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

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

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

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

5. 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

6. STEP-BD Baseline Findings

7. 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:

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

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

10. 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:

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

12. Lifetime Anxiety Comorbidity in Bipolar Disorder – STEP 500
51% % % % % % % 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:

13. 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:

14. 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

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

16. Prevalence of ADHD with Mood Disorders
% With % Without Other
Comorbid* Comorbid
Conditions Odds Ratio
MDD
Dysthymia
Bipolar
Any Mood
Disorder
*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:

17. Prevalence of Mood Disorders with Adult ADHD
% With % Without ADHD* ADHD
MDD
Dysthymia
Bipolar
Any Mood
Disorder
*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:

18. 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:

19. STEP-BD Results: Observational Prospective Findings

20. 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 Feb;163(2):

21. Less than 1/3 of symptomatic bipolar patients reach recovery and remain well over 2 years in STEP-BD
Achieved recovery %
(< 2 mood symptoms for at least 8 weeks)
Relapse into depression %
Relapse into mood elevation %
Total relapse rate %
Total that stayed recovered over 2 years
(100%-48.5%) %
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 Feb;163(2):

22. 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= for social anxiety disorder
with anxiety
Otto et al., Br J Psychiatry 2006 Jul;189:20-5.

23. 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.

24. Embedded Randomized Trials

25. 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; /NEJMoa064135

26. 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

27. 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 =
Miklowitz et al., Arch Gen Psychiatry, in press

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

29. 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

30. 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:

31. 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

32. 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

33. 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

34. 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.

35. 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.

36. 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

37. 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