUD’s –Odds ratio 4.0-8.0 Prevalence Comorbid Mood Disorders and AUDs

21. Medication Treatment of Depression in Patients with Substance Use Disorders Meta-analysis Meta-analysis Prospective, double -blind, controlled trials Prospective, double -blind, controlled trials 14 studies, 848 patients 14 studies, 848 patients –5 with tricyclics –7 with SSRI’s –2 other Nunes and Levin, JAMA, 2004

22. Nunes & Levin, JAMA,2004 Effect of Antidepressant Medication on Outcome of Depression (Hamilton Depression Scale)

23. Nunes & Levin, JAMA, April 21, 2004 Effect of Antidepressant Medication on Outcome of Substance Abuse

24. Conclusions Medications effective in treating depression Medications effective in treating depression –High placebo response in some studies may reflect inclusion of substance-induced depression –? SSRI’s less effective Effective treatment of depression associated with decreased substance use Effective treatment of depression associated with decreased substance use

25. Substance Use Disorder and Bipolar Disorder: Multiple Levels of Association Phenomenological similarities Phenomenological similarities –Impulsivity, irritability, etc. Neurobiological evidence Neurobiological evidence –Kindling, neuronal loss Pharmacological evidence Pharmacological evidence –Responsivity to anticonvulsant agents

26. Valproate Efficacy in Bipolar Alcoholics CR Placebo + Tau Lithium & DR Counseling Valproate + Tau Lithium & DR Counseling Salloum, IM et al, Archives Gen Psych, 2005 Stabilization 7-14 Days NIAAA-Funded Inclusion: Acute bipolar episode Active ETOH use Assessment q 2 weeks 24 Weeks N: C=72R=59ITT=52 (88%)Completers=20

27. Valproate vs. Placebo Number of Drinks per Heavy Drinking Day P=0.02* Valproaten=27Placebon=25 * Medication adherence as covariate in the Mixed Model Salloum, IM et al, Archives Gen Psychiatry, 2005 Number of Drinks Per Heavy Drinking Day

28. Conclusions Valproate treatment associated with significantly better drinking outcomes as compared to placebo Valproate treatment associated with significantly better drinking outcomes as compared to placebo

29. Moderate Alcohol Consumption and Illness Severity in Bipolar Disorder 148 bipolar patients with minimal alcohol consumption 148 bipolar patients with minimal alcohol consumption –Drinks/week - 3.8 men; 1.2 women Alcohol consumption associated with lifetime manic/depressive episodes, emergency department visits Alcohol consumption associated with lifetime manic/depressive episodes, emergency department visits ? Increased sensitivity to impact of alcohol ? Increased sensitivity to impact of alcohol Goldstein, B. I., et al (2006). Drugs, 66(9), 1229-1237

30. Psychotherapy in Substance-Using Bipolar Patients Cognitive behavioral therapies effective in both disorders Cognitive behavioral therapies effective in both disorders Development of specific “integrated” therapy Development of specific “integrated” therapy –topics relevant to both disorders –relationship of disorders Integrated Group Therapy had better outcomes Integrated Group Therapy had better outcomes –ASI scores –% months abstinent Weiss, R. D., et al. (2007). Am J Psychiatry, 164(1), 100-107.

31. ANXIETY DISORDERS

32. 12-Month Odds of Substance Use Disorders (SUDs) and Independent Anxiety Disorder Any SUD Alcohol Dependence Drug Dependence Any anxiety disorder1.92.6 6.2 Panic disorder with agoraphobia without agoraphobia 3.1 2.1 3.6 3.4 10.5 7.6 Social phobia GAD 1.9 2.3 2.5 3.1 5.4 10.4 Grant BF, et al. Arch Gen Psychiatry. 2004;61:807-816. GAD=generalized anxiety disorder.

33. Controlled Pharmacotherapy Trials Anxiety and Alcohol 2 placebo-controlled trials positive using buspirone for GAD/alcoholism 2 placebo-controlled trials positive using buspirone for GAD/alcoholism Small controlled trial of paroxetine in social phobia/alcoholism positive Small controlled trial of paroxetine in social phobia/alcoholism positive Controlled trial of sertraline in Post-traumatic Stress Disorder (PTSD)/alcoholism robust effects in subgroup of individuals with early trauma Controlled trial of sertraline in Post-traumatic Stress Disorder (PTSD)/alcoholism robust effects in subgroup of individuals with early trauma

34. Serotonin Reuptake Inhibitors Efficacious in treatment of anxiety disorders Efficacious in treatment of anxiety disorders Data in alcohol use disorders(AUDs) alone inconsistent Data in alcohol use disorders(AUDs) alone inconsistent –Overall studies predominantly negative or show only modest improvement –Subtyping by psychiatric comorbidity or other features of illness shows promise

35. Generalized Anxiety Disorder (GAD) Strongly associated with alcohol dependence (OR 3.1) Strongly associated with alcohol dependence (OR 3.1) Much symptom overlap - diagnostic difficulty Much symptom overlap - diagnostic difficulty GAD in adolescents associated with progression to alcohol dependence GAD in adolescents associated with progression to alcohol dependence Sartor et al., 2007 Sartor et al., 2007 AUDs worsen course of illness in GAD AUDs worsen course of illness in GAD Bruce et al., 2005 Bruce et al., 2005 Sartor, et al. (2007). Addiction, 102(2), 216-225. Bruce, et al. (2005). Am J Psychiatry, 162(6), 1179-1187.

