RSA Comorbidity Lecture.ppt

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					Alcohol and Co-Occurring
  Psychiatric Disorders
   Kathleen Brady, M.D., Ph.D.
Medical University of South Carolina
              Overview
• Prevalence
• Relationship between psychiatric and
  alcohol use disorders
• Differential Diagnosis
• Course of Illness
• Treatment
    Specific Disorders of Focus
•   Mood Disorders
•   Anxiety Disorders
•   Schizophrenia
•   Attention Deficit Hyperactivity Disorder
       12-Month Odds of AUD and Mood/Anxiety

                            Any AUD    Alcohol Abuse     Alcohol Dependence
Any Mood Disorder               2.6%             1.3%                  4.1%
    Major Depression            2.3%             1.2%                 *3.7%
    Dysthymia                   1.7%             0.8%                  2.8%
    Mania                       3.5%             1.4%                 *5.7%
    Hypomania                   3.5%             1.7%                 *5.2%

Any Anxiety Disorder           1.7%             1.1%                           2.6%
    Panic
       with Agoraphobia        2.5%             1.4%                          *3.6%
       without Agorphobia      2.0%             0.8%                          *3.4%
    Social Phobia              1.7%             0.9%                           2.5%
    GAD                        1.9%             0.9%                          *3.1%




                                                Grant et al., 2004 Arch Gen Psychiatry
 Alcohol Use Disorders and Psychiatric
    Disorders: Etiologic Connections

• Substance-induced
• Self-medication
• Common etiology
  – Common risk factors
  – Common neurobiology
      Diagnostic Confusion
• 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
      Complex Relationship
• 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
           Yale Family Study
•   Alcohol + anxiety increased risk for both
•   Alcohol only = no increased anxiety
•   Anxiety only = increased alcohol
•   Gender influence
•   Shared etiologic factors:
    – Genetic factors predisposing to both
    – Environmental risk factors




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


                           Merikangas KR, et al. Psychol Med. 1998;28:773-788.
Childhood Sexual Abuse and Psychiatric
         Disorders in Women

• Abuse positively associated with a number of
  disorders
• Strongest relationship with alcohol/drug use
• More severe abuse increases risk
• Not explained by background/familial factors




                      Kendler KS, et al. Arch Gen Psychiatry. 2000;57:953-959.
  Screening and Assessment
• Many screening tools available
• Diagnostic assessment requires more
  time/expertise
• 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
       Diagnostic Difficulties
Diagnose if:
  • Symptoms clearly began before the onset
    of substance use disorder
  • Symptoms persist during sustained
    periods of abstinence
  • Shorter period of abstinence may be
    necessary to accurately diagnose some
    disorders
        General Principles of
        Differential Diagnosis
• Order of onset
• Periods of abstinence
• Substance-induced symptoms abate
  relatively quickly
• Non-overlapping symptoms
• Family history positive
   APA Treatment Guidelines
• When possible, delay treatment by 1-4 weeks
  to allow for the identification of transient
  substance-induced symptoms
• Earlier treatment if:
   – Severe symptoms
   – Symptoms precede substance use/prior
     episodes
   – Family history positive
        General Principles in the
        Treatment of Comorbidity

• Careful screening/diagnostic evaluation
• Address psychiatric and AUD problems at same
  time
• Use medication with least abuse potential and
  least toxicity should relapse occur
• Maximize the use of non-pharmacologic
  treatment
            Benzodiazepines
• Use beyond detoxification is controversial
• Not absolute contraindication
• Difference in abuse potential within class:
  – Diazepam/alprazolam greater than
    clonazepam/oxazepam
                Psychotherapy
• Important to maximize non-pharmacologic
  strategies
• Cognitive-behavioral therapies efficacious in
  AUD’s and many psychiatric disorders
   Enhance self-efficacy
   Decrease helplessness/dependency
   Enhance coping strategies
Synergy Between Pharmacotherapy
       and Psychotherapy
• 95 methadone-maintained subjects
• No main effect of sertraline
• 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.
MOOD DISORDERS
  Prevalence Comorbid Mood Disorders
              and AUDs
• Depressive Disorders
   – Most common co-morbidity
   – Reflects prevalence in general population
   – Odds ratio approximately 2.0
• Bipolar Disorder
   – Less prevalent in general population, but
     higher percentage of BPAD have SUD’s
   – Odds ratio 4.0-8.0
 Medication Treatment of Depression in
 Patients with Substance Use Disorders

• Meta-analysis
• Prospective, double -blind, controlled
  trials
• 14 studies, 848 patients
  – 5 with tricyclics
  – 7 with SSRI’s
  – 2 other

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




                                       Nunes & Levin, JAMA,2004
Effect of Antidepressant Medication on
    Outcome of Substance Abuse




                           Nunes & Levin, JAMA, April 21, 2004
               Conclusions
• 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
         Substance Use Disorder and
                Bipolar Disorder:
         Multiple Levels of Association

