# Presentation: 103844

## Treatment Implications of Determining the Directionality of Comorbid Disorders 

- Edward Nunes MD
- New York State Psychiatric Institute
- Columbia University

## Overview

- Relationships between co-occurring substance use and other mental disorders
- Implications for directionality and treatment
- DSM-IV and co-occurring disorders
- Evidence from treating depression
- Evidence from treating anxiety, other co-occurring disorders

## Potential Relationships between Psychiatric (P) and Substance Use Disorder (SUD)

- I. P causes SUD
- “Self-medication”
- P alters brain response to substances
- SUD may take on a life of its own
- II. SUD causes P
- Intoxication, withdrawal
- SUD causes lasting brain changes leading to P
- P may take on a life of its own

## Relationships between Psychiatric (P) and Substance Use Disorder (SUD)

- III. Independent disorders
- IV. P + SUD leads to worse prognosis
- Interference with treatment, compounding
- V. P, SUD become related over time
- P symptoms become a conditioned cue triggering S
- VI. Common risk factors underlie P, SUD
- Stress, trauma, genetic factors

## Implications for Directionality, Treatment 

| Relationship | Prior Onset | Treatment Emphasis |
| --- | --- | --- |
| I. P  SUD | P | P (SUD) |
| II. SUD  P | SUD | SUD |
| III. Independent | ? | both |
| IV. P + SUD  Prognosis | ? | both |
| V. P, SUD related over time  | ? | both |
| VI. Common RFs | ? | Both and RF |

## Comorbidity and Prognosis

- Psychiatric Diagnosis associated with poor alcohol/drug use outcome
- Greenfield (Arch Gen Psychiatry. 1998 Mar;55(3):259-65)
- Major Depression in past year, not depression symptoms, predict worse drinking outcome 1 year after index hospitalization
- Hasin (Arch Gen Psych 2002;59:375-80)
- DSM-IV Substance Inducted Major Depression, by PRISM interview associated with failure to remit from alcohol or drugs
- DSM-IV Primary Major Depression associated with drug/alc relapse
- Depressive Symptoms prognostic effect less clear

## Clinical Implications

- Comorbidity is common, worsens prognosis
- Depression + substance use is most visible b/o prevalence of depression
- Other less prevalent disorders (e.g. bipolar, panic, schizoprenia, ASP, are more strongly associated with substance use disorders
- So: If you see depression + substance use, look for other disorders

## Early Onset Substance Use Disorders

- Adolescent onset
- Relationship to psychopathology

## Typologies of Alcoholism(Cloninger, Babor)

- Early onset, complicated type
- Teenage onset regular nicotine, alcohol, drug
- Externalizing and internalizing psychopathology
- Late Onset type
- After age 25, less psychopathology
- Depressed/anxious type
- Emerges in 3 or 4 subtype solutions(e.g.Lesch)

## Pathway to Early Onset Alcohol and Drug Dependence

- Premorbid temperament (irritable, hyperactive, impulsive, inattentive, anxious) and neuropsychological deficits
- School failure and association with deviant peer groups
- Early experimentation with nicotine, alcohol, drugs
- Abuse and dependence

## Clinical Implications

- Do a careful family history
- Substance, mood, other psychiatric problems
- Do a careful developmental history
- ADHD syndrome, school problems, learning problems, antisocial behavior, deviant peer groups, early onset substance use
- Separation anxiety, school phobia, extreme shyness, social anxiety, early onset depression
- Do a careful trauma history

## Diagnosis of Co-Occurring Psychiatric, Substance Use Disorders: Diagnostic Confusion; DSM-IV Solution

- Substance intoxication, withdrawal, chronic use produce depression, anxiety, mania, psychosis
- Alcohol
- Other co-occurring drugs (e.g. cocaine)
- Likely to resolve with abstinence
- Treat substance use disorder
- Outpatients often can’t get abstinent
- How to tell which psychiatric disorders to treat?

## Classic Inpatient Studies (Brown and Schuckit 1995):Order of onset and course during treatment; Hamilton Depression Scores in inpatient alcoholics

## DSM-IV Solution

- Primary (a.k.a. independent) depression:
- Temporally independent, i.e. preceded drug abuse, or persisted in abstinence
- Ideally abstinence is current, directly observed
- Substance-induced depression:
- Not temporally independent
- _Exceeds_ what would be expected from _usual toxic or withdrawal effects_ of substances
- Usual effects of substances
- See DSM-IV intoxication and withdrawal criteria

## Operationalize DSM-IV?: Modified SCID (Nunes et al)

- Establish ages at onset of regular substance use
- Establish periods of abstinence during the history
- Examine whether MDD, or syndromes antedate substance use or persist during abstinence

## Operationalize DSM-IV?: PRISM interview (Hasin et al Arch Gen Psychiatry 2002; Aharonovich et al., AJP 2002)

- Primary (“independent”, “abstinence”) MDD
- 1 year follow-up: predicts persistent depression, suicide attempts, relapse
- Substance-induced MDD
- Rigorous definition: full MDD syndrome, each symptom exceed usual substance effects
- Clinical sample: 50% of MDDs are substance induced
- 1 year follow-up: predicts persistent depression; suicide ideation; failure of substance disorder to remit
- Many/most convert to primary over follow-up

