Bipolar Disorder In Primary Care Settings Christopher Schneck, M.D. Associate Professor of Psychiatry Director, Outpatient Consultation Services University of Colorado Denver Depression Center Aurora, CO Disclosure: Funding Sources NIMH No pharmaceutical funding Case Example Patient L.R. • 33 year old single female, presents with chronic depression. – Depressed for 15 years – Current symptoms: hypersomnic, eating more, craves carbohydrates/sweets, feels like she is “nailed to the bed in the mornings,” crying spells, not suicidal but sometimes “prays she will not wake up,” irritable, anxious. – Never psychotic; no suicide attempts. Patient L.R. • Denies manic symptoms. At times, can feel more self-confident, “project a different self,” more impulsive. • No family history of mood disorder • Past Medical Hx: – Appendectomy – Mild asthma • Working 3 jobs; wants to return to graduate school • Intermittent alcohol problems • In psychotherapy Patient L.R. • All antidepressants “work for a while, then stop.” – – – – – – – – Paroxetine (Paxil) Fluoxetine (Prozac) Sertraline (Zoloft) Venlafaxine (Effexor) Buproprion (Wellbutrin) Amphetamine/d-amphetamine (Adderall) Escitalpram (Lexapro) Nefazodone (Serzone) Next Step? Diagnosis? Treatment? Bipolar Disorder in Patients Treated for Depression in a Family Medicine Clinic 21% MDQ+ 649 Hirschfeld RM, et al. J Am Board Fam Pract. 2005;18:233-239. Waiting Room Patients in a Family Practice Bipolar 8% 10% MDQ+ Neither 12% Depression 80% 1146 Outpatients Das AK, et al. JAMA. 2005;293(8):956. Challenges in the Diagnosis and Treatment of Bipolar Disorder •Unrecognized •Untreated Often •Misdiagnosed •Inadequately treated •Worsened by wrong treatment Ghaemi SN, et al. Can J Psychiatry. 2002;47:125-134. Misdiagnosis of Bipolar Disorder Percent 70 60 50 40 30 20 10 0 u Ab B er st lu oh Et C ty ie nx se a ni re n io ss re ep ph zo hi Sc A D Initial Diagnosis Hirschfeld RM, et al. J Clin Psychiatry. 2004;65(suppl 15):5-9. Possible Red Flags • Antidepressant Failure • Increased irritability/agitation on antidepressants • Post-partum depression • Seasonal mood changes • Legal, interpersonal, occupational chaos Marchand WR. Hosp Physician. 2003;39:21-30. Manning JS. Curr Psychiatry. 2003;2:6-9. Geller B, Luby J. J Am Acad Child Adolesc Psychiatry. 1997;36:1168-1176. Akiskal HS, et al. J Affect Disord. 1983;5:115-128. Possible Red Flags • Rapid onset/offset • “Too many to count” • Psychosis • Family history • Substance abuse Clinical Features of Bipolar Disorder Symptom Domains of Bipolar Disorder Manic Mood and Behavior • Euphoria • Grandiosity • Pressured speech • Impulsivity • Excessive libido • Recklessness • Social intrusiveness • Diminished need for sleep Psychotic Symptoms • Delusions • Hallucinations Dysphoric or Negative Mood and Behavior • • • • • BIPOLAR DISORDER Depression Anxiety Irritability Hostility Violence or suicide Cognitive Symptoms • • • • Racing thoughts Distractibility Disorganization Inattentiveness Slide courtesy of Keck PE Jr.; adapted from Goodwin FK, Jamison KR. Manic-Depressive Illness. Oxford University Press: New York, NY; 1990. Time Depressed vs. Manic 37:1 60 Weeks depressed Weeks manic Percent of Weeks 50 40 3:1 30 20 10 0 BP I (n=146) BP II (n=71) 1. Judd LL et al. Arch Gen Psychiatry. 2002; 59:530-537. 2. Judd LL et al. Unpublished data. Psychosocial Impairment: Depression More Impairing than Mania Percent With Disruption* Due to depressive symptoms Due to manic symptoms 35 32 30 25 20 27 23 20 22 17 15 10 5 0 Work/School P < 0.01 Social/Leisure P < 0.0001 *Marked or extreme over past 4 weeks Hirschfeld RM. Eur Neuropsychopharmacol. 