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%
mean age of onset 17.37 (SD 8.67)
7%
6%
5%
4%
3%
2%
1%
0%
2
5
8
11 14
17 20
23 26 29
32 35
Age of Onset
Perlis RH for the STEP-BD group, Biol Psych 2004
38 41
44 48
53
Childhood Onset With Greater
Anxiety Comorbid Conditions
80
Onset < 13
N=983
70
Onset 13 to 18
60
50
Onset > 18
40
30
20
10
0
Any
Anxiety
Panic w
Agor
Agor w/o
Panic
Social
Phobia
Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881
GAD
PTSD
Childhood and Adolescent Onset With
Greater Comorbid Substance
Abuse/Dependence and ADHD
80
Onset < 13
70
N=983
Onset 13 to 18
60
Onset > 18
50
40
30
20
10
0
Any Anxiety
Alcohol
Substance
Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881
ADHD
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
50
BP II
40
30
*
†
*
10
0
Any
Panic
±
Agor
*
*
*
20
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
Euthymic, d
250
Lifetime Anxiety Disorder
†
200
‡
‡
150
†
§
*
*
100
§
*
†
*
50
0
No
Anxiety
(n=233,
332)
Any
Anxiety
(n=236,
137)
PD w/
AGOR
PD w/out
AGOR
(n=81,
37)
(n 35,
17)
SAD
OCD
PTSD
GAD
(n=99,
55)
(n=49,
26)
(n=79, 22)
(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
ADHD Comorbid
• Shorter periods
of wellness
• More likely
9.5
5.9
%
Lifetime ADHD
Current ADHD
– 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
50
45
40
35
30
25
20
%15
10
5
0
ADHD
No ADHD
> 20 Manic
Episodes
Lifetime
suicide
attempts
Lifetime
violence
Lifetime legal
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
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.
52%
No SUD
12%
• 36%/48% (3/4) of those
with lifetime comorbid
SUD recover from SUD
Current SUD
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
With residual symptoms
Perlis et al., Am J Psychiatry. 2006 Feb;163(2):217-24.
Without residual symptoms
With residual symptoms
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
without anxiety
with anxiety
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
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
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
12
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
%
with new onset PCOS
12
10.5
10
8
6
4
2
1.4
0
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