• Phenomenological similarities
  – Impulsivity, irritability, etc.
• Neurobiological evidence
  – Kindling, neuronal loss
• Pharmacological evidence
  – Responsivity to anticonvulsant agents
                        Valproate Efficacy in
                         Bipolar Alcoholics
                                         NIAAA-Funded
   Inclusion:
   Acute bipolar episode
   Active ETOH use                                           Placebo + Tau
                                                       Lithium & DR Counseling


        C                   R

                                                            Valproate + Tau
                                                       Lithium & DR Counseling

               Stabilization                  Assessment q 2 weeks
           7-14 Days                              24 Weeks
     N: C=72      R=59                   ITT=52 (88%)                Completers=20

Salloum, IM et al, Archives Gen Psych, 2005
           Valproate vs. Placebo
   Number of Drinks per Heavy Drinking Day
        Per Heavy Drinking Day

                                               10.2
           Number of Drinks



                   12
                                                                             P=0.02*
                   10

                        8                                          5.59

                        6

                        4

                        2
                        0
                                     Placebo             Valproate
                                      n=25                 n=27
* Medication adherence as covariate in the Mixed Model

                                                         Salloum, IM et al, Archives Gen Psychiatry, 2005
            Conclusions
• Valproate treatment associated with
  significantly better drinking outcomes as
  compared to placebo
Moderate Alcohol Consumption and
Illness Severity in Bipolar Disorder
• 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
• ? Increased sensitivity to impact of
  alcohol

                      Goldstein, B. I., et al (2006). Drugs, 66(9), 1229-1237
      Psychotherapy in Substance-Using
              Bipolar Patients

• Cognitive behavioral therapies effective in both disorders
• Development of specific “integrated” therapy
   – topics relevant to both disorders
   – relationship of disorders
• Integrated Group Therapy had better outcomes
   – ASI scores

   – % months abstinent



                          Weiss, R. D., et al. (2007). Am J Psychiatry, 164(1), 100-107.
ANXIETY DISORDERS
   12-Month Odds of Substance Use
   Disorders (SUDs) and Independent
            Anxiety Disorder
                                            Alcohol
                           Any SUD                              Drug Dependence
                                          Dependence
Any anxiety disorder          1.9               2.6                       6.2
Panic disorder
  with agoraphobia            3.1               3.6                      10.5
  without agoraphobia         2.1               3.4                       7.6
Social phobia                 1.9               2.5                       5.4
GAD                           2.3               3.1                      10.4


GAD=generalized anxiety disorder.



                                     Grant BF, et al. Arch Gen Psychiatry. 2004;61:807-816.
 Controlled Pharmacotherapy Trials
        Anxiety and Alcohol
• 2 placebo-controlled trials positive using
  buspirone for GAD/alcoholism
• 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
Serotonin Reuptake Inhibitors
• Efficacious in treatment of
  anxiety disorders
• 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
Generalized Anxiety Disorder
          (GAD)
• Strongly associated with alcohol dependence
  (OR 3.1)
• Much symptom overlap - diagnostic difficulty
• GAD in adolescents associated with
  progression to alcohol dependence
     • Sartor et al., 2007
• AUDs worsen course of illness in GAD
     • Bruce et al., 2005

                                            Sartor, et al. (2007). Addiction, 102(2), 216-225.
                     Bruce, et al. (2005). Am J Psychiatry, 162(6), 1179-1187.
          Buspirone Treatment of
            Anxious Alcoholics
•   61 anxious alcoholics
•   12 week, placebo-controlled trial
•   Relapse prevention therapy
•   Buspirone associated with
    – Greater retention
    – Lower anxiety
    – Less consumption


                  Kranzler, et al. (1994). Arch Gen Psychiatry, 51(9), 720-731.
               Panic Disorder
• Risk of panic disorder elevated 2-4 fold in
  individuals with AUD’s
       Cosci, et al. (2007). J Clin Psychiatry, 68(6), 874-880.

• Panic attacks can be associated with alcohol
  withdrawal - substance-induced

• Few treatment studies of co-occurring
  – Cognitive behavioral therapy efficacious in
    uncomplicated panic
  – Selective serotonin reuptake inhibitors (SSRIs)
    efficacious in uncomplicated panic
Social Anxiety Disorder (SAD)
• 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%
• Prevalence of SAD in individuals with AUD
  approximately 20%

                       Grant, et al. (2005). J Clin Psychiatry, 66(11), 1351-1361.
         Paroxetine in Comorbid
          SAD and Alcoholism
• 15 men and women with social phobia and
  alcohol dependence or abuse
• Double-blind, placebo-controlled
• Paroxetine – flexible dosing up to 60 mg/d
• Brief motivational therapy for alcoholism