2004;14(suppl 2):S83-S88. Family Life P < 0.0001 Mania Depression Mania Depression Mania Depression Mania Depression Bipolar I vs Bipolar Bipolar I II Bipolar II • Manic or mixed episode • Hypomania + major • • • • depression • Female:male = 2:1 • Diagnostic challenges: Highly familial Female:male = 1:1 Suicide: 10%–15% 60% Comorbid substance – Hypomania not experienced as “abnormal” – Prior hypomania often not reported American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000. The Spectrum of Bipolar Disorder Major depression w/ strong family hx of bipolar disorder Antidepressant-induced manias & hypomanias Rapidly changing mood swings Bipolar II Secondary manias Bipolar I Cyclothymia Major Depression Bipolar Spectrum Disorders Gorman JM, Sullivan G. J Clin Psychiatry. 2000;6(1 Suppl 1):13-16. Bipolar Difficulties in Diagnosis: Bipolar Patients Previously Diagnosed with Unipolar MDD (N=29) 19.6 24.7 25.2 30 33.2 34.3 Depression DX: Bipolar Mania 9.1 years Ghaemi SN et al. J Clin Psych 61:10, 2000 Consequences of Misdiagnosis ATD Monotherapy Switches, Cycling ↑ Suicide Attempts ↑ Comorbidity ↑ Mortality ↑ Psychosocial Impairment Goldberg JF, Ernst CL. J Clin Psychiatry. 2002;63:985-991. Goldberg JF, Truman CJ. Bipolar Disord. 2003;5:407-420. Reasons for Misdiagnosis • Hypomania hard to identify – Patients typically do not seek care for hypomania – Patients often omit hypomania from clinical histories • Patients tend to seek care during depressive episode • Bipolar II may be common in primary care setting Zylstra RG, et al. Primary Care Companion J Clin Psychiatry. 1999;1:47-49. Can you tell the difference between bipolar & unipolar depression? Features Indicative of Bipolar versus Unipolar Depression Substance Abuse Family History First Episode < 25 yrs Postpartum Illness Psychosis < 35 yrs Atypical Features Rapid On/Off Pattern Recurrent MDE (> 3) Bipolar Unipolar Very High Moderate Almost Uniform Sometimes Very Common Sometimes Very Common Sometimes Highly Predictive Uncommon Common Occasional Typical Unusual Common Unusual Brief MDE (avg < 3 months) Suggestive MDE = major depressive episode Kaye NS. J Am Board Fam Pract. 2005;18:271-281. Uncommon Screening for Bipolar Disorder Bad day at the office The Mood Disorder Questionnaire (MDQ) + - Greater than 7 “yes” responses -”yes” to Question 2 -”Moderate” or “Serious” to Question 3 7 or fewer “yes” responses -no to Question 2 -”No problem” or “minor problem” to Question 3 Hirschfeld RMA, et al. Am J Psychiatry. 2000;157:1873-1875. Hirschfeld RMA, et al. Am J Psychiatry. 2003;160:178-180. Hirschfeld RMA, et al. J Clin Psychiatry. 2003;64:53-59. www.psycheducation.org/PCP/handouts/mdq.doc Bipolar Spectrum Diagnostic Scale √ √ √ √ √ √ √ √ Ghaemi SN et al. J Affect Dis, vol 84, 2005 √ √ “Has there ever been a time in your life, when, for several days or even weeks, you slept a lot less than usual and found you didn’t miss it?” Treatment Suicide Risk: Various Conditions Observed/Expected 1.8 Malignancy 7.1 Personality D/O 5.9 Alcohol 19.2 Mixed Drugs 8.5 Schizophrenia Bipolar Disorder 15.0 20.3 Major Depression History of Suicide Attempt 38.4 0 0 Inskip H et al. Br J Psych 1998;172:35-37. 5 5 10 10 15 1 5 20 20 25 2 5 30 30 35 3 40 40 5 36 Bipolar Disorder: Untreated vs Treated Standardized Mortality Ratios 29.2* *P < 0.001 †P < 0.05 Untreated Treated Zurich cohort, n = 406 1959–1997 6.4 1.4* 0.6 Neoplasm 2.2*1.7 1.6† 1.3 1.6 2.0 Cardiovascular Cerebrovascular Accidents Adapted from Angst F et al. J Affect Disorder. 2002;68:167-181. Suicide 2.0*1.3 2.2* 1.3 Other All Causes 37 Treatment Psychotherapy Medications Improved Outcome Therapies With Bipolar Disorder Indications Therapy Valproic acid Lithium Carbamazepine Divalproex Bipolar Mania √ √ √ √ Lamotrigine Aripiprazole Olanzapine √ √ Olanzapine+fluoxetine (OFC) Quetiapine Risperidone Ziprasidone *Limited Bipolar Depression Maintenance Relapse Prevention Yes No No No Yes No* Yes No No No Yes No* No No No No** Yes No Yes No Yes No Yes No No √ √ √ √ √ √ √ √ √ Yes Yes √ √ Yes Yes Yes No No Yes No No Yes No No No Yes No No No Yes data; **Emerging data Physicians’ Desk Reference®. 