andrew a. nierenberg, md massachusetts general hospital harvard medical school lessons from step-bd...
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Andrew A. Nierenberg, MD
Massachusetts General Hospital
Harvard Medical School
Lessons from STEP-BD for the Treatment of Bipolar Disorder
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%
37%
35%
• Only 35% with onset > 18
• About 65% with onset < 18
• Almost a third with onset < 13
> 18
13 to 18
< 13
Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881
Age of Onset in Bipolar Disorder (STEP-1000)
Age of Onset
5348444138353229262320171411852
8%
7%
6%
5%
4%
3%
2%
1%
0%
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
0
10
20
30
40
50
60
70
80
AnyAnxiety
Panic wAgor
Agor w/oPanic
SocialPhobia
GAD PTSD
Onset < 13
Onset 13 to 18
Onset > 18
Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881
N=983
Childhood and Adolescent Onset With Greater Comorbid Substance
Abuse/Dependence and ADHD
0
10
20
30
40
50
60
70
80
Any Anxiety Alcohol Substance ADHD
Onset < 13
Onset 13 to 18
Onset > 18
Perlis RH for the STEP-BD group, Biol Psych 2004;55:875-881
N=983
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
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.
*
51% 17% 9% 22% 10% 17% 18%
0
10
20
30
40
50
60
Any Panic±
Agor
Agor Without
Panic
SAD OCD PTSD GAD
BP I BP II
*P<0.001; †P<0.005
*
*
* *
†
Anxiety Comorbidity Associated With Reduction in Longest Time Euthymic in Bipolar Disorder in Past 2 Years (N=469)
Simon NM, et al. Am J Psychiatry. 2004;161:2222-2229.
(n=233, 332)
(n=236, 137)
Current Anxiety Disorder
Lifetime Anxiety Disorder
(n=81, 37)
(n 35, 17)
(n=99, 55)
(n=49, 26)
(n=79, 22) (n=86, 56)
Eu
thym
ic,
d
0
50
100
150
200
250
300
No Anxiety
PD w/AGOR
SAD PTSDAny Anxiety
PD w/out AGOR
OCD GAD
*
‡ P<0.05; † P<0.01; § P<0.001; * P<0.0001
**
†
†
‡‡
§
§*
†
ADHD Comorbidity in Bipolar Adults
9.5
5.9
012345
6789
10
Lifetime ADHD Current ADHD
ADHD Comorbid• 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
05
101520253035404550
> 20 ManicEpisodes
Lifetimesuicide
attempts
Lifetimeviolence
Lifetime legalproblems
ADHDNo 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
% 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
52%No SUD
Weiss RD, Ostacher M, et.al. Recovery from Substance Use in Bipolar Disorder: Does it MatterJ Clin Psychiatry. 2005; J Clin Psych. 2005; 66:730-735.
Past SUD
Current SUD
36%
12%
• 36% + 12% = 48% of bipolar patients have lifetime SUD.
• 36%/48% (3/4) of those with lifetime comorbid SUD recover from SUD
48% lifetime SUD
STEP-BD Results:Observational Prospective
Findings
Higher bipolar relapse rate with residual symptoms
Perlis et al., Am J Psychiatry. 2006 Feb;163(2):217-24.
Without residual symptoms
With residual symptoms
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%
Perlis et al., Am J Psychiatry. 2006 Feb;163(2):217-24.
N=1469 who entered symptomatic
Anxiety comorbid conditions with lower probability of recovery from bipolar depression in STEP-BD
Otto et al., Br J Psychiatry 2006 Jul;189:20-5.
N=248Overall recovery rate = 80.7%
Overall Hazard Ratio (HR)= 0.661 (Chi sq=5.41, P=0.020)
HR=0.452 for social anxiety disorder
without anxiety
with anxiety
Anxiety comorbid conditions with higher risk of relapse in bipolar disorder in STEP-BD
Otto et al., Br J Psychiatry 2006 Jul;189:20-5.
N=489Overall 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
Embedded Randomized Trials
Sachs G et al. N Engl J Med 2007;10.1056/NEJMoa064135
No Advantage or Disadvantage to Adding AD to Mood Stabilizers for Bipolar Depression
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
Miklowitz et al., Arch Gen Psychiatry, in press
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 12Month
% Well
Intensive Treatment
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
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
1.4
10.5
0
2
4
6
8
10
12
No Valproate Valproate
%
2/44 9/86
Joffe et al. Valproate is associated with new-onset oligoamenorrhea with hyper-Androgenism in women with bipolar disorder. Biol Psych 2006;59:1078-1086
Median time to onset = 3 months
with new onset PCOS
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
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