                       Randall CL, et al. Depress Anxiety. 2001;14:255-262.
Paroxetine in Comorbid SAD and
           Alcoholism
             Total Number of Drinks per Week
   35
   30
   25
   20
   15
   10
            Paroxetine
    5       Placebo
    0
        1     2       3       4      5       6       7        8
                         Weeks of Treatment


                                  Randall CL, et al. Depress Anxiety. 2001;14:255-262.
Treatment Studies: SAD/AUD
• 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
   – 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
   Comorbidity of PTSD and SUDs
     National Comorbidity Study
MEN                   %                        Odds Ratio
Alcohol
abuse/dependence    51.9                              2.06
Drug
abuse/dependence    34.5                              2.97
WOMEN
Alcohol
abuse/dependence    27.9                              2.48
Drug
abuse/dependence    26.9                              4.46

                   Kessler RC, et al. Arch Gen Psychiatry. 1995;52:1048-1060.
Post Traumatic Stress Disorder
          (PTSD)
 • Characteristic symptoms that persist for
   at least 1 month following trauma
 • 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

               Jacobsen LK, Am J Psychiatry, 158(8), 1184-1190.
   Co-Occurring PTSD/AUD
         Treatment
• Exposure therapy demonstrated
  efficacy in PTSD
• Reluctance to explore in individuals with
  co-occurring AUD for fear of provoking
  relapse
• Preliminary studies in cocaine-
  dependent individuals show promise

                    Brady, et al. (2001) J Subst Abuse Treat, 21(1), 47-54.
         PTSD Integrated Treatment:
              Seeking Safety
     • 24 sessions in 12 weeks1
     • Group therapy integrating CBT for SUDs
       and PTSD1
     • Emphasis of Seeking Safety :
       interpersonal relationships - no trauma
       exposure2

1. Hien DA, et al. Am J Psychiatry. 2004;161:1426-1432.
2. Najavits LM. Seeking Safety. New York, NY: Guilford Publications; 2001.
         PTSD and Alcoholism
       Treatment With Sertraline
• 12-week study
• Double-blind, placebo-controlled trial
• Weekly CBT targeting alcoholism
• Measure alcohol and PTSD outcomes
• 94 subjects with both PTSD and alcoholism
  – 43 women; 51 men


                        Brady KT, et al. Alcohol Clin Exp Res. 2005;29:343-352.
 Cluster Analysis – Sertraline
• 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.
    Adjusted Mean Average Days Drinking
           Over Treatment Period
  4.5                                          4.07
    4
  3.5
    3
  2.5                                                 2.35
                                                                     Sertraline
    2                                                                Placebo
  1.5                      1.1 1.13
                   1.02
    1
            0.36
  0.5
    0
            Cluster 1      Cluster 2           Cluster 3

Cluster by group P=.068.
                                   Brady KT, et al. Alcohol Clin Exp Res. 2005;29:343-352.
  Attention Deficit Hyperactivity
         Disorder - ADHD
• Characterized by excessive activity,
  inability to pay attention, impulsive
  behavior, poor organizational skills
• Must appear in childhood
• When unrecognized, associated with
  poor performance in school and work
          ADHD and
    Substance Use Disorders
• No controlled trials in
  pharmacotherapeutic strategies in
  substance users
• Conventional wisdom: Avoid
  psychostimulants, but not well studied
• Bupropion, venlafaxine, tricyclics,
  clonidine may be used
        Substance Use in
         Schizophrenia
• Approximately 50% have lifetime SUD -
  alcohol most common
• ? Reward dysfunction inherent in
  neuropathology, increased vulnerability
• Some suggestion of better response to
  atypical antipsychotics
    Naltrexone in Alcohol
Dependence and Schizophrenia
• 31 subjects with co-occurring alcohol
  dependence and schizophrenia
• Stabilized on antipsychotic medication
• 12 weeks treatment with naltrexone (50 mg)
  vs placebo
• Naltrexone group had fewer drinking days,
  fewer heavy drinking days and less craving
           » Petrakis et al., 2004
    Disulfram and Naltrexone in
        Comorbid Patients
• 254 patients with alcohol dependence plus
  comorbid Axis I diagnosis
  – 70% MDE; 42% PTSD; 19% Bipolar
• Disulfram and naltrexone alone and in
  combination
• Active medication associated with longer
  abstinence and less craving
• No advantage of combination therapy

                    Petrakis IL, et al. (2005). Biol Psychiatry, 57(10), 1128-1137.
     Alcohol Use and Psychiatric
        Disorders: The Future
• Exploration of agents that act on common
  neural pathways
• Exploration of medications targeting alcohol
  use disorders in individuals with psychiatric
  disorders
• Development and exploration of
  psychotherapeutic interventions specifically
  targeting co-occurring disorders
         CONCLUSIONS
• Substance use and psychiatric
  disorders
  – commonly co-occur
  – etiologic connections
  – impact course of illness
  – impact treatment decisions

				
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