59th ed. Montvale, NJ: Medical Economics Co; 2005. Treatment of Mania Response Rates in 20 Acute Mania Trials 70% 62% Percent Responders 60% 50% 50% 42% 40% 29% 30% 20% 10% 0% Li/DVX/CBZ/Atypicals From Ketter TA. Review of Psychiatry, vol 24, no. 3 Placebo Atypical+Li/DVX Combo Li/DVX Monotherapy Risperidone vs Placebo in Acute Mania: Mean Reduction in YMRS Score Mean Change in Total YMRS Score Baseline Day 3 Week 1 Week 2 Week 3 Endpoint 0 LOCF analysis; *P < 0.001 risperidone vs placebo -2 Placebo (n = 125; BL YMRS = 29.2) -4 -6 * -8 Risperidone (n = 134; BL YMRS = 29.1 ) Median dose 4.1 mg/day -10 * -12 * * BL = Baseline Hirschfeld RM et al. Presented at ACNP Annual Meeting. San Juan, Puerto Rico. December 2002. * Overview of 15 Acute Mania Monotherapy Studies Placebo Percent Responders 60% Atypical Antipsychotics Mood Stabilizers 50% 40% 30% 20% 10% 0% Lithium 1950 Mg/d DVX 1694 Mg/d CBZ 707 Mg/d Risp 4.9 Mg/d OLZ 16 Mg/d QUE 575 Mg/d Zip Ari 121 Mg/d 28 Mg/d PCB Adapted from Ketter TA. Advances in the Treatment of Bipolar Disorder. Review of Psychiatry, vol. 24, no. 3 Treatment of Bipolar Depression Positive Antidepressant Trials with Adequate Sample Size* in Bipolar Depression Slide Courtesy G Sachs *Statistical Power ≥ 0.8 to detect meaningful difference at p<.05 Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Disorder NS 30 % Patients 25 27 23.5 20 15 NS 10 11 MS + AD MS Alone 10 5 0 Durable Recovery Switch Rates Sachs GS et al. NEJM 2007; 356(17) Conversion to Rapid Cycling Antidepressant Problems with Antidepressants: Mrs. A ...”After 10 days noticed racing & distorted thoughts, increased irritability, hostility, aggressive behavior and decreased need for sleep. She described feeling “speedy” and began driving aggressively; she later described her state as one of ‘radical agitation.’” Schneck CD. J Clin Psychiatry 59:12, 1998 Antidepressant Associated with Increased Cycle Rates Episodes Odds Ratio Statistic 4+ Episodes (N=48) 3.8 95% CI=1.2-2.3, p=0.001 2-3 Episodes (N=225) 2.0 95% CI=1.4-2.9, p=0.0001 One episode (N=263) 1.7 95% CI=1.7-8.5, p=0.001 Schneck et al. Am J Psych 165 (3), 2008 Time to Relapse for Patients with Bipolar Disorder Who Discontinued Antidepressant Treatment Within 6 Months of Remission or Continued Treatment Beyond 6 Months Proportion of Subjects Not Relapsing 1.0 Medication Discontinuation Group Medication Continuation Group 0.8 0.6 0.4 0.2 0.0 0 8 16 24 32 Number of Weeks Until Relapse 40 48 Altshuler L et al. Am J Psych 160, 2003 Treatment Response in Response Rate Modern Trials with >100 Depressed Bipolar Subjects 70% Placebo Response Rate 60% Active Placebo Difference 50% 22% 22% 40% 29% 25% 29% 30% 20% 35% 35% 36% 36% 25% 10% 24% 19% 11% 4% 0% QUE 600 mg QUE 300 mg LTG 200 mg OFC 25% LTG 50 mg Li Pax Li IMI 8% OLZ Adapted from Ketter TA. Advances in the Treatment of Bipolar Disorder. Review of Psychiatry, vol. 24, no. 3 Psychotherapy by (buy) the Book Be on the look-out for: • • • • • • • • Repeated antidepressant failures Irritability/agitation on antidepressants Severe post-partum depression Rapid onset/offset of mood changes “Too many to count” Psychosis Family history of bipolar disorder Substance abuse Ask: • Duration of mood symptoms • Hypomanic symptoms • Friends, family • Family history • Prior response to antidepressants • MDQ or BSDS Refer When Possible…. Patient L.R. • Diagnosis: Bipolar Spectrum – Collateral information: episodic irritability, pressured speech at times • Antidepressants tapered • Started on lamotrigine • Dose pushed to 400 mg daily Questions?