Practical Clinical Trials in Mental Health II

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 28% 35% > 18 < 13 13 to 18 • Only 35% with onset > 18 • About 65% with onset < 18 • Almost a third with onset < 13 37% Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881 Age of Onset in Bipolar Disorder (STEP-1000) 8% 7% mean age of onset 17.37 (SD 8.67) 6% 5% 4% 3% 2% 1% 0% 2 5 8 11 14 17 20 23 26 29 32 35 38 41 44 48 53 Age of Onset Perlis RH for the STEP-BD group, Biol Psych 2004 Childhood Onset With Greater Anxiety Comorbid Conditions 80 70 60 50 40 30 20 10 0 Any Anxiety Panic w Agor Agor w/o Panic Social Phobia GAD PTSD Onset < 13 N=983 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 80 70 60 50 40 30 20 10 0 Any Anxiety Alcohol Substance ADHD Onset < 13 N=983 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% 60 50 40 30 20 BP I BP II 17% 9% 22% 10% 17% 18% * * † * * * 10 0 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 † ‡ § ‡ Euthymic, d 200 150 † * 100 50 0 No Anxiety (n=233, 332) * * § † * Any Anxiety (n=236, 137) PD w/ AGOR (n=81, 37) PD w/out AGOR (n 35, 17) SAD (n=99, 55) OCD (n=49, 26) PTSD (n=79, 22) GAD (n=86, 56) ‡ 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 10 9 8 7 6 5 4 3 2 1 0 9.5 ADHD Comorbid • Shorter periods of wellness • More likely 5.9 % – BPI – Symptomatic – > lifetime manic episodes – EtOH and drug abuse Lifetime ADHD Current ADHD • Less likely: – Recovered N = 1000; Nierenberg et al., Biol Psychiatry 2005;57:1467–1473 Comorbid ADHD with more lifetime problems 50 45 40 35 30 25 20 %15 10 5 0 > 20 Manic Episodes Lifetime suicide attempts Lifetime violence Lifetime legal problems ADHD No ADHD 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 MDD Dysthymia Bipolar Any Mood Disorder % With ADHD* 18.6 12.8 19.4 38.3 % Without ADHD 7.8 1.9 3.1 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 No SUD Current SUD 52% 12% 36% Past SUD 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% with anxiety Overall Hazard Ratio (HR)= 0.661 (Chi sq=5.41, P=0.020) HR=0.452 for social anxiety disorder 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 N=489 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 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 80 Intensive Treatment Collaborative Care 70 60 50 % Well 40 30 20 10 0 1 2 3 4 5 6 7 Month 8 9 10 11 12 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) • 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 % 12 10 8 6 4 2 0 1.4 with new onset PCOS 10.5 No Valproate Valproate 2/44 9/86 Median time to onset = 3 months Joffe et al. Valproate is associated with new-onset oligoamenorrhea with hyperAndrogenism 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? 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? 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 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? 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 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