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Bipolar Disorder: New Treatment Options

Bipolar Disorder: New Treatment Options. Michael A. Chan, MD Chair, Department of Psychiatry Mount Carmel. Bipolar Disorder. Significant Public Health Impact 0.5 – 1.7% lifetime prevalence 6.4% lifetime prevalence “bipolar spectrum”¹ Suicide rate ~ 12% Annual U.S. cost > $45.2 B²

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Bipolar Disorder: New Treatment Options

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  1. Bipolar Disorder:New Treatment Options Michael A. Chan, MD Chair, Department of Psychiatry Mount Carmel

  2. Bipolar Disorder • Significant Public Health Impact • 0.5 – 1.7% lifetime prevalence • 6.4% lifetime prevalence “bipolar spectrum”¹ • Suicide rate ~ 12% • Annual U.S. cost > $45.2 B² • 6th leading cause of disability worldwide³ • Co-morbid substance abuse (ETOH) ~70% • 90% recurrence rate (median # episodes = 9) • 50% recurrence within one year of 1st episode ¹Judd LL, et al. J Affect Disord 2003 Jan;73(1-2):123-31 ²Kleinman L, et al. Pharmacoeconomics 2003;21(9):601-22 ³Woods SW. J Clin Psych 2000;61(suppl 13):38-41.

  3. Bipolar Disorder • Often misdiagnosed or undiagnosed: • 35-60% have depression first¹ • May have several depressive episodes prior to manic episode² • Many will not report mania/hypomania • May progress to psychosis • Lag between symptom onset and first treatment with mood stabilizer³ ¹Goodwin FK, Jamison KR. Manic-Depressive Illness 1990:56-73;NY: Oxford Univ Press ²Lish JD, et al. J Affect Disord. 1994;31:281-294. ³Goldberg JF, Ernst CL. J Clin Psych. 2002 Nov;63(11):985-91.

  4. Bipolar Disorder:Clues to Diagnosis • History of mania • Family history of bipolar disorder • Earlier age of onset¹ • Multiple episodes • Abrupt onset and termination of depressive episodes • Worsening with antidepressant treatment² ¹Lish JD, et al. J Affect Disord. 1994 Aug;31(4):281-94. ²Ghaemi SN, et al. J Clin Psychiatry. 2000;61:804-808.

  5. Bipolar Disorder:DSM-IV Criteria for Manic Episode • Abnormally and persistently elevated, expansive, or irritable mood > 1 week • 3* or more activation symptoms: • Distractibility, Increased risk-taking, Grandiosity, Fast/racing thoughts, Activity increased, Sleep decreased, Talkativeness (“DIG FAST”) • Marked social/occupational impairment • Not due to drugs or medical condition *Four, if primarily irritable

  6. Bipolar Disorder:DSM-IV Criteria for Depression • 5 or more of following present > 2 weeks: • depressed mood most of day, nearly every day • decreased interest or pleasure in activities most of day, nearly every day • increased/decreased appetite & weight • increased/decreased sleep • psychomotor agitation/retardation • decreased energy • guilt/worthlessness • poor concentration • recurrent thoughts of death/suicide • “SIG: E-CAPS”

  7. Bipolar Patients Are Symptomatic Almost Half Their Lives N=146 12.8-year follow-up Judd et al. Arch Gen Psychiatry 2002;59:530-537

  8. Bipolar II Patients Are Symptomatic Most Of Their Lives N=86 13.4-year follow-up Judd LL, et al. Arch Gen Psychiatry 2003;60:261-269.

  9. Bipolar Disorder:Subtypes • Mixed Mania • Simultaneous mania and depression • May be > 40% prevalence of episodes* • Rapid Cycling • > 4 episodes/year • Bipolar II • Hypomania (< 4 days duration) alternating with depression • Secondary Mania • e.g., drugs, tumor, CVA, lupus, endocrine, infectious, Huntington’s, Wilson’s *Akiskal HS, et al. J Affect Disord 2000 Sep;59 Suppl 1:S5-S30

  10. Treatment:APA Practice Guidelines 2002 • Acute mania/mixed mania: • 1st line: lithiumor valproate or antipsychotic* • 1st line severe: lithiumor valproate + antipsychotic* • Acute depression: • 1st line: lithiumor lamotrigine • 1st line severe: lithium + antidepressant • Maintenance • lithiumor valproate: • Alternatives: lamotrigine, carbamazepine, oxycarbazepine • Atypical antipsychotics “may be considered” *APA recommends atypical antipsychotics > typical antipsychotics

