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Rethinking Bipolar Disorder:
Where We've Been, Where We
Are, Where We Need to Go
page 85 in syllabus
David J. Kupfer, MD
Professor, Department of Psychiatry
Professor of Neuroscience and Clinical and Translational Science,
Center for Neuroscience, University of Pittsburgh School of Medicine
Chair, DSM-5 Task Force
Sponsored by the Neuroscience Education Institute
Additionally sponsored by Fairleigh Dickinson University School of Psychology
This activity is supported by educational grants from: Lilly USA, LLC; Otsuka America Pharmaceutical, Inc.; Pamlab, L.L.C.; Sunovion Pharmaceuticals Inc.;
Takeda Pharmaceuticals International, Inc., U.S. Region and Lundbeck Pharmaceutical Services, LLC; Teva Pharmaceutical Industries Ltd. with additional support from: Assurex Health, Inc.; JayMac Pharmaceuticals, LLC; Neuronetics, Inc.. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Individual Disclosure Statements
Faculty Author / Presenter
David J. Kupfer, MD, is a professor in the department of psychiatry and a
professor of neuroscience and clinical and translational science in the
center for neuroscience at the University of Pittsburgh School of Medicine,
PA.
Consultant/Advisor: Servier (spouse)
Dr. Kupfer reports receiving consulting fees from the American Psychiatric
Association for serving as the Chair of the DSM-5 Task Force.
Contributing Author
Ellen Frank, PhD, is a Distinguished Professor of Psychiatry and a
professor of psychology in the department of psychiatry at the University of
Pittsburgh School of Medicine, PA.
Consultant/Advisor: Servier
Copyright © 2013 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Describe reasons for combined psychotherapy and
medication management in bipolar patients
• List the main treatment targets of one evidence-
based psychotherapy for bipolar disorder –IPSRT
• Describe the primary medical comorbidities that put
bipolar patients at medical risk
• Identify treatment approaches to bipolar patients
based on the stage of illness
Individuals with bipolar disorder typically spend
the majority of their lives:
1. In a euthymic state
2. In a subsyndromally manic or hypomanic state
3. In a subsyndromally depressed state
4. In a syndromally depressed state
Pretest Question 1
The most common co-morbidities with bipolar
disorder are:
1. Anxiety and substance use disorders
2. Substance use and eating disorders
3. Anxiety and eating disorders
4. Eating disorders and ADHD
Pretest Question 2
The most common medical comorbidities with
bipolar disorder are:
1. Cancer
2. Cardiovascular disease
3. Osteoporosis
4. Eczema
Pretest Question 3
Rethinking Bipolar Disorder
• Where have we been?
• Where are we now?
• Where do we need to go?
Rethinking Bipolar Disorder
• Where have we been?
• Where are we now?
• Where do we need to go?
Myths
1. Uncommon disorder
2. Presents mostly as mania
3. Onset usually at middle age
4. Lithium-responsive disease with a full
restoration of functioning
5. Lack of comorbidity
6. The major concern for mortality is suicide
• Epidemiological Catchment Area Study1
− Lifetime prevalence: 1.2%
− (3.3 million people in US)
• National Comorbidity Survey2
− Lifetime prevalence: 1.6%
− (4 million people in US)
• National Comorbidity Survey – Replication3
− Lifetime Prevalence (BI-II): 3.9%
• Equal sex distribution1
1. Goodwin FK, Jamison KR. Manic Depressive Illness, 1990. 2. Kessler RC et al. Arch Gen Psychiatry 51:8-19, 1994. 3. Kessler RC et al. Arch Gen Psychiatry 62:593-602, 2005.
Uncommon
Symptom free
Depressive symptoms
Manic/hypomanic
symptoms
Cycling/mixed symptoms Prospective Study N=146, follow-up > 12 years
Weekly affective symptom
status ratings
Judd LL et al. Arch Gen Psychiatry 59:530-537, 2002.
