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  • Summary of DSM-IV-TR Classification of Bipolar Disorders According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders , 4th edition (DSM-IV-TR), bipolar disorder can be divided into four classifications: Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, and Bipolar Disorder Not Otherwise Specified. Bipolar I Disorder is characterized by one or more manic or mixed episodes usually accompanied by major depressive episodes. Bipolar II Disorder focuses on one or more major depressive episodes accompanied by at least one hypomanic episode. A diagnosis of Cyclothymic Disorder is made when a patient experiences at least 2 years of numerous periods of hypomanic symptoms that do not meet the criteria for a manic episode and numerous periods of depressive symptoms that do not meet the criteria for a major depressive episode. Bipolar Disorder Not Otherwise Specified is characterized by bipolar features that do not meet the criteria for any of the specific bipolar disorders described above or for bipolar symptoms about which there is inadequate or contradictory information. Each classification of bipolar disorder is further defined by the presence (or history) of manic episodes, mixed episodes, or hypomanic episodes, usually accompanied by the presence (or history) of major depressive episodes. First, ed. Diagnostic and Statistical Manual of Mental Disorders . 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.
  • Symptoms of Bipolar Disorder —Heavy Impact on Daily Life Recently, 3,059 subjects from a large epidemiologic study of bipolar disorder, matched to scores on the Mood Disorder Questionnaire and US Census data, were surveyed using the Social Adjustment Scale-SR, Sheehan Disability Scale, and the Family History Screen to evaluate the psychological and social impact of bipolar I and II in the general population Note that this group is a subset of patients from the 85,358 reported in the prevalence study The results from this survey not only provided a clear picture of the personal and societal impact of bipolar disorder, but also confirmed the usefulness of the MDQ MDQ-positive subjects reported significantly more difficulty with work (1.96% vs 1.46%), social/leisure interactions (2.4% vs 1.87%), and extended family interactions (2.22% vs 1.66%), and more days of disruptive symptoms (6.41 vs 2.62) than MDQ-negative subjects Patients with a positive screen were significantly more likely to be fired or laid off, or be arrested, jailed, or convicted of a crime other than drunk driving Symptoms of bipolar disorder can have a devastating impact on patients and their families and places a heavy burden on society Cal a brese. J Clin Psychiatry . 2003;64:425-432.
  • Electroconvulsive therapy (ECT) is considered a mood-stabilizing treatment. It tends to be used for patients who are suicidal or severely ill and cannot wait for medications to work, or have a history of nonresponse to treatments. Lithium has been the main treatment for acute mania for over 40 years. Lithium appears to be effective for individuals with euphoric mania, but is less effective in mixed manic episodes and in rapid-cycling bipolar disorder. First-generation antipsychotic treatments have been prescribed to combat the psychotic symptoms sometimes associated with manic episodes of bipolar I disorder. Antipsychotics are also used to treat symptoms of anxiety, insomnia, and agitation often associated with manic episodes, even when no psychosis occurs. Antipsychotics are used both as monotherapy and as adjuncts to mood stabilizers for the initial treatment of acute mania. However, intolerable side effects associated with conventional antipsychotics, such as EPS and tardive dyskinesia (TD), can increase patient health burden and have a negative impact on compliance. Valproic acid and its salts (divalproex sodium and sodium valproate), originally developed as an anticonvulsant to treat seizures, have been used to treat bipolar disorder for a number of years. While data support its efficacy in treating euphoric and mixed manic episodes, the data to support efficacy in prophylaxis are considerably weaker. Preliminary research suggests that several other anticonvulsants (eg, lamotrigine, gabapentin, and topiramate) may also possess mood- stabilizing properties. Second-generation antipsychotics have a greatly improved side-effect profile over conventional antipsychotics in terms of EPS and TD liability. Currently, olanzapine is the only atypical agent approved for use in acute mania. Although atypical agents show improvements over conventional agents, concerns remain regarding the emergence of drug-specific side effects such as excessive weight gain, diabetes, lipid abnormalities, QTc prolongation, and somnolence. Aripiprazole is a novel antipsychotic with a unique mechanism of action. This new agent shows promise as a treatment with efficacy against acute mania and an improved safety and tolerability profile. 1. Nemeroff CB. An ever-increasing pharmacopoeia for the management of patients with bipolar disorder. J Clin Psychiatry . 2000;61(suppl 13):19-25. 2. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry . 2000;48:539-557. This slide provides a historic overview of current therapies used to treat acute mania and potential treatments that may help to improve treatment outcomes.
