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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 888-536-HOPE (4673) lindnercenterofhope.org