Principles of Treating Individuals with Complex Co-Morbidity

1. Principles of Treating Individuals with Complex Co-Morbidity • Paul E. Keck, Jr., MD • Lindner Center of HOPE • University of Cincinnati College of Medicine

2. Key Recommendations • Realize that co-morbidity is the rule, not the exception, in bipolar disorder (BP) 2. Assess affective and co-morbid symptoms concurrently • Focus pharmacotherapy on achieving mood stabilization. Use psychological treatments–eg., patient education or illness management–to address co-morbidity issues.

3. Key Recommendations (continued) • Know the evidence–or the lack thereof–for the therapies used to treat BP with co-morbidities • Avoid prematurely treating co-morbidities with mood-destabilizing agents • Before using antidepressants to treat anxiety disorders co-morbid with BP, consider mood stabilizers and atypical antipsychotics with demonstrated efficacy in anxiety • Rethink requiring active alcoholics to “stop drinking” before treating their BP, and select BP therapies accordingly

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

5. # LifetimeDSM-III Disorders % General Population* % Sample With BP I† 0 100 96 1 2 ≥ 3 21 13 14 National Co-morbidity Survey *N=8098; †Percentage of patients witheuphoric-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.

6. Prevalence of Selected Co-morbidities with BP I* (N=29) Patients (%) *Euphoric-grandiose subtype. Kessler RC, et al. Psychol Med. 1997;27:1079-1089.

7. Odds Ratio for Anxiety Disorders in Bipolar vsUnipolar Disorders 20.8 Odds Ratio PD† 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.

8. 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.

9. Key Recommendation 2 • Assess affective and co-morbid symptoms concurrently

10. 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

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

12. 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 monotherapyvs 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.

13. 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 ClinPsychopharmacol. 1996;16(suppl 1):S56-S66.

14. 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.

15. 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

16. Lithium in Co-morbid Conditions: Randomized Placebo-controlled Trials Condition OCD Impulsiveaggression Anorexianervosa Conductdisorder Alcohol dependence + + + – – + + + + – Outcome (# studies) 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 GenPsychiatry. 1987;44:248-256; McDougle CJ, et al. J ClinPsychopharmacol. 1991;11:175-184; Pigott TA, et al. J ClinPsychopharmacol. 1991;11:242-248; Gross HA, et al. J ClinPsychopharmacol. 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.

17. Divalproex in Co-morbid Conditions: Randomized Placebo-controlled Trials Condition Alcohol dependence(relapse to prevention) Migraine(prophylaxis) Intermittent explosive disorder (modified) Posttraumatic stress disorder (modified) Panicdisorder Borderlinepersonality disorder + + + + + + + + – + + Outcome (# studies) – Brady KT, et al. Drug & Alcohol Dependence. 2002;67:323-330; Lum M, et al. ProgNeuropsychopharmacolBiol 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.

18. Carbamazepine in Co-morbid Conditions: Randomized Placebo-controlled Trials Condition Panicdisorder Alcoholdependence Borderlinepersonality disorder Alcohol withdrawal Bulimia nervosa – + – + + + + + + Outcome (# studies) Malcolm R, et al. Am J Psychiatry. 1989;146:617-621; Bjorkqvist SE, et al. ActaPsychiatr 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.

19. Atypical Antipsychotics in Co-morbid Conditions: Placebo-controlled Trials Condition Cocaine dependence Conduct disorder Tourette syndrome OCD GAD Autism + (RIS) + (RIS) – (RIS) + (RIS) + (RIS) + (RIS)+/– (OLZ) + (RIS) Outcome (Agents) 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 ClinPsychopharmacol. 2002;22:31-39; McDougle CJ, et al. Arch Gen Psychiatry. 1998;55:633-641; Grabowski J, et al. J ClinPsychopharmacol. 2000;20:305-310. The FDA has not approved the use of olanzapine or risperidone for any of these disorders.

20. Key Recommendation 5 • Avoid prematurely treating co-morbidities with mood-destabilizing agents

21. 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

22. 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

23. 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

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

25. 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.

26. 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

27. 0 4 8 12 Placebo (n=48) 0 Topiramate (n=55) -1 -3.36 ± 1.04 -2 -3 -4 Drinks/d -6.24 ± 1.23 -5 -6 -7 -8 -9 Topiramate in Alcohol Dependence Mean Change ± 95% CI From Baseline on Drinks/Day Study Weeks 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.

28. Key Recommendations: Summary • Realize that co-morbidity is the rule, not the exception, in bipolar disorder (BP) • Assess affective and co-morbid symptoms concurrently • Focus pharmacotherapy on achieving mood stabilization. Use psychological treatments–eg, patient education or illness management–to address co-morbidity issues.

29. Key Recommendations: Summary • Know the evidence–or the lack thereof–for the therapies used to treat BP with co-morbidities • Avoid prematurely treating co-morbidities with mood-destabilizing agents • Before using antidepressants to treat anxiety disorders co-morbid with BP, consider mood stabilizers and atypical antipsychotics with demonstrated efficacy in anxiety • Rethink requiring active alcoholics to “stop drinking” before treating their BP, and select BP therapies accordingly

30. Q & A

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