  • Rajiv Tandon, M.D. 2001 Pfizer Talk 1
  • Identical to previous slide, but with additional of PBO and LTG 12 & 18 month relapse rates in lower left inset. On the combined primary outcome measure: Lamotrigine was significantly superior to placebo on time to intervention for any mood episode Lithium was also superior to placebo. There was no significant difference between lamotrigine and lithium. P-values on the slide are unadjusted for study. When these combined analyses were adjusted for study (stratified) p-values were: LTG vs. PBO p=0.002 Li vs. PBO p<0.001 Li vs. LTG p=0.644 Source: SCAB2003 & SCAB2006
  • Identical to previous slide, but with additional of PBO and LTG 12 & 18 month relapse rates in lower left inset. This analysis examines time to intervention for depressive episodes only. Manic and hypomanic events and other dropouts were censored in the analysis. On this measure: Lamotrigine was superior to placebo in prolonging time to intervention for a depressive event Lithium did not separate statistically from placebo, only reaching a statistical trend despite the large sample size (larger than any other previous lithium sample) There was no significant difference between lamotrigine and lithium. P-values on the slide are unadjusted for study. When these combined analyses were adjusted for study (stratified) p-values were: LTG vs. PBO p=0.004 Li vs. PBO p=0.076 Li vs. LTG p=0.281 Source: SCAB2003 & SCAB2006
  • This analysis examines time to intervention for manic or hypomanic episodes only. Depressive events and other dropouts were censored in the analysis. On this measure: Lithium was superior to placebo in prolonging time to intervention for a manic event. Lamotrigine was also superior to placebo in prolonging time to intervention for a manic event. Lithium was superior to lamotrigine in prolonging time to intervention for a manic event. P-values on the slide are unadjusted for study. When these combined analyses were adjusted for study (stratified) p-values were: LTG vs. PBO p=0.149 Li vs. PBO p<0.001 Li vs. LTG p=0.024 This alternative analysis provides additional evidence that the efficacy of lamotrigine against mania is less robust than its effect against depression. Source: SCAB2003 & SCAB2006
  • NP From Bip Depr ECNP GSK 9 20 03 NDMDA, National Depressive and Manic-depressive Association References Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry 2003; 64: 161-174. Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994; 31: 281-294.
  • Bipolar Disorder—3.4% of the US Population Screened Positive by MDQ The Mood Disorder Questionnaire is a screening tool that can be used to identify patients most likely to have bipolar disorder 1,2 In 2001, a large-scale epidemiologic survey (n=85,358) was conducted using the MDQ to screen respondents for the presence of symptoms of bipolar disorder (based on DSM-IV criteria) 3 The overall prevalence rate (weighted to match US census data) for patients with symptoms of bipolar disorder was estimated to be 3.4%, or about 7 million adults 3 When adjusted for response bias, the estimated prevalence rate rises to 3.7%, or 7.6 million adults 3 Symptoms were much more common among younger rather than older people (those aged 18 to 24 years vs those over 65), and in households with incomes less than $20,000 3 1. Hirschfeld. Prim Care Companion J Clin Psychiatry. 2002;4:9-11. 2. Hirschfeld et al. Am J Psychiatry. 2000;157:1873-1875. 3. Hirschfeld et al. J Clin Psychiatry. 2003;64:53-59.
