Treatment of Bipolar Disorder An Update


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1 : Treatment of Bipolar Disorder An UPDATE Rajiv Tandon, MD Chief of Psychiatry State of Florida Tallahassee, Florida, U.S.A.
2 : 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.
3 : 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 1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156. 2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.
4 : Murray, Lopez, 1994; Updated 2004 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
5 : Bipolar Disorder Particularly recalcitrant mental health problem Symptomatic at least half the time Can have impaired social function even when symptom-free 1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156. 2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.
6 : 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 1Riedel W J. Psychol Med. 2004; 34: 3-8. 2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.
7 : 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
8 : 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
9 : Impact of Bipolar Disorder Vs. Unipolar Disorder — Heavy Impact on Daily Life Calabrese. J Clin Psychiatry. 2003;64:425-432. Percent * P<0.0001 * * *
10 : Bipolar Disorder > 50% alcohol and/or other substance abuse About 50% attempt suicide About 15% succeed 1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156. 2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.
11 : Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S. 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
12 : Berk M, Dodd S Hum Psychopharmacol. 2005;20:1-2. 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
13 : Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S. Treatment Challenges in Bipolar Disorder Often unrecognized Often untreated Often misdiagnosed Often inadequately treated Exacerbated by incorrect treatment
14 : 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
15 : Bipolar Disorder: Summary of Efficacy Evidence from RCTs Drug Acute Mania Mono Combo Acute Depression Maintenance
16 : 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
17 : 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
18 : 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
19 : Other ANTICONVULSANTS Gabapentin Pregabalin Levetiracetam Tiagabine Topiramate NO PROVEN EFFICACY
20 : Antipsychotics
21 : Current Antipsychotic Therapies 14 First-Generation Typicals vs. 6 Second-Generation Atypicals
22 : Adapted from Jibson MD, Tandon R. J Psychiatr Res. 1998;32:215-228. Essence of Atypicality
23 : 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
24 : Bipolar Depression
25 : Change From Baseline of MADRS Lamotrigine in Acute Treatment of Bipolar Depression 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 * * † † † † † † † † † † † † †
26 : 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
:
28 : 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
29 : 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
30 : 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
31 : 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.
32 : Maintenance
33 : 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
34 : 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
35 : 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
36 : 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.
37 : APA Guidelines for Bipolar Disorder 37 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
38 : 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.
39 : 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.
40 : 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.
41 : 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.
42 : 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
43 : 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
44 : 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
45 : 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
46 : * Weighted to match US census data. Weighted Percent * Bipolar Disorder — 3.4% of the US Population Screened Positive by MDQ Overall Prevalence Age Group Income Hirschfeld et al. J Clin Psychiatry. 2003; 64:53-59.
47 : 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.

 

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