  11. Treatment:Mood Stabilizers Lithium* Depakote* (divalproex sodium) Lamictal* (lamotrigine) Tegretol (carbamazepine) Trileptal (oxcarbazepine) Neurontin (gabapentin) Topamax (topiramate) Gabitril (tiagibine) Keppra (levetiracetam) *FDA-approved

  12. Mood Stabilizers:Lithium • Advantages: • 50+ years worldwide experience (FDA-approved 1970) • effective in euphoric mania and hypomania • inexpensive • reduces suicide rate¹‚² • Disadvantages: • slow onset ~ 14 days • narrow therapeutic index • non-response in > 50% (usually bipolar subtypes) • frequent side effects (polyuria, tremor, GI symptoms) and non-compliance • discontinuation associated with high relapse rate³ ¹Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52. ²Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73. ³Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.

  13. Mood Stabilizers:Lithium • Predictors of response to Lithium: • euphoric mania • good inter-episode functioning • family history of Bipolar Disorder (and of Lithium response¹) • mania/depression/euthymia sequence vs. depression/mania/euthymia² ¹Duffy A, et al. J Clin Psych. 2002 Dec;63(12):1171-8. ²Kleindienst N, Greil W. Neuropsychobiology. 2002;42 Suppl 1:2-10.

  14. Mood Stabilizers:Divalproex • Advantages: • extensive experience (FDA-approved for epilepsy 1983; for bipolar mania 1995) • rapid onset (1-4 days) • loading dose strategy¹ well-tolerated: • 20 mgs/kg • 77% moderate to marked response • effective in Bipolar subtypes • effective for psychotic symptoms² • plasma levels (50-125 mcg/ml) • less cognitive impairment than lithium³ ¹McElroy SL, Keck PE. Neuropsychobiol. 1993;27(3):146-9. ²McElroy SL, et al. J Clin Psych. 1996 Apr;57(4):142-6. ³Zajecka J, et al. J Clin Psych. 1996 Aug;57(8):356-9.

  15. Mood Stabilizers:Divalproex • Disadvantages: • sedation • transient hair loss • weight gain • tremor • GI upset • dose-related thrombocytopenia • rare hepatotoxicity, pancreatitis • possible Polycystic Ovarian Syndrome • plasma level monitoring

  16. Mood Stabilizers:Lamictal • FDA-approved for maintenancetreatmentof Bipolar I Disorder • Black box warning for serious rash (includes Stevens-Johnson Syndrome and toxic epidermal necrolysis) • Slow titration necessary • Interaction with other AEDs (especially valproic acid and carbamazepine)

  17. Lamictal:Efficacy in Bipolar Disorder • Placebo controlled 18-month trials of lamotrigine and lithium – pooled analysis • 8-16 week open label treatment with lamotrigine or lithium before randomization: • N = 191 for placebo • N = 280 for lamotrigine (100-400 mgs/d) • N = 167 for lithium (0.8-1.1 mEq/L) • 18-month maintenance treatment phase • Both lamotrigine and lithium superior toplacebo in preventing any mood episode Goodwin GM, et al;J Clin Psych 2004 Mar;65(3):432-441 Bowden CL, et al;Arch Gen Psych 2003 Apr;60(4):392-400 Calabrese JR, et al;J Clin Psych 2003 Sep;64(9):1013-1024

  18. Treatment:Atypical Antipsychotics • Clozaril (clozapine) • Risperdal* (risperidone) • Zyprexa* (olanzapine) • Seroquel* (quetiapine) • Geodon* (ziprasidone) • Abilify* (aripiprazole) *FDA-approved

  19. Atypical Antipsychotics • Comparable efficacy on positive symptom • Better efficacy for improving cognitive and affective (“negative”) symptoms • Less risk of extrapyramidal symptoms ______________________________________ • “Brightening” effects related to receptor actions that differ from one agent to another • Appropriate dosing is key for optimal benefits with any atypical

  20. Antipsychotic Receptor Binding Profiles Haloperidol Olanzapine Clozapine Quetiapine Risperidone Ziprasidone Receptor: A1, 2 = a1, a2 adrenergic D1,2 = dopamine H1 = histamine 5HT1A, 2A = serotonin M = muscarinic Goldstein 1999

  21. Atypical Antipsychotics • High 5HT2:DA blockade (aripiprazole: unique mechanism) • 5HT-2a antagonism: • Mesolimbic: does not reverse antipsychotic action at D2 receptors • Nigrostriatal: reverses enough D2 blockade to EPS • Mesocortical: DA enough to improve cognition