Long-term Symptomatic Status of
Patients With Bipolar I Disorder
1. Post et al. Clin Neurosci Res 2:142-157, 2002.
2. Ketter et al. J Clin Psychiatry 63:146-151, 2002.
It Is Important to Recognize and
Treat Bipolar Depression
• Bipolar depression is more pervasive than mania1
• Mean duration of the depressive episode in bipolar
disorder is longer than manic episodes2
• Depression is chronic in more than 20% of patients with
bipolar disorder2
• Recently introduced medications (anticonvulsants and
atypical antipsychotics) have predominantly antimanic
rather than antidepressant properties2
Kupfer DJ et al. Acta Neuropsychiatrica 12:110-114, 2000.
*p
Treatment of Bipolar Depression
• Whether or not to use an antidepressant
• How long is long enough?
• Guideline recommendations (2–6 months)
• Is risk of cycling increased?
• Discontinuation risks
Age of First Onset
0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45+
%
0
5
10
15
20
25
30 Men Women
Age of first onset
Mean = 19.8 Median = 17.5
Kupfer DJ et al. J Clin Psychiatry 63:120-125, 2002.
Distribution of Age of First Onset
Major Goals of Treatment in
Bipolar Disorder
• Prevent future episodes of mania
• Prevent mixed episodes
• Prevent episodes of depression
• Diminish the presence of subsyndromal
depression over extended periods of time
• Improve functioning
• Decrease morbidity and mortality
"I cannot imagine leading a normal life without
both taking lithium and having had the benefits of
psychotherapy…ineffably, psychotherapy heals. It
makes some sense of the confusion, reigns in the
terrifying thoughts and feelings, returns some
control and hope and possibility of learning from it
all…It is where I have believed—or have learned
to believe—that I might someday be able to
contend with all of this."
- Kay Jamison, Ph.D., An Unquiet Mind, 1995
Why Treat Bipolar Disorder With
Psychotherapy?
• Increase adherence to medication
• Enhance social and occupational functioning
• Enhance capacity to manage stressors in the social-occupational milieu
• Enhance protective effects of family and other social supports
• Decrease denial and trauma and encourage acceptance of the disorder
• Decrease the risk of recurrence
Swartz HA, et al. Psychotherapy for bipolar disorder. In: American Psychiatric Publishing Textbook of Mood
Disorders. DJ Stein, DJ Kupfer & AF Schatzberg (eds.) American Psychiatric Press Publishing, 405-420, 2006.
Empirically Tested Psychotherapies for
Bipolar Disorder
• Cognitive Behavioral Therapy (CBT)
• Psychoeducation (Group)
• Psychoeducation (Individual)
• Family Focused Therapy (FFT)
• Interpersonal and Social Rhythm Therapy
(IPSRT)
1. Simon et al. Arch Gen Psychiatry 63:500-508, 2006.
2. Torrent et al. Am J Psychiatry 170:852-859, 2013.
Other Currently Available
Psychosocial Approaches
• Systematic core management1
• Functional remediation2
STEP-BD Psychosocial Treatment of
Acute Depression: Study Design
• 293 acutely depressed patients with bipolar I or II
disorder were randomly assigned to intensive
treatment (up to 30 sessions of FFT, CBT, or IPSRT
over 9 months) or a brief control treatment (CC)
• Each site provided 2 of the intensive treatments and
the CC
• Only patients with family members were eligible for
assignment to FFT
• Primary outcome: time to "recovered" status (< 2
moderate symptoms for 8 weeks)
0 200 250 300 350 400 50 100 150
0.0
0.2
0.4
0.6
0.8
1.0
Cu
mu
lati
ve
Pro
po
rtio
n n
ot
Re
co
ve
red
Days to Recovered Treatment Intensive Psychosocial Intervention Collaborative Care
Time to Recovered Status: Intensive Treatments vs. Control
LogRank Chi square = 6.93, P = 0.009
Miklowitz et al. Arch Gen Psych 64:419-426, 2007.
Miklowitz et al. Arch Gen Psych 64:419-426, 2007.
