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Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York

Bipolar d/o/Mania in Late Life. Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York. Lecture available at www.robertkelly.us. Financial Conflicts of Interest.

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Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York

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  1. Bipolar d/o/Mania in Late Life Robert Kelly, MD Assistant Professor of Psychiatry Weill Cornell Medical College White Plains, New York Lecture available at www.robertkelly.us

  2. Financial Conflicts of Interest • As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation. • I do not have an interest in any commercial products or services—Robert Kelly, MD

  3. Outline • Introduction • Bipolar Disorders in The Elderly • Differential Diagnosis • Management

  4. Famous People with “Bipolar Disorder”

  5. Other “Bipolars”

  6. Honore de Balzac, writer Charles Baudelaire, poet Ludwig von Beethoven, composer Marlon Brando, actor Albert Camus, writerTruman Capote, writerJim Carrey, actor and comedianRay Charles, R&B performerFrederic Chopin, composerKurt Cobain, rock starRodney Dangerfield, comedianTheodore Dostoevski, writerLarry Flynt, magazine publisherMichel Foucault, writer, philosopherPaul Gascoigne, athlete (soccer)Paul Gauguin, artist Bill Wilson, co-founder of Alcoholics Anonymous Ernest Hemingway, writer Robin Williams, Actor Audrey Hepburn, actress Sir Anthony Hopkins, actor Victor Hugo, author Andrew Jackson, U.S. President Kay Redfield Jamison, psychologist, writerElton John, musician, composerFranz Kafka, writerJessica Lange, actorRobert E. Lee, U.S. generalJohn Lennon, musicianCourtney Love, musicianImelda Marcos, Philippine dictator's wifeClaude Monet, artistMarilyn Monroe, actorBoris Yeltsin, former President, RussiaVirginia Woolf, writer The list goes on….. Celebrity Meltdown, Psychology Today, December 1999, pp. 46-49,70,78

  7. Bipolar Disorder in The Elderly By DSM-IV • Type I –the subtype most studied in the aged. • Type II- hypomania; seen in ambulatory populations; little data. Rapid cycling—no systematic study in elders.

  8. Bipolar Spectrum Disorders • Bipolar I – History of mania • Bipolar II – History of hypomania and major depressive episodes • Cyclothymia • Hyperthymic temperament • Secondary mania – to other illnesses or drugs • Antidepressant-induced mania and hypomania = DSM-IV categories DSM-IV™. Washington, DC: American Psychiatric Association; 1994:317-391. Akiskal HS. J Clin Psychopharmacol. 1996;16(2 suppl 1):4S-14S.

  9. Mood Disorder Criteria • Distress or Impairment • Clinically Significant • “Abnormal” • Involves Mood • Elevated • Expansive • Irritable • Depressed

  10. Manic Episode • Elevated, Expansive, or Irritable • DIGFAST • Distractibility • Involvement in pleasurable, risky activities • Grandiosity • Flight of Ideas • Activity Increase • Sleep not needed • Talkative (pressured speech) • One Week • Not Mixed Episode • Not Substance- or Treatment-Induced • Not General Medical Condition • Marked Impairment

  11. Hypomanic Episode • Elevated, Expansive, or Irritable • DIGFAST • Distractibility • Involvement in pleasurable, risky activities • Grandiosity • Flight of Ideas • Activity Increase • Sleep not needed • Talkative (pressured speech) • Four Days • Unequivocal, Observable Change • Not Substance- or Treatment-Induced • Not General Medical Condition • NOT Marked Impairment

  12. Major Depressive Episode • Depressed Mood or Anhedonia • Mood + SIGECAPS (most sx) • Two Weeks • Not Mixed Episode • Not Substance-Induced • Not General Medical Condition • Not Bereavement • Clinically Significant Distress or Impairment

  13. Mixed Episode • Manic and Major Depressive Episode • One Week • Not Substance- or Treatment-Induced • Not General Medical Condition • Marked Impairment

  14. Mood Disorders, DSM-IV • Mood Disorder Due to a General Medical Condition • Substance-Induced Mood Disorder • Adjustment Disorders • Depressive Disorders • Major Depressive Disorder • Dysthymic Disorder • Depressive Disorder NOS • Bipolar Disorders • Bipolar I Disorder • Bipolar II Disorder • Cyclothymic Disorder • Bipolar Disorder NOS • Schizoaffective Disorder • Depressive Type • Bipolar Type • Mood Disorder NOS

  15. Mood Disorder Due to a General Medical Condition • Prominent and Persistent • Depressed Mood or Anhedonia • Elated, Expansive, or Irritable • Evidence • Direct Physiological Consequence • Not Due to Other Mental Disorder • Not During Delirium • Clinically Significant Distress or Impairment