## Weekly prevalence of major depression (MDD) over 1 year after hospitalization in 110 substance dependent patients as a function of DSM-IV MDD diagnosis at baseline (BL):
Whether baseline MDD is independent (BL Ind MDD) or substance induced (BL SI MDD)
Whether there is a past episode of independent MDD (Past Ind MDD)
(Nunes, Liu, Samet, Matseone and Hasin, J Clin Psych 2006) 

- Whether baseline MDD is _independent _(**BL** **Ind MDD**) or _substance induced_ (**BL** **SI MDD**)
- Whether there is a past episode of independent MDD (**Past Ind MDD**)
- (Nunes, Liu, Samet, Matseone and Hasin, J Clin Psych 2006)

## Weekly prevalence of major depression (MDD) over 1 year after hospitalization in 110 substance dependent patients as a function of DSM-IV MDD diagnosis at baseline (BL):
Whether baseline MDD is independent (BL Ind MDD) or substance induced (BL SI MDD)
Whether there is a past episode of independent MDD (Past Ind MDD)
(Nunes, Liu, Samet, Matseone and Hasin, J Clin Psych 2006) 

- <date/time>

- Weekly prevalence of major depression (**MDD**) over 1 year after hospitalization in 110 substance dependent patients as a function of DSM-IV MDD diagnosis at baseline (**BL**):
- Whether baseline MDD is _independent _(**BL** **Ind MDD**) or _substance induced_ (**BL** **SI MDD**)
- Whether there is a past episode of independent MDD (**Past Ind MDD**)
- (Nunes, Liu, Samet, Matseone and Hasin, J Clin Psych 2006)

## Clinical Implications

- Get history of substance use problems, including age at first onset, and periods of abstinence
- Take parallel history of mood or other psychiatric problems
- Construct a time-line
- Apply DSM-IV criteria for independent, or substance-induced disorders
- _Caveat_: DSM-IV substance-induced implies more than “usual effects of substances”
- Substance-induced depression, rigorously defined like this, often turns out, over time, to be independent of substance abuse

## What’s the Evidence on Treatment?

- _Treat the Substance Use Disorder_
- If substance use decreases, mood likely to improve
- _Treat the Psychiatric Disorder:_
- _Hypothesis_: Identification and treatment of comorbid psychiatric disorders in substance dependent patients will:
- 1) improve psychiatric symptoms
- 2) improve and drug/alcohol outcome
- 3) improve psychosocial functioning

## Early Antidepressant Trials in Alcoholism

- 1960s and 1970s, numerous trials
- Rationale: reduce dysphoria
- Mainly Tricyclic antidepressants, low doses, short trial lengths, no diagnosis
- Two reviews (Ciraulo & Jaffe J Clin Psychopharm 1981; Liskow & Goodwin J Stud Alcohol 1987)
- No clear evidence of efficacy

## SRIs and alcohol

- SRIs found to reduce alcohol intake in animal models
- SRIs reduced alcohol intake in heavy drinkers not seeking treatment
- SRI clinical trials disappointing
- May reduce drinking in late onset (Type A) alcoholism
- But may make early onset (Type B) drinking _worse_
- _Kranzler et al., Alc Clin Exp Res 1996_
- _Pettinati et al., Alc Clin Exp Res 2000_

## Antidepressants and Nicotine

- Hx of depression predicts failure to quit; after quit depression sometimes emerges
- Noradrenergic antidepressants effective in smoking cessation
- Bupropion, Nortriptyline
- Does not seem to depend on history of depression
- SRIs ineffective
- Clinical trials have large sample sizes, probably good compliance

## Meta-Analysis(Nunes and Levin JAMA 2004; 291:1887-1896)

- 14 placebo-controlled trials of antidepressant medication
- Patients
- DSM depression diagnosis, and
- Alcohol, opiate, or cocaine dependence

## Meta-Analysis(Nunes and Levin JAMA 2004; 291:1887-1896)

- Hamilton Depression Scale (HamD)
- ES = 0.38 (95% CI: 0.18 - 0.58)
- heterogeneity significant (p < .02)
- Self-reported substance use outcome
- HamD ES > 0.50: Substance use ES = 0.56 (0.33 - 0.79)
- HamD ES < 0.50: Substance use ES ~ 0.0
- Remission or abstinence rates low

## 14 Placebo-Controlled Trials of Antidepressants Depressed Substance Patients (Nunes and Levin JAMA 2004)   

## What Distinguished Studies Where Antidepressant Medication was Effective vs Ineffective?

- Medication Effective
- Low placebo response
- Diagnosis during abstinence
- No structured psychotherapy
- Tricyclic or other noradrenergic med

- Medication = Placebo
- High placebo response
- Diagnosis during active substance use
- Manual guided psychotherapy
- Serotonin re-uptake inhibitor?