Time to Recovered Status: Individual Treatments vs. Control
Empirically Tested Psychotherapies for
Bipolar Disorder
• Cognitive Behavioral Therapy (CBT)
• Psychoeducation (Group)
• Psychoeducation (Individual)
• Family Focused Therapy (FFT)
• Interpersonal and Social Rhythm Therapy
(IPSRT)
Essential Elements of Interpersonal and
Social Rhythm Therapy (IPSRT)
• Social rhythm therapy¹
– Regularizes daily routines
– Emphasizes link between mood and regular routines
– Uses Social Rhythm Metric to monitor routines
• Interpersonal psychotherapy²
– Emphasizes link between mood and life events
– Focuses on interpersonal problem areas (grief, role transition, role disputes, interpersonal deficits)
1. Frank E et al. Biol Psychiatry 2000;48:593-604; Frank E et al. Arch Gen Psychiatry 62:996-1004, 2005.
2. Klerman GL et al. Interpersonal Psychotherapy of Depression, Basic Books, New York, 1984.
Maintenance Therapies in
Bipolar Disorder Study Design
Acute Treatment Maintenance Treatment
IPSRT and
protocol pharmacotherapy
IPSRT and
protocol pharmacotherapy
Strategy #1
ICM and
protocol pharmacotherapy
ICM* and
protocol pharmacotherapy
Strategy #2
ICM and
protocol pharmacotherapy
IPSRT and
protocol pharmacotherapy
Strategy #3
IPSRT and
protocol pharmacotherapy
ICM and
protocol pharmacotherapy
Strategy #4
Patient enters study
and is randomly assigned
* ICM = Intensive Clinical Management
FPC = Functional Principal Components
Interpersonal and Social Rhythm Therapy
0 10 20 30 40
0
2
4
6
Weeks in acute phase
SRM
scores
FPC1: 85% FPC2: 8%
Intensive Clinical Management
0 10 20 30 40
0
2
4
6
Weeks in acute phase
SRM
scores
FPC1: 75% FPC2: 19%
SRM = Social Rhythm Metric
Effect of Acute Treatment Assignment on Change in SRM Scores
Frank E et al. Arch Gen Psychiatry, 62:996-1004, 2005.
Maintenance Therapies in Bipolar
Disorder: Key Outcomes
• Acute IPSRT was associated with significantly greater (more rapid) improvement in occupational functioning and...
• Significantly longer survival without a new mood episode in the maintenance phase, regardless of maintenance treatment assignment (p = 0.01)
• Participants in IPSRT had significantly higher regularity of daily routines (p < 0.001)
• Increased regularity of daily routines in the acute phase was associated with a reduced risk of relapse in the maintenance phase (p < 0.05)
Frank et al. Arch Gen Psychiatry, 2005; Frank et al. Am J Psychiatry, 2008.
Treatment of Bipolar Disorder:
Current Summary (1)
• Overall, advances in drug treatment remain
quite modest
• Antipsychotic drugs are effective in the acute
treatment of mania; their efficacy in the
treatment of depression is variable, with the
clearest evidence for quetiapine
• Despite the widespread use of antidepressants,
considerable uncertainty and controversy
remains about the use of antidepressants in the
management of depressive episodes
Adapted from Geddes et al., The Lancet 381:1672-1682, 2013.
Treatment of Bipolar Disorder:
Current Summary (2)
• Lithium has the strongest evidence for long-term
relapse prevention; the evidence for
anticonvulsants such as divalproex and
lamotrigine is less robust, and there is much
uncertainty about the longer-term benefits of
antipsychotics
• Substantial progress has been made in the
development and assessment of adjunctive
psychosocial interventions
Adapted from Geddes et al. Lancet 381:1672-1682, 2013.
Treatment of Bipolar Disorder:
Current Summary (3)
• Long-term maintenance and possibly acute
stabilization of depression can be enhanced by
the combination of psychosocial treatments and
drugs
Adapted from Geddes et al. Lancet 381:1672-1682, 2013.
Rethinking Bipolar Disorder
• Where have we been?
• Where are we now?
• Where do we need to go?
Bipolar Disorder
The Perpetual Co-traveler
With Other Disorders
Bipolar Disorder
• Considerable psychiatric comorbidity
• Substance abuse
• Medical disorders
• Medical "risk factors" (smoking, obesity)
JAMA 293:2528-2530, 2005.