  16. Substance-Induced Mood Disorder • Prominent and Persistent • Depressed Mood or Anhedonia • Elated, Expansive, or Irritable • Evidence • Temporal--intoxication or withdrawal • Etiologically Related • Not Due to Other Mental Disorder • Not During Delirium • Clinically Significant Distress or Impairment

  17. Bipolar I Disorder • Manic or Mixed Episode • Major Depressive Episode • Not Schizoaffective Disorder • Not Superimposed on Psychotic Disorder • Clinically Distress or Impairment

  18. Bipolar II Disorder • Hypomanic Episode • Major Depressive Episode • Never Manic or Mixed Episode • Not Schizoaffective Disorder • Not Superimposed on Psychotic Disorder • Clinically Distress or Impairment

  19. Schizoaffective Disorder • Mood Episode + Schizophrenia Criterion A • Mood, not anhedonia • Bipolar or depressive types • Schizophrenia-like period • Two weeks • No prominent mood symptoms • Delusions or hallucinations • Mood Episode “Substantial” Portion • 40% or more • Not Substance-Induced • Not General Medical Condition

  20. Lifetime Prevalence • Bipolar Disorders • Bipolar I Disorder (0.4-1.6%) • First manic/mixed episode very late in life • Bipolar II Disorder (0.5% ??) • Cyclothymic Disorder (0.4-1%) • Bipolar Disorder NOS

  21. Symptom Domains of Bipolar Disorder Manic Mood and Behavior Dysphoric or NegativeMood and Behavior • Euphoria • Grandiosity • Pressured speech • Impulsivity • Excessive libido • Recklessness • Social intrusiveness • Diminished need for sleep Depression Anxiety Irritability Hostility Violence or suicide BipolarDisorder CognitiveSymptoms Psychotic Symptoms Racing thoughts Distractibility Disorganization Inattentiveness Delusions Hallucinations Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY:Oxford University Press; 1990:85-125.

  22. Differential Diagnosis of Mania • The differential diagnosis of manic and mixed states in late life is broad and includes: delirium, dementia, schizophrenia, bipolar (BP) disorders, schizoaffective disorder- BP type, drug intoxication, and mood disorder due to medical disorders or treatments. • Lack of detection and misdiagnosis are likely

  23. Additional Heterogeneity • BP elders have a broad range of clinical features, prior illness course, treatment history, comorbidity, functional status, psychosocial circumstances, and outcomes. • The heterogeneity includes additional age-associated factors.

  24. Neurobiology of bipolar disorder • Meta-analysis of MRI Brain Morphometry Studies in Adults With Bipolar Disorder26 studies comprising 404 patients • Compared volumetric brain measurements of patients with bipolar disorder with controls • Patients with bipolar disorder had enlarged rightlateral ventricles compared with controls • Findings suggest that bipolar disorder is more likely to be associated with right-sided cerebral pathology McDonald C, et al. Biol Psychiatry. 2004;56:411-417.

  25. Mania and acute brain lesions • Stroke and other focal brain disease • especially right orbitofrontal andbasotemporal areas Brooks et al Am J Psychiatry 2005

  26. Mania in Neurological Disorders • Associations with other neurological disorders • Huntington’s Disease • Multiple sclerosis • Alzheimer’s disease—Confabulation versus Grandiosity Starkstein et al 1991; Shulman 1997

  27. Bipolar Disorder and the Brain • New theory from Autopsy studies – mitochondrial malfunction • Mitochondria – vital organelle for energy production • Depletion of Mitochondria in autopsied bipolar brains; mutant mitochondrial DNA – two suspect genes Kato, University of Tokyo2000 • Decreased expression of genes that coded for mitochondrial proteins in hippocampus of bipolar patients Christine Konradi Harvard and McLean Hospital, Archives of General Psychiatry 2004

  28. Neurobiology of mania • Less studied than that of major depression • Current hypothesis posits deficient serotonergic neurotransmission as a pathophysiological cause of both depression and mania • In mania, neurotransmission may be related to GABA deficits • Without usual GABA functioning, unopposed relative increases in NE and DA activity may underlie the development and progression of mania • Hypothesis supported by efficacy of GABA agents in the treatment of mania

  29. Neurotransmitters and mania • Several neurotransmitters involved (SE, NE, Dopamine, ? Cortisol) • Increase dopamine transmission from the substantia nigra to the neostriatum increased sensory stimuli and movement. • Dopamine activity in the other two pathways, from the ventral tegmentum and the tubero-infundibular, remains unchanged in mania Berns and Nemeroff 2003

  30. Secondary Mania • Antidepressant Associated Mania • Neurological disorders with mania as initial clinical presentation • Delirium (medications, drugs, infections, other…)

