Lessons from STEP-BD for the Treatment of Bipolar Disorder Andrew A. Nierenberg, MD Massachusetts General Hospital Harvard Medical School

STEP-BD Systematic Treatment Enhancement Program for Bipolar Disorder www.stepbd.org Evidence guided treatment Specialty bipolar clinics Integration of measurement and management Embedded randomized trials

Methods Mini International Neuropsychiatric Interview Affective Disorders Evaluation Form Clinical Monitoring form Self-administered waiting room form www.manicdepressive.org Quarterly and yearly evaluations Participants followed for up to 2 years

Collaborative Care: Integration of Measurement and Management Shared measurement Symptoms Depression Mania/hypomania Anxiety Irritability Stress, alcohol, smoking, weight Side effects Functioning

Collaborative Care: Integration of Measurement and Management Shared measurement Mood monitoring Medication concordance Non-concordance open for discussion Negotiate Goals Medication changes Menu of reasonable choices Collaborative Care Workbook

STEP-BD Baseline Findings

Most Bipolar Patients report onset in childhood or adolescence Only 35% with onset > 18 About 65% with onset < 18 Almost a third with onset < 13 < 13 > 18 13 to 18 Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881

Age of Onset in Bipolar Disorder (STEP-1000) mean age of onset 17.37 (SD 8.67) Perlis RH for the STEP-BD group, Biol Psych 2004

Childhood Onset With Greater Anxiety Comorbid Conditions Onset 13 to 18 Onset > 18 Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881

Childhood and Adolescent Onset With Greater Comorbid Substance Abuse/Dependence and ADHD Onset 13 to 18 Onset > 18 Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881

Depressive Polarity of First Episode: More lifetime depression Perlis et al., Biological Psychiatry 2005;58:549–553

Lifetime Anxiety Comorbidity in Bipolar Disorder – STEP 500 51% 17% 9% 22% 10% 17% 18% 60 BP I BP II 50 40 30 * * * * 20 † * 10 Any Panic ± Agor Agor Without Panic SAD OCD PTSD GAD *P<0.001; †P<0.005 Agor=agoraphobia; GAD=generalized anxiety disorder; OCD=obsessive-compulsive disorder; PTSD=posttraumatic stress disorder; SAD=social anxiety disorder. Simon N, et al. Am J Psychiatry. 2004;161:2222-2229.

Anxiety Comorbidity Associated With Reduction in Longest Time Euthymic in Bipolar Disorder in Past 2 Years (N=469) 300 Current Anxiety Disorder 250 Lifetime Anxiety Disorder 200 † ‡ ‡ † Euthymic, d § 150 * * § † 100 * * 50 No Anxiety Any Anxiety PD w/ AGOR PD w/out AGOR SAD OCD PTSD GAD (n=99, 55) (n=49, 26) (n=79, 22) (n=86, 56) (n=233, 332) (n=236, 137) (n=81, 37) (n 35, 17) ‡ P<0.05; † P<0.01; § P<0.001; * P<0.0001 Simon NM, et al. Am J Psychiatry. 2004;161:2222-2229.

ADHD Comorbidity in Bipolar Adults Shorter periods of wellness More likely BPI Symptomatic > lifetime manic episodes EtOH and drug abuse Less likely: Recovered % N = 1000; Nierenberg et al., Biol Psychiatry 2005;57:1467–1473

Comorbid ADHD with more lifetime problems % N = 1000; Nierenberg et al., Biol Psychiatry 2005;57:1467–1473

Prevalence of ADHD with Mood Disorders % With % Without Other Comorbid* Comorbid Conditions Odds Ratio MDD 9.4 3.7 2.7 Dysthymia 22.6 3.7 7.5 Bipolar 21.2 3.5 7.4 Any Mood Disorder 13.1 2.9 5.0 *eg, 21.2% of those with Bipolar Disorder during the previous 12 months have ADHD compared to 3.5% of those without MDD who have ADHD. Kessler RC, et al. Am J Psychiatry. 2006;163:716-723.

Prevalence of Mood Disorders with Adult ADHD % With % Without ADHD* ADHD MDD 18.6 7.8 Dysthymia 12.8 1.9 Bipolar 19.4 3.1 Any Mood Disorder 38.3 5.0 *eg, 19.4% of those with ADHD during the previous 12 months have Bipolar Disorder compared to 3.1% of those without ADHD who have Bipolar Disorder. Kessler RC, et al. Am J Psychiatry. 2006;163:716-723.

Most bipolar patients with lifetime comorbid substance use disorder recover from SUD 36% + 12% = 48% of bipolar patients have lifetime SUD. 36%/48% (3/4) of those with lifetime comorbid SUD recover from SUD 52% No SUD 12% Current SUD 36% Past SUD As you can see from the 2000 National Depressive and Manic Depressive Association’s Bipolar Survey, correct diagnosis has been a tough challenge, historically. Just three years ago, 69 percent of patients in the survey had been misdiagnosed as having unipolar depression, when in fact they were suffering with bipolar disorder. And 35 percent of them waited at least 10 years for the correct diagnosis to be made. 48% lifetime SUD Weiss RD, Ostacher M, et.al. Recovery from Substance Use in Bipolar Disorder: Does it Matter J Clin Psychiatry. 2005; J Clin Psych. 2005; 66:730-735.

STEP-BD Results: Observational Prospective Findings

Higher bipolar relapse rate with residual symptoms Without residual symptoms Without residual symptoms With residual symptoms With residual symptoms Perlis et al., Am J Psychiatry. 2006 Feb;163(2):217-24.