Standardized Mortality Ratio (SMR) of Patients With Unipolar Disorder (N = 147)
vs. Bipolar Disorder (N = 158)
Unipolar (UP) Bipolar (BP) UP vs. BP
(t-test)
P-value
Observed Deaths
SMR Observed
Deaths SMR
Cardiovascular 40 1.36 59 1.84*
Mortality in Bipolar Disorder
Cause of Death Observed Expected Mortality
Deaths* Deaths** Ratio
Suicide 15.7 0.67 23.4
Cardiovascular causes 42.1 14.0 3.0
Respiratory causes 33.3 1.08 3.1
472 Bipolar Patients
* % study group
** % Registrar General's figures
Adapted from: Sharma R & Markar HR. J Affective Disord 31:91-96, 1994.
Mortality and General Medical Healthcare Severely Compromised in Bipolar Disorder
Patients with bipolar disorder (N=15,386) followed for 10 years (average). Mental disorder=dementia, drug or alcohol addiction, psychosis.
Ösby U et al. Arch Gen Psychiatry 58:844-850, 2001; Druss BG et al. Arch Gen Psychiatry 58:565-572, 2001.
2.0
2.5
3.2
4.0
4.8
14.2
22.0
1.9
3.4
4.4
5.0
15.0
2.4
3.2
2.3
3.3
3.7
10.3
1.9
3.1
0 5 10 15 20 25
Cerebrovascular
Cardiac
Respiratory
Accident
Infection
Mental Disorder
Traffic Accident
Homicide
Undetermined Violent Death
Suicide
Men
Women
Standardized Mortality Ratio
Prevalence of Comorbidities Among Patients
With a Diagnosis of Bipolar I Disorder
Compared to the VA National Population
Comorbidity % Mean Age %
Mean Age P-value
Hypertension 34.4 57 36.8 64 0.0066
Diabetes 17.1 58 15.6 64 0.0038
Hepatitis C 5.8 47 1.1 49 0.00002
Lower back pain
15.0 51 10.6 55 0.00002
COPD 11.1 60 9.4 67 0.007
Bipolar I Disorder General Population
COPD = chronic obstructive pulmonary disease
Kilbourne A et al. Bipolar Disord 6:368-373, 2004.
Time to Depressive Recurrence C
um
ula
tive
Pro
po
rtio
n
Rem
ain
ing
Wel
l
Weeks in Maintenance Treatment
0.0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120
Nonobese
Obese
Obese patients had a shorter time to depressive recurrence than nonobese patients
Fagiolini A et al. Am J Psychiatry 160:112-117, 2003.
Log Rank Chi-square = 7.33, df = 1, p < 0.007)
Obesity in Bipolar Disorder
• 68% overweight, 32% met criteria for obesity (relative to
< 20% of controls) (Fagiolini et al., 2003)
– Shorter time to relapse, particularly into depression
– More previous episodes
• 58% overweight, 21% obesity (McElroy et al., 2002)
– Arthritis
– Hypertension
– Diabetes mellitus
• Quality of life (Fontaine & Bartlett, 1998)
• Social life (Wolf & Colditz, 1996)
• Self-esteem (Kawachi, 1999)
Adapted from Harvey AG 2005.
Obesity and Its Longitudinal Course in
Bipolar Disorder
• The association between obesity and increased
prospective depressive burden appears to be
explained by baseline demographic variables
• In contrast, obesity independently predicts the
accumulation of medical conditions among
adults with BD
• Treatment of obesity could potentially mitigate
the psychiatric and medical burden of BD
Adapted from Goldstein et al. Bipolar Disorders 15:284-293, 2013.
Medical Risk Profile for Bipolar Disorder
Obesity
Smoking
"Metabolic Syndrome"
Metabolic Syndrome
"Metabolic syndrome" is the presence of 3 or more
of the following characteristics:
• Abdominal obesity (waist circumference)
• Hypertriglyceridemia
• Low high-density lipoprotein cholesterol (HDL-C)
• High blood pressure
• Fasting hyperglycemia
Adapted from: Fagiolini et al. Bipolar Disord 7:424-430, 2005.