  31. Antidepressant Associated Mania • Controversial nature; can occur in elders • SSRIs involve less risk than TCAs? • Avoided by use of mood stabilizers • Can occur with ECT Bittman and Young 1991

  32. Treatment • Multidisciplinary approach +++ • Medications • Psychotherapies • Psychosocial interventions

  33. Psychopharmacotherapy • Mood stabilizers • Atypicals • Others

  34. APA Practice Guidelines for Bipolar Disorder: First-Line Treatments • Manic/mixed episodes • Severe cases: combination therapy (lithium/divalproex + antipsychotic) • Mild to moderate cases: monotherapy(lithium, divalproex, or atypical antipsychotic) • Depressed episode • Lithium or lamotrigine monotherapy • Severe cases may require combination therapy • Maintenance: lithium, divalproex, or other agents (reasonable to continue same agent used to achieve remission) American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.

  35. Mania and FDA • Currently FDA approved • lithium (Eskalith or Lithobid),divalproex sodium (Depakote), carbamazepine (Tegretol), • olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify) • At least one adequate well controlled study with positive data: haloperidol (Haldol) NAMI website 2007

  36. Mood Stabilizers: Lithium • Theory: Urea is related to mania, so urea salts may have a calming effect–John Cade, 1940’s • Finding: Lithium urate made guinea pigs lethargic, but careful controls revealed that this appeared to be due to due to lithium rather than urea. • New hypothesis: Lithium may be useful in treating the manic phase of bipolar disorder • Finding: Lithium effective for Bipolar Disorder.

  37. Mood Stabilizers: Lithium • For BP since 1960’s, FDA ‘74 • Effective Antimanic, mood stab, BP depr. • If Discontinued relapse near 100% 2 yr • Therapeutic Levels: 0.6-1.5 mEq/ml • 0.3-0.8 in elderly • Same levels for prophylaxis • Narrow therapeutic index

  38. “Gold standard” (for classic mania) Established efficacy in maintenance therapy Efficacy in augmenting antidepressants Suicide prevention Less effective in rapid cycling and (?) mixed states Limited efficacy against depression? Slow onset of action Need for plasma-level monitoring Low therapeutic index Mood Stabilizers: Lithium STRENGTHS WEAKNESSES American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.Carney SM, Goodwin GM. Acta Psychiatr Scand Suppl. 2005;426:7-12. Nolen WA, Bloemkolk D. Neuropsychobiology. 2002;42 suppl 1:11-17.Swann AC, et al. Arch Gen Psychiatry. 1997;54:37-42.Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441.

  39. Effective against mania Superior to lithium in mixed states Useful in comorbid substance abuse Can be started at a therapeutic dose Less cognitive dysfunction than lithium? Limited efficacy against depression? Weight gain and hair loss Teratogenesis Thrombocytopenia Polycystic ovary syndrome Pancreatitis Need for plasma-level monitoring Long-term efficacy not clearly established Mood Stabilizers: Divalproex STRENGTHS WEAKNESSES American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.Albanese MJ, et al. J Clin Psychiatry. 2000;61:916-921.Gyulai L, et al. Neuropsychopharmacology.;180:23-32. 2003;28:1374-1382. Hirsch E, et al. Acta Neurol Scand Suppl. 2003 Stoll AL, et al. J Clin Psychiatry. 1996;57:356-359.Polifka JE, Friedman JM. CMAJ. 2002;167:265-273.

  40. Effective against mania Useful with comorbid substance abuse Relatively little weight gain Limited efficacy against depression? Complex pharmacokinetics (many drug-drug interactions) Lowers steroidal contraceptive blood levels Hyponatremia, agranulocytosis, Stevens-Johnson syndrome Mood Stabilizers: Carbamazepine WEAKNESSES STRENGTHS American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.Weisler RH, et al. J Clin Psychiatry. 2005;66:323-330.Goldberg JF, et al. J Clin Psychiatry. 1999;60:733-740.Goldberg JF, Citrome L. Postgrad Med. 2005;117:25-26, 29-32, 35-36.Wilbur K, Ensom MH. Clin Pharmacokinet. 2000;38:355-365.

  41. Extended-Release Carbamazepine: Efficacy in 239 Hospitalized Manic or Mixed Episode Patients Reduction in YMRS Total Scores Reduction in HAM-D Total Scores 0 0 -2 YMRS ScoresBaselinePBO = 27.93CBZ = 28.46 End PointPBO = 20.82CBZ = 13.38 HAM-D ScoresBaselinePBO = 9.45CBZ = 9.60 End PointPBO = 8.47CBZ = 6.88 -0.5 -4 -1 -6 Mean Change in YMRS Score (LOCF) Mean Change in HAM-D Score (LOCF) -8 -1.5 *P <.0001; †P <.01. -10 -2 -12 -1.7 -8.0 -14 -2.5 * † -16 -3 PBO (n=115) CBZ (n=120) CBZ = carbamazepine; HAM-D = Hamilton Rating Scale for Depression; LOCF = last observation carried forward; PBO = placebo; YMRS = Young Mania Rating Scale.Weisler RH, et al. J Clin Psychiatry. 2005;66:323-330.