Less than 1/3 of symptomatic bipolar patients reach recovery and remain well over 2 years in STEP-BD Achieved recovery 58.5% (< 2 mood symptoms for at least 8 weeks) Relapse into depression 34.7% Relapse into mood elevation 13.8% Total relapse rate 48.5% Total that stayed recovered over 2 years (100%-48.5%) 51.5% Total who recovered and remained free of depressive and mood elevation recurrences over 2 years (51.5% out of 58.5% who achieved remission) 30.1% N=1469 who entered symptomatic Perlis et al., Am J Psychiatry. 2006 Feb;163(2):217-24.

Anxiety comorbid conditions with lower probability of recovery from bipolar depression in STEP-BD without anxiety N=248 Overall recovery rate = 80.7% Overall Hazard Ratio (HR)= 0.661 (Chi sq=5.41, P=0.020) HR=0.452 for social anxiety disorder with anxiety Otto et al., Br J Psychiatry 2006 Jul;189:20-5.

Anxiety comorbid conditions with higher risk of relapse in bipolar disorder in STEP-BD Overall relapse rate = 41.4% Overall Hazard Ratio (HR)= 1.764 ( 2=10.9, P=0.001) HR=1.55 for one disorder HR=2.17 for two or more disorders HR=2.07 for social anxiety disorder HR=2.45 for PTSD without anxiety with anxiety Otto et al., Br J Psychiatry 2006 Jul;189:20-5.

Embedded Randomized Trials

No Advantage or Disadvantage to Adding AD to Mood Stabilizers for Bipolar Depression Table 4. Outcomes According to Treatment Group. Sachs G et al. N Engl J Med 2007;10.1056/NEJMoa064135

Adjunctive Psychosocial Interventions with Empirical Support for Adult Bipolar Disorder Cognitive-Behavioral Therapy (CBT) Family-Focused Therapy (FFT) Interpersonal and Social Rhythm Therapy (IPSRT) Collaborative Care Plus

Intensive psychosocial interventions for bipolar depression better than collaborative care 1-year recovery rate for intensive group, 105/163 [64.4%]; for CC, 67/130 [51.5%]; log-rank 2(1) = 6.20, p = 0.013; hazard ratio (HR) = 1.47; 95% CI = 1.08-2.00 Miklowitz et al., Arch Gen Psychiatry, in press

Treatment Resistant Bipolar Depression: Lamotrigine Added Might Help Nierenberg et al., Am J Psychiatry 2006;163;1-8

Valproate Associated Polycsytic Ovarian Syndrome (PCOS) Menstrual cycle irregularities < or = 9 cycles per year Hyperandrogenism Hirsuitism Acne Male pattern alopecia Elevated serum androgens Obesity, insulin resistance, polycystic ovarian morphology

New Onset Oligoamenorrhea with Hyperandrogenism with Valproate with new onset PCOS % 2/44 9/86 Median time to onset = 3 months Joffe et al. Valproate is associated with new-onset oligoamenorrhea with hyper- Androgenism in women with bipolar disorder. Biol Psych 2006;59:1078-1086

Questions that remain after STEP-BD What are the best acute and long-term treatments for bipolar depression? What are the best treatments to prevent mood episodes and restore functioning in generalizable populations? Burden of depressive phase documented by others and in STEP. 25% sustained recovery in RAD. Need better options, additional studies. Note need esp in BD II Chronic disease - Need for longer follow-up. Most relapse preventions studies to date by Industry with narrowly defined populations Surprisingly high rates of comorbid anxiety disorders

Questions that remain after STEP-BD What are the best treatments for comorbid conditions (anxiety, substance abuse, ADHD)? Substance use disorders are untreated What can decrease medical morbidity and overall mortality, including suicide? Burden of depressive phase documented by others and in STEP. 25% sustained recovery in RAD. Need better options, additional studies. Note need esp in BD II Chronic disease - Need for longer follow-up. Most relapse preventions studies to date by Industry with narrowly defined populations Surprisingly high rates of comorbid anxiety disorders

Questions that remain after STEP-BD What biomarkers can be used to personalize acute and long-term treatment? Molecular Genetic Imaging Cognitive assessments Other biomarkers Burden of depressive phase documented by others and in STEP. 25% sustained recovery in RAD. Need better options, additional studies. Note need esp in BD II Chronic disease - Need for longer follow-up. Most relapse preventions studies to date by Industry with narrowly defined populations Surprisingly high rates of comorbid anxiety disorders

What are the best treatments of bipolar depression? Novel therapeutic interventions Do patients with BPII depression need mood stabilizers? After recovery from bipolar depression, what treatments promote long-term functioning and prevent relapse? Network well suited to study novel treatments after demonstration of efficacy in smaller, single site studies. Not optimal for first priority given our lack of knowledge of best first line treatments for most patients, particular need BDII Highlight how our study plan is different from Amsterdam and Stanley group Highlight need for longer-term follow-up and cost efficiency of adding longer-term arms. Make point that this applies to all network studies, if possible with funding constraints.

What are the best treatments for comorbid conditions and symptoms? Anxiety Pharmacologic Psychotherapeutic Substance abuse Unique challenge of difficult to treat patients ADHD Benefits and risks of psychostimulants Cognitive dysfunction Medical burdens We could include suicide in the presentation, but not here.

What is the best treatment for bipolar disorder with comorbid anxiety? Anxiety comorbidity 51% of STEP-BD cohort associated with poorer outcomes No evidence-based treatment options Antidepressants can exacerbate disease course Benzodiazepines of concern due to high comorbid substance abuse rates in BP No studies of psychotherapies for comorbid anxiety Novel psychosocial interventions needed

The sun and moon allude to the cyclical nature of bipolar disorder and the mission of the BTN: enduring commitment to clinical research on behalf of patients with bipolar disorder and their families. Designed by Gianna Marzilli Ericson