  • This new research reveals on untapped point of entry for patients to receive either a diagnosis or a referral to a mental health professional who can make a correct diagnosis. The research team looked at the number of patients who had received a diagnosis of either bipolar disorder or depression from a community physician, and then compared that with the number of patients who were identified as having bipolar disorder through the Mood Disorder Questionnaire. As you can see, nearly half of the patients identified by the questionnaire received a diagnosis for neither bipolar disorder or depression from their community physician.

[PowerPoint] [PowerPoint] Presentation Transcript

  • Treatment of Bipolar Disorder An UPDATE Rajiv Tandon, MD Chief of Psychiatry State of Florida Tallahassee, Florida, U.S.A.
  • Summary of DSM-IV-TR Classification of Bipolar Disorders * Symptoms do not meet criteria for manic and depressive episodes. Bipolar features that do not meet criteria for any specific bipolar disorders At least 2 years of numerous periods of hypomanic and depressive symptoms* One or more major depressive episodes accompanied by at least one hypomanic episode FEMALE>MALE One or more manic or mixed episodes, usually accompanied by major depressive episodes MALE=FEMALE Bipolar Disorder Not Otherwise Specified Cyclothymic Bipolar II Bipolar I First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.
  • Bipolar Disorder
    • Common illness affecting 2% of the world population (5% if one includes spectrum disorders)
    • 6th leading cause of medical disability in the developed nations
    • Prominent cognitive abnormalities
    1 Cookson J. Br J Psychiatry . 2001;178(suppl. 41): s148 – s156. 2 Strakowski SM, et al. Expert Opin. Pharmacother . 2003;4:751-760.
  • Economic Impact and Disability from Bipolar Disorder
    • Consistently among 10 leading causes of medical disability in the world
    • Total Annual Cost (in the USA): $ 80 Billion
      • Lost Productivity: $ 50 Billion
      • Direct treatment costs: $ 10 Billion
    Murray, Lopez, 1994; Updated 2004
  • Bipolar Disorder
    • Particularly recalcitrant mental health problem
    • Symptomatic at least half the time
    • Can have impaired social function even when symptom-free
    1 Cookson J. Br J Psychiatry . 2001;178(suppl. 41): s148 – s156. 2 Strakowski SM, et al. Expert Opin. Pharmacother . 2003;4:751-760.
  • Bipolar Disorder- Neurobiology
    • Highly heritable (80% genetic contribution)
      • Multiple genes
      • 16 different chromosomal regions
    • Structural and Functional Brain Abnormalities
      • amygdala, anterior cingulate and prefrontal cortex, putamen, thalamus/hypothalamus
    1 Riedel W J. Psychol Med . 2004; 34: 3-8. 2 Strakowski SM, et al. Expert Opin. Pharmacother . 2003;4:751-760.
  • Bipolar Depression
    • 50% of first bipolar episodes are depressive episodes
    • Depressive episodes in bipolar disorder are associated with considerable morbidity and mortality
    • Bipolar depressive episodes have a chronic course
    Goodwin FK and Jamison KR. Manic Depressive Illnessn
  • Bipolar Depression
    • 80% of patients exhibit significant suicidality
    • 60% of patients with dysphoric mania exhibit suicidality
    • Depressive episodes dominate course of bipolar disorder (twice the amount of time as in mania)
    • 25-30% of patients initially diagnosed with unipolar depression subsequently have a manic or hypomanic episode
    Goodwin FK and Jamison KR. Manic Depressive Illnessn
  • Impact of Bipolar Disorder Vs. Unipolar Disorder — Heavy Impact on Daily Life Cal a brese. J Clin Psychiatry . 2003;64:425-432. Percent * P <0.0001 * * *
  • Bipolar Disorder
    • > 50% alcohol and/or other substance abuse
    • About 50% attempt suicide
      • About 15% succeed
    1 Cookson J. Br J Psychiatry . 2001;178(suppl. 41): s148 – s156. 2 Strakowski SM, et al. Expert Opin. Pharmacother . 2003;4:751-760.