  22. Atypical Antipsychotics • Receptor actions that improve mood and cognition: • 5HT2a antagonism(CLZ/RIS/OLZ/QTP/ZIP/ARI) • 5HT2c antagonism (RIS/OLZ/ZIP) • 5HT1a agonism (CLZ/QTP/ZIP/ARI) • 5HT/NE reuptake blockade (ZIP)

  23. Atypical Antipsychotics Proper dosing:

  24. Evaluation of Mania • Young Mania Rating Scale items*: • Elevated mood • Increased motor activity • Sexual interest • Sleep • Irritability • Speech • Language • Content • Disruptive/aggressive behavior • Appearance • Insight *Possible Score = 0-60

  25. Antipsychotics:Olanzapine • FDA-approved for acute mania (2000) and bipolar maintenance (2004) • First-line treatment for mania per APA 2002Practice Guidelines (along with lithium & divalproex) • Superior to placebo¹ • Equivalent to lithium² • Superior efficacy (vs. placebo) as add-on to lithium or valproate ³ • Superior to divalproex4 1. Tohen M, et al. Am J Psych. 1999 May;156(5):702-9. 2. Berk M, et al. Int Clin Psychopharmacol. 1999 Nov;14(6):339-43. 3. Tohen M, et al. Arch Gen Psych. 2002 Jan;59(1):62-9. 4. Tohen M, et al. Am J Psych. 2003 Jul;160(7):1263-71.

  26. Antipsychotics:Risperidone • FDA-approved for acute mania (2003) • Superior to placebo (equivalent tohaloperidol) as add-on to mood stabilizer (lithium or divalproex)¹ • Equivalent to lithium or haloperidol monotherapy² ¹Sachs, et al. Am J Psych 2002 Jul;159(7):1146-54 ²Segal J, et al. Clin Neuropharm 1998 May-Jun;21(3):176-80

  27. Antipsychotics:Quetiapine • FDA-approved for acute mania up to 12 weeks (2004) • 2 monotherapy and 2 adjunct therapy studies completed* • Superior efficacy on YMRS, PANSS, CGI (including Response and Remission rates on YMRS) for 3 of 4 studies *Data on file, AstraZeneca Pharmaceuticals LP, Wilmington, DE Presented at 16th Annual U.S. Psychiatric & Mental Health Congress. Nov 6-9, 2003. Orlando, FL

  28. Quetiapine:Safety SummaryMonotherapy/Adjunct Therapy • No clinically significant changes observed on ECG parameters (including QTc) • No clinically significant changes in glucose levels (random test) from baseline to endpoint • No other laboratory abnormalities occurred • No clinically significant change observed in blood pressure (including orthostatic) • No difference from placebo in EPS or prolactin levels • No difference from placebo in withdrawal due to adverse events

  29. Antipsychotics:Ziprasidone • FDA-approved for mania August 2004 • 3-week, double-blind, randomized trial (DSM-IV mania/mixed mania) • N = 210 • Ziprasidone 40-80 mgs B.I.D. vs. placebo • Outcome: SADS (MRS), PANSS, CGI-I, CGI-S, GAF • Ziprasidone superior from day 2 on all primary and most secondary efficacy measures Keck PE, et al. Am J Psych. 2003 Apr; 160(4):741-8.

  30. Antipsychotics:Aripiprazole • FDA-approved for mania October 2004 • 3-week, multi-center, double-blind, randomized trial (acute mania/mixed mania) • N=262 • aripiprazole 30 mgs vs. placebo • Outcome: YMRS change from baseline and response rate ( > 50%) • aripiprazole superior from day 4: • YMRS (-8.2 vs. –3.4) • YMRS response (40% vs. 19%) • Similar discontinuation rate, weight, prolactin, QTc Keck PE, et al. Am J Psych. 2003 Sep; 160(9):1651-8.

  31. Atypical Antipsychotics:Metabolic Abnormalities (+) = increase; (–) = no effect; D = discrepant results Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care. 2004 Feb. 27(2):596-601.

  32. Atypical Antipsychotics:Case Reports Summary* *Data from MedWatch and Koller et al. Am J Med. 2001;111:716-23/ Koller et al. Pharmaotherapy. 2002;22:841-52. °J Clin Psychiatry 2004;65:857-863 Literature reports through July 2003 and post-marketing surveillance date through August 2002

  33. Comparative Side Effect Profile of Atypical Neuroleptics

  34. Benefits of Lower EPS • “Negative” symptom benefits • Cognitive benefits • Decreased dysphoria • Improved compliance • Lower risk for tardive dyskinesia Tandon R, Jibson MD. Annals Clin Psychiatry 2002;14(2):123-9.

