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Principles of Treating Individuals with
Complex Co-Morbidity
Paul E. Keck, Jr., MD
Lindner Center of HOPE
University 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 comorbidity issues.
Key Recommendations (continued)
4. Know the evidence–or the lack thereof–for the therapies
used to treat BP with co-morbidities
5. Avoid prematurely treating co-morbidities with mooddestabilizing agents
6. 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
# Lifetime
DSM-III Disorders
% General
Population*
% Sample
With BP I†
1
21
0
2
13
100
≥3
14
96
*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)
100
93
90
Patients (%)
80
71
70
61
59
60
50
41
40
29
30
20
10
0
Any Anxiety
Disorder
Any
Substance
Abuse
*Euphoric-grandiose subtype.
Kessler RC, et al. Psychol Med. 1997;27:1079-1089.
Alcohol
Drug
Dependence Dependence
Conduct
Disorder
Adult
Antisocial
Behavior
Odds Ratio for Anxiety Disorders
in Bipolar vs Unipolar Disorders
Odds Ratio
20.8
20
18
16
14
12
10
8
6
4
2
0
10.0
3.2
1.6
Bipolar
Unipolar
PD†
Bipolar
Unipolar
OCD†
*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.
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
Co-morbid
•
Manic
•
Obsessive-compulsive
•
Depressive
•
Panic/agoraphobia
•
Mixed
•
Generalized anxiety
•
Cycling
•
Phobia
•
Psychotic
• 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
(# studies)
Outcome
Condition
Alcohol
dependence
+
+
+
–
OCD
Anorexia
nervosa
Conduct
disorder
Impulsive
aggression
–
–
+
+
+
+
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
Condition
Outcome (# studies)
Alcohol
dependence
(relapse to
prevention)
+
Panic
disorder
+
Posttraumatic stress Intermittent explosive
disorder (modified) disorder (modified)
–
–
Borderline
personality
disorder
Migraine
(prophylaxis)
+
+
+
+
+
+
+
+
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.
The FDA has approved the use of divalproex for migraine prophylaxis but has not approved any of the
other disorders.
Carbamazepine in Co-morbid Conditions:
Randomized Placebo-controlled Trials
Condition
(# studies)
Outcome
Alcohol
withdrawal
+
+
+
+
+
Alcohol
dependence
+
Panic
disorder
–
Bulimia
nervosa
Borderline
personality disorder
–
+
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.
The FDA has not approved the use of carbamazepine for any of these disorders.
Atypical Antipsychotics in Co-morbid
Conditions: Placebo-controlled Trials
Outcome (Agents)
Condition
OCD
GAD
Conduct
disorder
Tourette
syndrome
Autism
+
(RIS)
+/–
(OLZ)
+
(RIS)
+
(RIS)
+
(RIS)
+
(RIS)
+
(RIS)
Cocaine
dependence
–
(RIS)
RIS=risperidone; OLZ=olanzapine
McDougle 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.
The FDA has not approved the use of olanzapine or risperidone for any of these disorders.
Key Recommendation 5
• Avoid prematurely treating co-morbidities with mooddestabilizing 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
Mean Change ± 95% CI From Baseline on Drinks/Day
Study Weeks
0
4
8
0
12
Placebo (n=48)
Topiramate (n=55)
-1
-2
-3
Drinks/d
-3.36 ± 1.04
-4
-5
-6
-7
-8
-9
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.
-6.24 ± 1.23
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 comorbidity issues.
Key Recommendations: Summary
4. Know the evidence–or the lack thereof–for the therapies
used to treat BP with co-morbidities
5. Avoid prematurely treating co-morbidities with mooddestabilizing agents
6. 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
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