  • Predictors of Suicide in Bipolar Disorder
    • High Impulsivity
    • Alcohol and Substance Abuse
    • DEPRESSION and MIXED Episodes
    • History of Abuse in Childhood
    • Exacerbated by incorrect treatment
    Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S.
  • Antidepressants, Adolescents, and Suicide The Bipolar Confound
    • Antidepressants can induce mixed states, rapid cycling, and mania in bipolar disorder
    • Mania thus induced more likely to be dysphoric rather than euphoric
    • Characterized by high impulsivity & irritability
    • DOES THAT EXPLAIN THE INITIAL INCREASED RISK OF SUICIDALITY
    Berk M, Dodd S Hum Psychopharmacol. 2005;20:1-2.
  • Treatment Challenges in Bipolar Disorder
    • Often unrecognized
    • Often untreated
    • Often misdiagnosed
    • Often inadequately treated
    • Exacerbated by incorrect treatment
    Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S.
  • The Evolution of Therapies for Bipolar Disorder 1950 1960 1970 1980 1990 2000 Chlorpromazine* Trifluoperazine Fluphenazine Thioridazine Haloperidol Mesoridazine Anticonvulsants 1940 ECT Lithium* First-generation antipsychotics and antidepressants Risperidone + Clozapine Anticonvulsants Gabapentin Lamotrigine Topiramate Oxcarbazepine Second-generation antipsychotics and antidepressants Olanzapine* Quetiapine + Ziprasidone + Carbamazepine Valproate* 2002 Aripiprazole+ * Approved for use for acute mania ECT = electroconvulsive therapy
  • Bipolar Disorder: Summary of Efficacy Evidence from RCTs Drug Acute Mania Mono Combo Acute Depression Maintenance + ND ND ++ Aripiprazole ND +/- ND ++ Ziprasidone ND + ++ ++ Quetiapine ND +/- + ++ Risperidone ++ + + ++ Olanzapine ++ + ND - Lamotrigine + ND ND ++ Carbamazepine + + ++ ++ Divalproex ++ + ++ ++ Lithium
  • Lithium
    • Uses
      • acute and prophylactic treatment of mania / hypomania
      • acute and prophylactic treatment of bipolar depression
    • Adverse events
      • cognitive
      • tremor
      • gastrointestinal
      • weight gain
    • Fetal abnormalities
  • Valproate / Divalproex
    • Uses
      • acute mania and maintenance treatment of bipolar disorder
      • ? bipolar depression
    • Advantages
      • better tolerability than lithium
      • can be loaded rapidly
      • once-a-day formulation available
    • Disadvantages
      • drug-drug interactions
      • fetal abnormalities
  • Carbamazepine
    • Uses
      • acute and prophylactic treatment of mania
    • Disadvantage
      • drug-drug interactions
      • lab monitoring
      • adverse events
    Oxcarbazepine
    • Uses
      • acute treatment of mania
    • Probable equivalent efficacy to carbamazepine
    • Dosing
      • 1 mg carbamazepine = 1.5 mg oxcarbazepine
      • Less Data
      • Not FDA-approved for mania
  • Other ANTICONVULSANTS
    • Gabapentin
    • Pregabalin
    • Levetiracetam
    • Tiagabine
    • Topiramate
    • NO PROVEN EFFICACY
  • Antipsychotics
  • Current Antipsychotic Therapies 14 First-Generation Typicals vs. 6 Second-Generation Atypicals Ziprasidone 1950 1960 1970 1980 1990 2000 2002 ECT, etc. Chlorpromazine Fluphenazine Thioridazine Haloperidol Clozapine Risperidone Olanzapine Quetiapine Aripiprazole
  • Essence of Atypicality Adapted from Jibson MD, Tandon R. J Psychiatr Res. 1998;32:215-228. Less tardive dyskinesia Improve compliance Less dysphoria Better cognition Fewer EPS Fewer negative symptoms EPS Advantage
  • Summary Atypical Antipsychotics