## Clinical Implications

- Treatment of Co-occurring depression works
- Good diagnosis (DSM-IV, PRISM)
- Abstinence preferable, not mandatory
- TCAs, SRIs?, Psychotherapy?
- Not a panacea (mood effect > substance effect)

## What if you can’t get the patient abstinent to make a diagnosis?

- Evaluate order of onset/offset of psychiatric and substance use disorders by history
- Modified SCID
- PRISM

## Trials of venlafaxine (Ven; N=128) or desipramine (DMI; N = 111) for patients with cocaine dependence and depression,diagnosed as primary (Prim) or secondary (Sec) by modified SCID:Proportion of patients with depression response (> 50% reduction in Hamilton Depression Scale

## Other Common Treatable Psychiatric Syndromes

- In general, other psychiatric syndromes more strongly associated with substance use disorders than depression, and co-occur with depression
- Anxiety disorders
- Attention Deficit Hyperactivity Disorder
- Explosive temper-aggression
- Developmental Perspective
- Bipolar Illness
- Cognitive impairment
- Schizophrenia

## Anxiety Disorders and Addiction

- Anxiety disorders prevalent, often co-occur with depression in addicted patients
- Panic disorder, agoraphobia
- Social Phobia (early onset)
- Post-Traumatic Stress Disorder
- ? Link to childhood anxious temperament risk factor for addiction?

## Anxiety Disorders and Addiction

- Symptoms often distinct from drug toxicity or withdrawal
- Respond to antidepressant medications or cognitive behavioral psychotherapy
- Few studies in addicted patients

## Buspirone for Generalized Anxiety in Alcohol Dependent Patients

- Buspirone (Kranzler et al)
- Inpatient alcoholics
- Elevated Ham-Anxiety scale score _after detoxification_
- Buspirone superior to placebo on drinking outcomes

## CBT for Alcohol Dependent Patients with PTSD(Back, Jackson, Sonne, & Brady, JSAT 2005)

- Examined order of onset (alcohol dependence primary vs PTSD primary) and treatment response
- CBT more effective for those with primary PTSD (early onset PTSD, later onset substance abuse)
- Women with primary alcohol dependence vulnerable to persistent depression

## Attention Deficit Hyperactivity Disorder and Addiction

- Childhood onset: inattention, hyperactivity, school and social problems
- Onset before age of risk for substance abuse
- A risk factor for later substance use disorder
- Prevalence in adults with substance abuse (Levin, Evans, Kleber)
- ~10% clear childhood + adult syndromes
- another 10% adult syndrome, unclear early Hx

## Clinical Trials for ADHD and Cocaine Dependence(Levin, Evans, Kleber, et al)

- Methylphenidate, bupropion improve both ADHD and cocaine use in open label trials
- Methylphenidate reduced cocaine euphoria in human laboratory
- Placebo controlled trials
- Cocaine, methadone patients with cocaine dependence
- Results are equivocal

## Impulsive Aggression and Drug Abuse:Treatment (Donovan et al.)

- Affective subtype of aggression with irritability
- Frequent aggressive outbursts
- Intermittent explosive disorder vs childhood bipolar
- Childhood onset, before age of risk for drug dependence
- Associated with cannabis dependence
- Both irritability/aggression and cannabis use respond to divalproex in placebo controlled trials

## Cognitive Impairment and Treatment(Aharonovich et al)

- Pre-exisinting learning problems, verbal learning, and executive cognitive deficits in children at risk for substance abuse
- Cognitive deficits may be toxic effects of substance use
- Alcoholics and cocaine dependent patients have deficits
- Deficits predict poor outcome
- Treatments (e.g. CBT) require intact cognition

## Bipolar Disorder

- Strong association with substance abuse and dependence
- Variable age of onset (childhood thru adulthood)
- Two positive medication trials
- Lithium for adolescents with prior onset bipolar disorder and substance abuse (Geller et al., JACAP 1999)
- Divalproex for adults with alcohol dependence and bipolar disorder by SCID after detoxification (Salloum et al., Arch Gen Psychiatry 2005)

## Kaplan-Meier survival curve for time to relapse to sustained heavy drinking (3 consecutive heavy drinking days [&ge;5 drinks per day for men and &ge;4 drinks per day for women]), by treatment group (log-rank test, P = .048)

**Salloum, I. M. et al. Arch Gen Psychiatry 2005;62:37-45.**

**Kaplan-Meier survival curve for time to relapse to sustained heavy drinking (3 consecutive heavy drinking days [&ge;5 drinks per day for men and &ge;4 drinks per day for women]), by treatment group (log-rank test, P = .048)**

## Conclusions, Clinical Implications

- Treatment of co-occurring psychiatric disorders is an effective medication strategy for substance use disorders
- Always treat the substance use disorder, shoot for abstinence to clarify the diagnosis
- Directionality matters
- Stronger evidence for treatment effect if co-occurring disorder is primary/independent in DSM-IV sense
- More research is needed, also on DSM-IV substance-induced or secondary disorders
- Where there is one comorbid disorder, look for others

## Acknowledgements

- National Institute on Drug Abuse
- National Institute on Alcoholism and Alcohol Abuse
- New York State