Prevalence of Metabolic Syndrome
in Patients With Bipolar Disorder (N = 441)
Criterion Description %
MS 1 Waist circ. > 40 in. (men) or > 35 in. (women) 51
MS 2 Triglycerides > 150 mg/dL 47
MS 3 HDL < 40 mg/dL (men) or < 50 mg/dL (women) or being on cholesterol-lowering medication
45
MS 4 Systolic bp > 130 mm/Hg and diastolic bp > 85 mmHg or being on blood pressure medication
55
MS 5 Fasting glucose > 110 mg/dL or being on a glucose-lowering drug
19
MS At least 3 of MS 1 – MS 5 40
Fagiolini et al. J Clin Psychiatry 69:678-679, 2008.
Model of Bipolar Disorder
Modifiable Medical
Risk Factors
Sleep–Wake and
Social Rhythms
Medical Diseases
Bipolar Symptoms
Functioning
• Multidisciplinary treatment team (CRNP,
psychiatrist, internist, and lifestyle coach)
• Individual lifestyle interventions
• Early intervention for medical risk factors and
disease
• Efforts to increase adherence to medical and
psychiatric treatment
• Psychopharmacological management that takes
risks and diseases into account
An Integrated Care Model for
Bipolar Disorder
Rethinking Bipolar Disorder
• Where have we been?
• Where are we now?
• Where do we need to go?
Premature Mortality From General Medical Illness
Among Persons With Bipolar Disorder: A Review
• Cardiovascular disorder appeared to be the most consistent cause of excess mortality in larger studies
• Patients with bipolar disorder face a greater risk of death from medical illness than the general population
• Studies suggest that an unhealthy diet, binge eating, lack of exercise, substance abuse, and/or delaying medical care can lead to premature death
Roshanaei-Moghaddam B & Katon W. Psychiatric Services 60:147-159, 2009.
Goldstein et al. Bipolar Disord 2009.
Cardiovascular Disease and Hypertension
Among Adults With Bipolar I Disorder O
dd
s R
atio
(ad
just
ing
fo
r ag
e, s
ex,
and
rac
e)
• Excessive obesity, hypertension, and diabetes
• Obesity is associated with psychiatric hospitalization, polypharmacy, substance abuse, physical abuse, minority race
• Increased sensitivity to metabolic side effects of mood-stabilizing medications
• Cardiometabolic problems often precede treatment for bipolar disorder
Adapted from Goldstein BI 2011; Goldstein et al. J Clin Psychiatry 2008; Evans-Lacko et al. J Clin
Psychiatry 2009; Jerrell et al. J Clin Psychiatry 2010; Correll et al. Bipolar Disord 2010.
Cardiovascular Risk Among Youth
With Bipolar Disorder
Why Is the Risk of Cardiovascular
Disease Increased in Mood Disorders?
Cardiovascular risk
Platelet
aggregation
Inflammation HPA
dysregulation
Endothelial
dysfunction
Adrenergic
hyperactivity Genetics e.g., CACNA1C
Adapted from Goldstein BI 2011; Kupfer. JAMA 2005; Frasure-Smith & Lesperance. Can J Psychiatry 2006.
Future Directions (1)
• Identification of subgroups with circadian
fragility or vulnerability
• Identification of subgroups most "prone" to
develop a high metabolic risk profile
Future Directions (2)
• How do we prevent acute illness from becoming
chronic?
• Can early intervention prevent "comorbid
accumulation"?
Time to Challenge Our View of
Bipolar Disorder?
Leboyer & Kupfer. J Clin Psychiatry 2010;71:1689.
A cyclical illness
characterized by full-blown
manic or depressive
episodes interspaced with
normal euthymic periods
Traditional perspective Modern holistic perspective
A subtle chronic
progressive multisystem
disorder
Manic
phase
Depressed
phase
Cognitive
function
Comorbid disorders
Cardiovascular disease
Cerebrovasular disease
Diabetes mellitus
Obesity
Hypertension Bipolar
disorder
STRESS
SLEEP & CIRCADIAN DYSFUNCTION
AUTOIMMUNE DISORDER
RETROVIRUS
BRAIN & PERIPHERAL IMMUNO-INFLAMMATION
Genetic Risk Factors
Environmental Risk Factors
Oxidative Stress
Apoptosis Cell Damage
Figure 1: Different mechanisms that might cause abnormal immuno-inflammation and inactivity with genetic susceptible background and environmental factors will lead to bipolar disorder best conceptualized as a multisystem disorder
Bipolar Disorder: From a Mental to a Multisystem Disorder
Ada
pted
from
Mar
ion
Lebo
yer,
2013
.