    • Convincing evidence for efficacy in acute treatment of mania, especially for olanzapine, risperidone, aripiprazole, ziprasidone, and quetiapine. Onset of action within 2-4 days
    • Strong evidence for maintenance efficacy (both mania and depression) for olanzapine
  • Bipolar Depression
  • Lamotrigine in Acute Treatment of Bipolar Depression Change From Baseline of MADRS LTG 50 mg/day (n = 64) LTG 200 mg/day (n = 63) Placebo (n = 65) * P <0.1; † P <0.05. LOCF = last-observation-carried-forward. Calabrese et al. J Clin Psychiatry . 1999;60:79-88. LOCF Observed * * † † † † † † † † † † † † † Week 0 -5 -10 -15 -20 0 1 2 3 4 5 6 7 Week 0 -5 -10 -15 -20 0 1 2 3 4 5 6 7
  • Olanzapine for Bipolar I Depression
    • Double blind, random assignment, 8 week inpatient study
    • 6 months open extension
    • Treatment groups
      • Olanzapine monotherapy (N = 351)
      • Olanzapine + Fluoxetine (N = 82)
      • Placebo (N = 355)
    Tohen, 2002
  • Improvement over 8 weeks -20 -15 -10 -5 0 0 1 2 3 4 6 8 * * P < 0.001; ** P < 0.01 MADRS change from BL Mean Dose Tohen, 2002 Weeks * * * * * * * * * * ** OLZ 351 9.7 - PCB 355 - - OFC 82 7.4 39.3 N OLZ FXT
  • Paroxetine for Bipolar Depression
    • Most well studied: three double blind studies
    • All add-on
    • All double blind against placebo, imipramine, venlafaxine, and combined lithium and divalproex
    Young et al., Am J Psychiatry 2002; Nemeroff et al., Am J Psychiatry 2001; Vieta et al., J Clin Psychiatry 2002
  • Paroxetine for Bipolar Depression Conclusions
    • Lithium alone as good as lithium combined with antidepressant either (PXT or IMI), except
      • At low lithium levels (< 0.8), antidepressants better that lithium alone
    • Combination mood stabilizers equal to combined mood stabilizer and paroxetine (but mood stabilizer combination has more side effects)
    • Venlafaxine and paroxetine equally effective
    • Paroxetine has very low switch rates
    Young et al., Am J Psychiatry 2002; Nemeroff et al., Am J Psychiatry 2001; Vieta et al., J Clin Psychiatry 2002
  • Switch Rates on Antidepressants
    • All while on mood stabilizers
    • High rates of switch (over 10% short term)
      • TCA’s, venlafaxine, MAOI’s
    • Low rates of switch (under 10% short term)
      • Bupropion, SSRIs
    • Much higher if not on a mood stabilizer
  • ON THE OTHER HAND Depression Following Antidepressant Discontinuation in Bipolar Patients (Chart Review) Weeks After Improvement % Well ( Not Depressed) Altshuler et al., J Clin Psychiatry, 2001; 62:612-616. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0 13 26 39 52 Discontinued Antidepressant n=25 Continued Antidepressant n=19
  • Maintenance
  • Maintenance Treatment with Divalproex Time to Any Affective Episode Bowden et al., Arch Gen Psychiatry 2000 0 0.2 0.4 0.6 0.8 1.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks Survival Divalproex Lithium Placebo P = .33
  • Time to Intervention for a Mood Episode Lamotrigine vs Lithium vs Placebo Goodwin et al., 2003 submitted 12 Mon. 18 Mon. Index Manic or Depressed LTG v. PBO, p < 0.001 Li v. PBO, p < 0.001 LTG v. Li, p = 0.629
  • Time to Intervention for Depression Goodwin et al., 2003 submitted 12 Mon. 18 Mon. Index Manic or Depressed LTG v. PBO, p = 0.009 Li v. PBO, p = 0.120 LTG v. Li, p = 0.325
  • Time to Intervention for Mania LTG v. PBO, p = 0.034 Li v. PBO, p < 0.001 LTG v. Li, p = 0.030 Goodwin et al., 2003 submitted Index Manic or Depressed 12 Mon. 18 Mon.
