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

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