  35. Prolactin Elevation* • Loss of libido • Anorgasmia/Ejaculation difficulty • Amenorrhea • Gynecomastia • Galactorrhea • Osteoporosis *DA blockade in tubero-infundibular tract

  36. Treatment:Antidepressants • Appropriate use and effectiveness is controversial • Antidepressant-induced mania in 20-40% with all antidepressant classes (TCAs > others)¹‚² • Increased risk of switching³: • Previous antidepressant-induced mania • Bipolar family history • Exposure to multiple antidepressant trials ¹Stoll AL, et al. Am J Psych 1994 Nov;151(1):1642-45 ²Calabrese JR, et al. Eur Neuropsychopharm 1999 Aug;9 Suppl 4:S109-12 ³Goldberg JF, et al. Bipolar Disord 2003 Dec;5(6):407-20

  37. Treatment:Antidepressants • Conflicting evidence for efficacy against depressive relapse: • Protective?: • Altshuler L, et al¹ (retrospective, 39 pts, 1 year): • 35% relapse rate with antidepressant continuation • 68% relapse rate with antidepressant discontinuation • Altshuler L, et al² (prospective, 84 pts, 1 year): • 36% relapse rate with antidepressant continuation • 70% relapse rate with antidepressant discontinuation ¹Altshuler L, et al. J Clin Psychiatry. 2001;62:612-16. ²Altshuler L, et al. Am J Psychiatry. 2003;160:1252-62.

  38. Treatment:Antidepressants • No benefit?: • Frankle WG, et al¹ (retrospective, 50 pts, 30 weeks): • No difference in length of depressive episode regardless of antidepressant status • Ghaemi S, et al² (open, randomized 33 pts, 1 year): • Relapse rate 50% within 20 weeks regardless of antidepressant status ¹Frankle WG, et al. Psychol Med. 2002 Nov;32:1417-23. ²Ghaemi S, et al. San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2003.

  39. Treatment:Antidepressants • Antidepressants can be safe and effective* • Review of 12 randomized, controlled trials in Bipolar Depression (1,088 patients): • Antidepressants more effective than placebo • Switch rate 3.8% for antidepressants and 4.7% for placebo • Tricyclics had 10% switch rate vs. 3.2% for all other antidepressants *Gijsman HJ, et al. Am J Psychiatry 2004; 161:1537-1547.

  40. Treatment:Antidepressants • Recommendations for Bipolar depression*: • Augment mood stabilizer with antidepressant, unless: • “ultra-rapid” cycler (>4 episodes/week) • History of antidepressant-induced cycle acceleration • History of multiple episodes antidepressant-induced mania despite mood stabilizer treatment • Continue maintenance antidepressant if stable for 2 months *Post RM. Current Psychiatry. 2004 July. 3(7):40-49.

  41. Treatment • Electroconvulsive treatment¹‚²: • superior to pharmacotherapy • bilateral ECT superior to unilateral ECT • psychotic depression predicts better response • effective in depressed and manic phases • > 300 case reports of ECT during pregnancy • Phototherapy (bright light treatment) • Benefit as monotherapy³ or augmentation4 • especially if seasonal component • Sleep deprivation5 • improvement in 40-60% (may last weeks) • some risk of hypo-mania ¹UK ECT Review Group. Lancet. 2003 Mar 8;361(9360):799-808; ²Kho KH, et al. J ECT. 2003 Sep;19(3):139-47; ³Levitt AJ, et al. J Affect Disord. 2002 Sep;71(1-3):243-8; 4Loving RT, et al. Depress Anxiety. 2002;16(1):1-3; 5Giedke H, Schwarzler F. Sleep Med Rev. 2002 Oct;6(5):361-77.

  42. Treatment • Psychotherapy issues: • acceptance of illness • effect of illness on relationships • effect on employment • enhance compliance (>50% non-compliance: M>F, white>non-white, combination therapy>monotherapy, substance abusers)* • identify precipitants to mood episodes • manage/reduce stress *Keck PE, et al. Psychopharm Bull 1997;33(1):87-91

  43. Summary • Bipolar disorder: • Significant public health impact • Highly recurrent • Must look to find • Usually presents in depressed phase • Subtypes exist and are less lithium-responsive • First-line treatment: • Mood stabilizers • Atypical antipsychotics

  44. Bipolar Disorder:New Treatment Options Michael A. Chan, MD Chair, Department of Psychiatry Mount Carmel

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