  • APA Guidelines for Bipolar Disorder
    • Revised APA guidelines released April 2002, updated 2004
    • Changes in the pharmacotherapy of manic and mixed episodes
    • Refocus of the approach to depression
    • New approaches to maintenance therapy and to rapid cycling
    • New section on children and adolescents
  • Approach to the Patient With Mania
    • Initiate either lithium or divalproex plus a second-generation antipsychotic
    • For less ill patients, monotherapy with lithium, divalproex, or antipsychotic may be sufficient
    • For mixed episodes, divalproex or antipsychotic is preferred over lithium
    • Atypical antipsychotics are preferred over typicals
    • Carbamazepine or oxcarbazepine are alternatives to lithium or divalproex
    APA Practice Guidelines Am J Psychiatry . 2002;159(4)supplement.
  • Approach to the Patient With Mania
    • For breakthrough episodes, first optimize the maintenance medication dose
    • Consider adding an antipsychotic
    • If this does not work, consider adding lithium, divalproex, carbamazepine, or oxcarbazepine
    • Clozapine or ECT should be considered for treatment-refractory patients
    APA Practice Guidelines Am J Psychiatry . 2002;159(4)supplement.
  • Approach to the Patient With Bipolar Depression
    • Is the patient already in treatment with a mood stabilizer?
    • Yes
      • Then optimize the dose of the mood stabilizer
      • Then add antidepressant
    • No
      • Then …
    APA Practice Guidelines Am J Psychiatry . 2002;159(4)supplement.
  • Approach to the Patient with Bipolar Depression Then...
    • For less severely ill patients
      • initiate lithium or lamotrigine
    • For more severely ill patients
      • initiate lithium and an antidepressant
    • For those with psychosis or at high suicide risk
      • add antipsychotic
      • ECT
    APA Practice Guidelines Am J Psychiatry . 2002;159(4)supplement.
  • Emerging Trends Pharmacotherapy of Acute Mania
    • Combination treatment the rule, not the exception
    • Continued use of Lithium and Divalproex as cornerstones of treatment
    • Increasing use of atypical antipsychotics for acute treatment and ?for maintenance
  • BIPOLAR DISORDER The Major Challenge: Misdiagnosis Goodwin & Jamison (1990); Hirschfeld et al (2003); Lish et al (1994) NDMDA survey of its bipolar members Rate of misdiagnosis 1994 2000 73% 69%
    • Most frequent misdiagnosis: Unipolar depression
    • Treatment as unipolar depression can lead to worsening of symptoms by switching into mania or cycle acceleration
  • Steps to Increase Recognition of Bipolar Disorder and to Improve Diagnosis
    • Education of physicians about the illness, particularly how it presents itself in clinics
    • Ask patients directly about history of symptoms of Bipolar Disorder
    • Involve family members in clinical evaluations
    • Increase patients’ and families’ awareness of the illness
    • Screen for Bipolar Disorder, especially in depressed patients
  • Screening for Bipolar Disorder Mood Disorder Questionnaire
    • A brief, simple, self-report questionnaire for bipolar disorder--13 yes-no items regarding bipolar disorder
    • Well validated in psychiatric clinical and general population samples
    • Translated into several languages
    Hirschfeld RMA, et al. Am J Psychiatry. 2000; 157:1873-1875
  • Bipolar Disorder — 3.4% of the US Population Screened Positive by MDQ * Weighted to match US census data. Weighted Percent * Overall Prevalence Age Group Income Hirschfeld et al. J Clin Psychiatry. 2003; 64:53-59.
  • Physician Diagnoses Among MDQ Positives in the Community Dx with bipolar disorder Dx with depression but not bipolar disorder Neither bipolar disorder nor depression Dx 20% 31% 49% Hirschfeld RMA, et al. J Clin Psychiatry . 2003;64:53-59. 80% of patients who screened positive for BP were not diagnosed w/ BP