Principles of Treating Individuals with Complex Co-Morbidity

Paul E. Keck, Jr., MD

Lindner Center of HOPEUniversity of Cincinnati College of

Medicine

Key Recommendations

1. Realize that co-morbidity is the rule, not the exception, in bipolar disorder (BP)

2. Assess affective and co-morbid symptoms concurrently

3. Focus pharmacotherapy on achieving mood stabilization. Use psychological treatments–eg., patient education or illness management–to address co-morbidity issues.

Key Recommendations (continued)4. Know the evidence–or the lack thereof–for the therapies

used to treat BP with co-morbidities5. Avoid prematurely treating co-morbidities with mood-

destabilizing agents6. Before using antidepressants to treat anxiety disorders

co-morbid with BP, consider mood stabilizers and atypical antipsychotics with demonstrated efficacy in anxiety

7. Rethink requiring active alcoholics to “stop drinking” before treating their BP, and select BP therapies accordingly

Key Recommendation 1

• Realize that co-morbidity is the rule, not the exception, in bipolar disorder (BP)

National Co-morbidity Survey

1

2

≥ 3

# LifetimeDSM-III Disorders

21

13

14

% General Population*

0

100

96

% Sample With BP I†

*N=8098; †Percentage of patients with euphoric-grandiose subtype of BP I with comorbidities (N=29).Kessler RC, et al. Arch Gen Psychiatry.1994;51:8-19; Kessler RC, et al. Psychol Med. 1997;27:1079-1089.

Prevalence of Selected Co-morbidities with BP I* (N=29)

93

71

61

41

59

29

0

10

20

30

4050

60

70

80

90

100

Any AnxietyDisorder

AnySubstance

Abuse

AlcoholDependence

DrugDependence

ConductDisorder

AdultAntisocialBehavior

*Euphoric-grandiose subtype.Kessler RC, et al. Psychol Med. 1997;27:1079-1089.

Patie

nts (

%)

Odds Ratio for Anxiety Disorders in Bipolar vs Unipolar Disorders

*Epidemiologic Catchment Area (ECA) Survey.†P<.0001.PD=panic disorder; OCD=obsessive-compulsive disorder.Chen YW, et al. Am J Psychiatry. 1995;152:280-282; Chen YW, et al. Psychiatry Res. 1995;59:57-64.

3.21.6

10.0

02468

101214161820

Bipolar Unipolar Bipolar Unipolar

Odd

s Rati

o

20.8

PD† OCD†

BP and Mental and Medical Disorder Co-morbidity—Clinical Studies

• Eating disorders• Impulse control

disorders• Tourette syndrome• Attention-deficit/

hyperactivity disorder • Conduct disorder • Sexual disorders

• Migraine– Other chronic pain

syndromes?• Obesity• Type II diabetes

mellitus

Kruger S et al. Int J Eat Disord. 1996;19:45-52; McElroy SL et al. Compr Psychiatry. 1996; 37:229-240; Comings BG et al. Am J Hum Genet. 1987;41:804-821; Biederman J et al. Biol Psychiatry. 2000;48:458-466; Frazier JA et al. Am J Psychiatry. 2002;159:13-21; McElroy SL et al. J Clin Psychiatry. 1999;60:414-420; Merikangas KR et al. Arch Gen Psychiatry. 1990;47:849-853; Elmslie JL et al. J Clin Psychiatry. 2000;61:179-184; McElroy SL et al. J Clin Psychiatry. 2002;63:207-213; Regenold WT et al. J Affect Disord. 2002;70:19-26.

Key Recommendation 2

• Assess affective and co-morbid symptoms concurrently

Affective and Comorbid Symptoms of BP

Affective• Manic• Depressive• Mixed• Cycling• Psychotic

Co-morbid• Obsessive-compulsive• Panic/agoraphobia• Generalized anxiety• Phobia• Alcohol use• Substance use• Binge eating

Key Recommendation 3

• Focus pharmacotherapy on achieving mood stabilization. Use psychological treatments–eg, patient education or illness management–to address co-morbidity issues.

Comorbid BP: Treatment Guidelines• First goal of pharmacotherapy is mood stabilization• Start with medications that might be effective for both BP

and the co-morbid disorder(s)• Weigh the severity of bipolarity and co-morbidity when

considering monotherapy vs combination therapy • Monitoring patients through daily mood charting helps

recognition of mood states, co-morbidities, their relation with one another, Rx response

Freeman MP, et al. J Affect Disord. 2002;68:1-23.