Bipolar Disorder (BP): A Heterogeneous Disorder
BP characteristics Age at onset Polarity of episodes Delusions
Physiopathology Polygenic Environment
Interepisode profile Sleep and circadian Emotion reactivity Cognition Comorbid disorders
Regions of interest Hippocampus Amygdala Prefrontal area
Lithium and other mood stabilizers
Overlap between psychiatric disorders: MDD, schizoaffective, schizophrenia, autism….
At risk to be handicapped: staging
Ada
pted
from
Mar
ion
Lebo
yer,
2013
.
Taking a Broader View:
Interepisodic Symptom Domains
Traditional
perspective Diagnostic and statistical
manuals of mental
disorders have focused
on major
mood episodes
Modern holistic perspective
Interepisodic dysfunctional
symptom domains need to
be considered
Psychiatric and medical
comorbid disorders
Abnormal emotional reactivity
Sleep and circadian rhythm
disturbances
Cognitive impairment
Leboyer & Kupfer. J Clin Psychiatry 2010;71:1689.
Abnormal Emotional Reactivity:
Brain Imaging Impaired neural networks subserving emotional regulation
Hypoactivation of response
inhibition to emotion (in red, cingulate cortex and basal ganglia)
fMRI emotional go / no-go
in euthymic bipolar patients
Overactivation of brain
structures mediating
automatic emotion recognition (in blue, oribitofrontal cortex)
Wessa et al. Am J Psychiatry 2007;164:638; Houenou et al. Mol Psychiatry 2008.
Evidence of altered emotional processing
Several genes important
in sleep and circadian
systems have been associated
with bipolar disorder
(TIMELESS, CLOCK, ARNTL)
Sleep and circadian rhythm disturbances should
be assessed throughout the course of illness
and treated to prevent relapse
Sleep and circadian rhythm
disturbances
induce mood episodes
Evidence suggests weak
coupling of circadian system to
external environment
Euthymic bipolar patients show: Variability in sleep duration
Circadian rhythm instability
Low and delayed melatonin peak
Interepisodic Symptom Domains: Sleep and Circadian Rhythm Disturbances
Harvey et al. Am J Psychiatry 2005;162:50; Mansour et al. Ann Med 2005;37:196;
Harvey. Am J Psychiatry 2008;165:820; Leboyer & Kupfer. J Clin Psychiatry 2010;71:1689.
Delayed verbal memory is the
best cognitive predictor of poor
functional outcomes
Martinez-Aran et al. Bipolar Disord 2007;9:103; Goodwin et al. Eur Neuropsychopharmacol 2008;18:787;
Leboyer & Kupfer. J Clin Psychiatry 2010;71:1689.
Regular assessment of cognitive impairment
is needed during follow-up to plan
personalized cognitive remediation
Patients with bipolar disorder
have cognitive impairment in
attention, memory, and
executive function
Some cognitive impairments
appear early in the course of
illness and persist over time in
euthymic patients
Interepisodic Symptom Domains: Cognitive Impairment
Preliminary evidence of
accelerated cognitive decline
as disorder progresses
Cardiovascular
disease
Cerebrovascular
disease
Diabetes
mellitus
Obesity
Hypertension Bipolar
disorder
Bipolar Disorder: From a Mental to a Multisystem Disorder
Interepisodic Symptom Domains: Medical Comorbidity
● Greater risk of cardiovascular mortality associated with bipolar disorder
(1.5–2.5X) than schizophrenia or unipolar depression
● Under-recognition of medical disorder and risk factors has a major
impact on outcome
Leboyer & Kupfer. J Clin Psychiatry 2010;71:1689.