  42. Effective as depression prophylaxis and (to a lesser extent) as mania prophylaxis Little cognitive dysfunction Generally well tolerated, little or no adverse effect on weight Acute antidepressant effect less established Very slow titration rate Drug interactions (eg, valproate, carbamazepine, OCs) Rash, Stevens-Johnson syndrome Mood Stabilizers: Lamotrigine WEAKNESSES STRENGTHS American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441. Goldberg JF, Burdick KE. J Clin Psychiatry. 2001;62(suppl 14):27-33.Bowden CL, et al. Drug Saf. 2004;27:173-184.Sabers A, et al. Neurology. 2003;61:570-571.

  43. Lithium vs Carbamazepine • 2.5-year study; N = 171 patients with bipolar disorder • Lithium statistically superior to carbamazepine in “classical” euphoric bipolar I disorder, but less well tolerated • Carbamazepine better than lithium for mood-incongruent, atypical, non classical bipolar disorder • Patient satisfaction statistically higher in carbamazepine group Kleindienst N, Greil W. Neuropsychobiology. 2000;42(suppl 1):2-10.

  44. Atypical Antipsychotics for Bipolar Mania • Recommended both as monotherapy and as combination therapy with a mood stabilizer1-3 • Base selection on4 • Efficacy • Onset of action • Safety and tolerability profile • Individual patient factors: history, characteristics, prior response • American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50. • Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. • Yatham LN, et al. Bipolar Disord. 2005;7(suppl 3):5-69. • Keck PE Jr. J Clin Psychiatry. 2005;66(suppl 3):5-11.

  45. Stage 1 Euphoric Mixed 1A: Li, VPA, ARP, QTP, RIS, ZIP 1A: VPA, ARP, RIS, ZIP 1B: OLZ or CBZ 1B: OLZ or CBZ CONT TIMA Treatment Algorithm forAcute Hypomanic/Manic/Mixed Episodes in Patients With Bipolar I Disorder Monotherapy Nonresponse: Try Alternate Monotherapy Nonresponse: Try Alternate Monotherapy Response Response Partial Response Partial Response ARP = aripiprazole; CBZ = carbamazepine; CONT = continuation; Li = lithium; OLZ = olanzapine; QTP = quetiapine; RIS = risperidone; TIMA = Texas Implementation of Medication Algorithms; VPA = valproate; ZIP = ziprasidone. Adapted with permission from Suppes T, et al. J Clin Psychiatry. 2005;66:870-886.

  46. Stage 2 CONT CONT Stage 3 Stage 4 TIMA Treatment Algorithm forAcute Hypomanic/Manic/Mixed Episodes in Patients With Bipolar I Disorder cont. Li, VPA, AAP Choose 2 (not 2 AAPs, not ARP or CLOZ) Two-Drug Combination Response Partial Response or Nonresponse Li, VPA, AAPs, CBZ, OXC, TAP Choose 2 (not 2 AAPs, not CLOZ) Two-Drug Combination Response Partial Response or Nonresponse ECT or Add CLOZ or Li + [VPA or CBZ or OXC] + AAP AAP = atypical antipsychotic; ARP = aripiprazole; CBZ = carbamazepine; CLOZ = clozapine; CONT = continuation; ECT = electroconvulsive therapy; Li = lithium; OXC = oxcarbazepine; TAP = typical antipsychotic; TIMA = Texas Implementation of Medication Algorithms; VPA = valproate. Adapted with permission from Suppes T, et al. J Clin Psychiatry. 2005;66:870-886.

  47. Risks Associated With Antidepressant Use in Bipolar Depression • Antidepressant monotherapy (eg, TCAs, MAOIs, SSRIs, SNRIs) are associated with risk of • Mania induction • Cycle acceleration • SSRIs and bupropion may be relatively safer with regard to these risks than TCAs El-Mallakh RS, Karippot A. Psychiatr Serv. 2002;53:580-584.Wehr TA, Goodwin FK. Am J Psychiatry. 1987;144:1403-1411.Vieta E, et al. J Clin Psychiatry. 2002;63:508-512.

  48. ECT

  49. ECT

  50. ECT • Effective in manic and mixed episodes, and in BP depression • Can be used in pharmacologically refractory or intolerant patients, and in severe cases • Clinicians have often used bilateral electrode placement in younger manic/mixed patients; efficacy of high dose unilateral ECT awaits study in elders • Many clinicians avoid using lithium during ECT

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