Goals of Psychotherapy for BP Patients• Modify social risk factors to

• Enhance protective effects of patient’s social environment

• Improve patient’s abilities to manage effects of stressors

• Enhance medication adherence• Increase patient’s and family’s willingness to accept the

reality of the disorder• Reduce risk for suicide• Identify, understand, and manage co-morbid disorders

Miklowitz DJ. J Clin Psychopharmacol. 1996;16(suppl 1):S56-S66.

Psychotherapy for BP Patients:Clinical Trial of Integrated Group Therapy

• Integrated group therapy (IGT): manual-based group psychotherapy integrating treatment for 2 disorders

• 6-month pilot study for outpatients (N=45) with BP and substance abuse• Compared outcomes in patients receiving IGT (12 or 20

weekly sessions) or not receiving IGT• Results: Patients receiving IGT had

• Significantly better outcomes on Addiction Severity Index (P<.03), percentage of months abstinent (P<.01), likelihood of achieving 3 consecutive abstinent months (P<.004)

• Significantly greater improvement on YMRS (P<.04), but no difference on HAM-D

Weiss RG, et al. J Clin Psychiatry. 2000;61:361-367.

Key Recommendation 4

• Know the evidence–or the lack thereof–for the therapies used to treat BP with co-morbidities

• Know the evidence–or the lack thereof–for mood stabilizers/atypical antipsychotics in treating conditions commonly co-morbid with BP when those conditions do not occur with B

Lithium in Co-morbid Conditions: Randomized Placebo-controlled Trials

Condition

Alcohol dependence

Anorexianervosa

Conductdisorder

Impulsiveaggression

OCD

Out

com

e(#

stud

ies)

+++–

+ ++

+––

Judd JL, et al. Am J Psychiatry. 1984;141:1517-1521; Kline NS, et al. Am J Med Sci. 1974;268:15-22; Fawcett J, et al. Arch Gen Psychiatry. 1987;44:248-256; McDougle CJ, et al. J Clin Psychopharmacol. 1991;11:175-184; Pigott TA, et al. J Clin Psychopharmacol. 1991;11:242-248; Gross HA, et al. J Clin Psychopharmacol. 1981;1:376-381; Campbell M, et al. J Am Acad Child Adolesc Psychiatry. 1995;34:445-453; Malone RP, et al. Arch Gen Psychiatry. 2000;57:649-654; Sheard MH, et al. Am J Psychiatry. 1976;133:1409-1413; Dorus W, et al. JAMA. 1989; 262:1646-1652.

The FDA has not approved the use of lithium for any of these disorders.

Divalproex in Co-morbid Conditions: Randomized Placebo-controlled Trials

Brady KT, et al. Drug & Alcohol Dependence. 2002;67:323-330; Lum M, et al. Prog Neuropsychopharmacol Biol Psychiatry. 1991;15:269-273; Hollander E, et al. Neuropsychopharmacology. 2003;28:1186-1197; Hollander E, et al. J Clin Psychiatry. 2001;62:199-203; Freitag FG, et al. Neurology. 2002;58:1652-1659.

Condition

Alcohol dependence(relapse to prevention)

The FDA has approved the use of divalproex for migraine prophylaxis but has not approved any of the other disorders.

Panicdisorder

Borderlinepersonality

disorder

Migraine(prophylaxis)

Intermittent explosive disorder (modified)

Out

com

e (#

stud

ies) +

+++++

++

+–

Posttraumatic stress disorder (modified)

+ –

Carbamazepine in Co-morbid Conditions: Randomized Placebo-controlled Trials

Malcolm R, et al. Am J Psychiatry. 1989;146:617-621; Bjorkqvist SE, et al. Acta Psychiatr Scand. 1976;53:333-342; Uhde TW, et al. Am J Psychiatry. 1988;145:1104-1119; Kaplan AS, et al. Am J Psychiatry. 1983;140:1225-1226; Cowdry RW, et al. Arch Gen Psychiatry. 1988;45:111-119.

Condition

Alcohol withdrawal

The FDA has not approved the use of carbamazepine for any of these disorders.