36. Buspirone Treatment of Anxious Alcoholics 61 anxious alcoholics 61 anxious alcoholics 12 week, placebo-controlled trial 12 week, placebo-controlled trial Relapse prevention therapy Relapse prevention therapy Buspirone associated with Buspirone associated with –Greater retention –Lower anxiety –Less consumption Kranzler, et al. (1994). Arch Gen Psychiatry, 51(9), 720-731.

38. Panic Disorder Risk of panic disorder elevated 2-4 fold in individuals with AUD’s Risk of panic disorder elevated 2-4 fold in individuals with AUD’s Panic attacks can be associated with alcohol withdrawal - substance-induced Panic attacks can be associated with alcohol withdrawal - substance-induced Few treatment studies of co-occurring Few treatment studies of co-occurring –Cognitive behavioral therapy efficacious in uncomplicated panic –Selective serotonin reuptake inhibitors (SSRIs) efficacious in uncomplicated panic Cosci, et al. (2007). J Clin Psychiatry, 68(6), 874-880.

39. Social Anxiety Disorder (SAD) Key symptom, fear of scrutiny or social situations, has early onset, typically before development of AUD Key symptom, fear of scrutiny or social situations, has early onset, typically before development of AUD Lifetime prevalence of AUD in individuals with SAD is 48% Lifetime prevalence of AUD in individuals with SAD is 48% Prevalence of SAD in individuals with AUD approximately 20% Prevalence of SAD in individuals with AUD approximately 20% Grant, et al. (2005). J Clin Psychiatry, 66(11), 1351-1361.

40. Paroxetine in Comorbid SAD and Alcoholism 15 men and women with social phobia and alcohol dependence or abuse 15 men and women with social phobia and alcohol dependence or abuse Double-blind, placebo-controlled Double-blind, placebo-controlled Paroxetine – flexible dosing up to 60 mg/d Paroxetine – flexible dosing up to 60 mg/d Brief motivational therapy for alcoholism Brief motivational therapy for alcoholism Randall CL, et al. Depress Anxiety. 2001;14:255-262.

41. Paroxetine in Comorbid SAD and Alcoholism Weeks of Treatment Adjusted Group Means Randall CL, et al. Depress Anxiety. 2001;14:255-262.

42. Treatment Studies: SAD/AUD Shade et al. (2005) Alcoholism: Clinical Experimental Research Shade et al. (2005) Alcoholism: Clinical Experimental Research –87 subjects with SAD plus AUD –CBT plus optional fluvoxamine vs TAU –Combined treatment better than TAU Randall CL, et al (2001) Alcoholism: Clinical Experimental Research Randall CL, et al (2001) Alcoholism: Clinical Experimental Research –CBT targeting both SAD and AUD symptoms vs CBT for AUD only –Combined treatment group had worse drinking outcomes - ? Exposure to social situations increased urge to drink

43. MEN% Odds Ratio Alcohol abuse/dependence 51.92.06 Drug abuse/dependence 34.52.97 WOMEN Alcohol abuse/dependence 27.92.48 Drug abuse/dependence 26.94.46 Kessler RC, et al. Arch Gen Psychiatry. 1995;52:1048-1060. Comorbidity of PTSD and SUDs National Comorbidity Study

44. Characteristic symptoms that persist for at least 1 month following trauma Characteristic symptoms that persist for at least 1 month following trauma High incidence of traumatic life events in individuals with AUD’s High incidence of traumatic life events in individuals with AUD’s Treatment seeking individuals with SUD’s : 36-50% lifetime PTSD 25-42% current PTSD Treatment seeking individuals with SUD’s : 36-50% lifetime PTSD 25-42% current PTSD Jacobsen LK, Am J Psychiatry, 158(8), 1184-1190. Post Traumatic Stress Disorder (PTSD)

45. Co-Occurring PTSD/AUD Treatment Exposure therapy demonstrated efficacy in PTSD Exposure therapy demonstrated efficacy in PTSD Reluctance to explore in individuals with co-occurring AUD for fear of provoking relapse Reluctance to explore in individuals with co-occurring AUD for fear of provoking relapse Preliminary studies in cocaine- dependent individuals show promise Preliminary studies in cocaine- dependent individuals show promise Brady, et al. (2001) J Subst Abuse Treat, 21(1), 47-54.