Alcoholdependence

Borderlinepersonality disorder

Panicdisorder

Bulimia nervosa

Out

com

e(#

stud

ies) +

++++

+ +––

Atypical Antipsychotics in Co-morbid Conditions: Placebo-controlled Trials

RIS=risperidone; OLZ=olanzapineMcDougle CJ, et al. Arch Gen Psychiatry. 2000;57:794-801; Brawman-Mintzer O, et al. Unpublished data; Shapira NA, et al. American College of Neuropsychopharmacology; 2002; San Juan, Puerto Rico; Findling RL, et al. J Am Acad Child Adolesc Psychiatry. 2000;39:509-516; Snyder R, et al. J Am Acad Child Adolesc Psychiatry. 2002;41:1026-1036; Dion Y, et al. J Clin Psychopharmacol. 2002;22:31-39; McDougle CJ, et al. Arch Gen Psychiatry. 1998;55:633-641; Grabowski J, et al. J Clin Psychopharmacol. 2000;20:305-310.

Condition

OCD

The FDA has not approved the use of olanzapine or risperidone for any of these disorders.

Conduct disorder

Tourette syndrome Autism

+(RIS)

Cocaine dependence

Out

com

e (A

gent

s)

+(RIS)+/–

(OLZ)

+(RIS)

+(RIS)

+(RIS)

–(RIS)

GAD

+(RIS)

Key Recommendation 5

• Avoid prematurely treating co-morbidities with mood-destabilizing agents

Co-morbid BP: Treatment Guidelines

• Avoid treatments that destabilize mood• Antidepressants, stimulants may precipitate

hypomania, mania, mixed states, rapid cycling• “Uncovering” psychotherapies may increase

psychological stress• Destabilization of mood often worsens

co-morbid conditions• Concentrate initial therapies on producing mood

stability or pure depression; once a patient is depressed, antidepressants usually can be added

Key Recommendation 6

• Before using antidepressants to treat anxiety disorders co-morbid with BP, consider mood stabilizers and atypical antipsychotics with demonstrated efficacy in anxiety

Mood Stabilizers and Atypical Antipsychotics with Efficacy in Anxiety

• Mood stabilizers: valproate/divalproex for panic disorder

• Atypical antipsychotics: risperidone for generalized anxiety and obsessive-compulsive disorders

Key Recommendation 7

• Rethink requiring active alcoholics to “stop drinking” before treating their BP, and select BP therapies accordingly

Treating Co-morbid Alcohol Abuse• Alcoholic, bipolar patients should not be refused

treatment for BP • Do not postpone therapy until patients achieve

sobriety• Patients denied therapy for BP until they stop drinking

very often never return for treatment• Many problems of co-morbid alcohol abuse occur with

other addictive substances• Consider adjunctive psychological treatment

Bipolar Care OPTIONS Southeast Regional Working Group; June 6-7, 2003; Atlanta, GA.

Effects of BP Treatments on Comorbid Alcohol Abuse

• Divalproex: may be effective in preventing relapse• Carbamazepine: effective in alcohol withdrawal • Lithium: may be effective but need to monitor

electrolytes and hydration when taken in combination with alcohol

Topiramate in Alcohol Dependence

Study WeeksPlacebo (n=48)Topiramate (n=55)

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 4 8 12

Drinks/d

-6.24 ± 1.23

-3.36 ± 1.04

Mean Change ± 95% CI From Baseline on Drinks/Day

P<.0001 Baseline: 7.78 (topiramate) vs 6.52 (placebo).

Johnson BA, et al. Lancet. 2003;361:1677-1685.

The FDA has not approved this use.

Key Recommendations: Summary

1. Realize that co-morbidity is the rule, not the exception, in bipolar disorder (BP)

2. Assess affective and co-morbid symptoms concurrently

3. Focus pharmacotherapy on achieving mood stabilization. Use psychological treatments–eg, patient education or illness management–to address co-morbidity issues.

Key Recommendations: Summary4. Know the evidence–or the lack thereof–for the therapies

used to treat BP with co-morbidities5. Avoid prematurely treating co-morbidities with mood-

destabilizing agents6. Before using antidepressants to treat anxiety disorders

co-morbid with BP, consider mood stabilizers and atypical antipsychotics with demonstrated efficacy in anxiety

7. Rethink requiring active alcoholics to “stop drinking” before treating their BP, and select BP therapies accordingly

Q & A

888-536-HOPE (4673)lindnercenterofhope.org