46. PTSD Integrated Treatment: Seeking Safety 24 sessions in 12 weeks 1 24 sessions in 12 weeks 1 Group therapy integrating CBT for SUDs and PTSD 1 Group therapy integrating CBT for SUDs and PTSD 1 Emphasis of Seeking Safety : interpersonal relationships - no trauma exposure 2 Emphasis of Seeking Safety : interpersonal relationships - no trauma exposure 2 1. Hien DA, et al. Am J Psychiatry. 2004;161:1426-1432. 2. Najavits LM. Seeking Safety. New York, NY: Guilford Publications; 2001.

47. PTSD and Alcoholism Treatment With Sertraline 12-week study 12-week study Double-blind, placebo-controlled trial Double-blind, placebo-controlled trial Weekly CBT targeting alcoholism Weekly CBT targeting alcoholism Measure alcohol and PTSD outcomes Measure alcohol and PTSD outcomes 94 subjects with both PTSD and alcoholism 94 subjects with both PTSD and alcoholism –43 women; 51 men Brady KT, et al. Alcohol Clin Exp Res. 2005;29:343-352.

48. Cluster Analysis – Sertraline 3 distinct clusters 3 distinct clusters –Cluster 1: Early-onset PTSD; later onset, less severe alcoholism (N=14) –Cluster 2: Onset PTSD/alcohol relatively close; less severe alcohol dependence (N=53) –Cluster 3: Early onset, severe alcoholism; later-onset PTSD (N=27) Brady KT, et al. Alcohol Clin Exp Res. 2005;29:343-352.

49. Adjusted Mean Average Days Drinking Over Treatment Period Cluster by group P=.068. Brady KT, et al. Alcohol Clin Exp Res. 2005;29:343-352.

50. Attention Deficit Hyperactivity Disorder - ADHD Characterized by excessive activity, inability to pay attention, impulsive behavior, poor organizational skills Characterized by excessive activity, inability to pay attention, impulsive behavior, poor organizational skills Must appear in childhood Must appear in childhood When unrecognized, associated with poor performance in school and work When unrecognized, associated with poor performance in school and work

51. ADHD and Substance Use Disorders No controlled trials in pharmacotherapeutic strategies in substance users No controlled trials in pharmacotherapeutic strategies in substance users Conventional wisdom: Avoid psychostimulants, but not well studied Conventional wisdom: Avoid psychostimulants, but not well studied Bupropion, venlafaxine, tricyclics, clonidine may be used Bupropion, venlafaxine, tricyclics, clonidine may be used

52. Substance Use in Schizophrenia Approximately 50% have lifetime SUD - alcohol most common Approximately 50% have lifetime SUD - alcohol most common ? Reward dysfunction inherent in neuropathology, increased vulnerability ? Reward dysfunction inherent in neuropathology, increased vulnerability Some suggestion of better response to atypical antipsychotics Some suggestion of better response to atypical antipsychotics

53. Naltrexone in Alcohol Dependence and Schizophrenia 31 subjects with co-occurring alcohol dependence and schizophrenia 31 subjects with co-occurring alcohol dependence and schizophrenia Stabilized on antipsychotic medication Stabilized on antipsychotic medication 12 weeks treatment with naltrexone (50 mg) vs placebo 12 weeks treatment with naltrexone (50 mg) vs placebo Naltrexone group had fewer drinking days, fewer heavy drinking days and less craving Naltrexone group had fewer drinking days, fewer heavy drinking days and less craving »Petrakis et al., 2004

54. Disulfram and Naltrexone in Comorbid Patients 254 patients with alcohol dependence plus comorbid Axis I diagnosis 254 patients with alcohol dependence plus comorbid Axis I diagnosis –70% MDE; 42% PTSD; 19% Bipolar Disulfram and naltrexone alone and in combination Disulfram and naltrexone alone and in combination Active medication associated with longer abstinence and less craving Active medication associated with longer abstinence and less craving No advantage of combination therapy No advantage of combination therapy Petrakis IL, et al. (2005). Biol Psychiatry, 57(10), 1128-1137.

55. Alcohol Use and Psychiatric Disorders: The Future Exploration of agents that act on common neural pathways Exploration of agents that act on common neural pathways Exploration of medications targeting alcohol use disorders in individuals with psychiatric disorders Exploration of medications targeting alcohol use disorders in individuals with psychiatric disorders Development and exploration of psychotherapeutic interventions specifically targeting co-occurring disorders Development and exploration of psychotherapeutic interventions specifically targeting co-occurring disorders

56. CONCLUSIONS Substance use and psychiatric disorders Substance use and psychiatric disorders –commonly co-occur –etiologic connections –impact course of illness –impact treatment decisions