Psychiatric assessment
Risk factor assessment
– Weight, BMI, hypertension,
glucose tolerance, lipids,
C-reactive protein
Summary: Assessment and Treatment
of Interepisodic Symptom Domains Domain Assessment
Abnormal emotional
reactivity
Cognitive
impairment
Sleep and circadian
rhythm disturbances
Psychiatric and medical
comorbidities
Treatment
BMI, body mass index
Affective Lability Scale
Affect Intensity Measure
Sleep diary
Pittsburgh Sleep Quality
Index
Neuropsychological
assessment
Stress management
Relaxation
Treatment to be developed
Psychoeducation
Interpersonal and social
rhythm therapy
Cognitive behavioral
therapy
Cognitive remediation
Treatment of comorbid
psychiatric and medical
disorders
Diet, exercise, and
smoking cessation…
Patient follow-up is pivotal; also important to consider
benefit-risk profile of current or planned psychotropic medication
Leboyer & Kupfer. J Clin Psychiatry 2010;71:1689.
Clinical Staging Framework for Bipolar Disorders (1)
Clinical
Stage Characteristics
Target
Populations
Potential
Interventions
0
Increased risk of bipolar
disorder
No symptoms currently
First-degree relatives of
patients with bipolar
disorder
Improved mental health,
family education, drug
education, brief social
rhythm training
1a Mild or non-specific
symptom
Screening of teenage
populations, referral by
primary care
physicians, referral by
school counselors
Psychoeducation, active
substance abuse
reduction
1b
Ultra high risk: moderate
but subthreshold
symptoms, with
neurocognitive changes
and functional decline to
caseness
Psychiatric intervention
Family psychoeducation,
active substance abuse
reduction, atypical
antipsychotic agents for
episode, antidepressant
agents or mood
stabilizers
Adapted from McGorry et al. Aust N Z J Psych 2006.
Clinical Staging Framework for
Bipolar Disorders (2)
Clinical
Stage Characteristics
Target
Populations
Potential
Interventions
2
First episode of bipolar
disorder
Full threshold disorder
with moderate to severe
symptoms,
neurocognitive deficits
and functional decline
Referral by primary
care physicians,
emergency
departments,
specialist care
agencies, drug and
alcohol services
Family
psychoeducation,
active substance
abuse reduction,
atypical antipsychotic
agents for episode,
antidepressant agents
or mood stabilizers
Adapted from McGorry et al. Aust N Z J Psych 2006.
Clinical
Stage Characteristics
Target
Populations
Potential
Interventions
3a
Incomplete remission from
first episode
Could be linked or fast-
tracked to Stage 4
Primary and specialist
care services
Additional emphasis on
medical and psychosocial
strategies to achieve full
remission
3b
Recurrence or relapse of
psychotic or mood disorder
that stabilizes with
treatment, residual
symptoms, or
neurocognition below the
best level achieved
following remission from
first episode
Primary and specialist
care services
Additional emphasis on
relapse prevention and
"early warning signs"
strategies
4
Severe, persistent illness
judged by symptoms,
neurocognition, and
disability criteria
Specialized care
services
Emphasis on integrated
medical/psychiatric care
Adapted from McGorry et al. Aust N Z J Psych 2006.
Clinical Staging Framework for Bipolar Disorders (1)
Bipolar Disorder:
How Can We Do Better?
Today
A major public health concern but underfunded and under-
investigated
Often diagnosed with delay, inaccuracy, and poor
management of comorbid conditions
A heterogeneous, complex, multisystem disorder
Tomorrow, we should improve…
…course of disease via early, accurate, and thorough diagnosis
…prognosis via personalized therapeutic strategies
…monitoring of medical risk factors and comorbid conditions
Leboyer and Kupfer, J Clin Psy, 2010
Individuals with bipolar disorder typically spend
the majority of their lives:
1. In a euthymic state
2. In a subsyndromally manic or hypomanic state
3. In a subsyndromally depressed state
4. In a syndromally depressed state
Posttest Question 1
The most common co-morbidities with bipolar
disorder are:
1. Anxiety and substance use disorders
2. Substance use and eating disorders
3. Anxiety and eating disorders
4. Eating disorders and ADHD
Posttest Question 2
The most common medical comorbidities with
bipolar disorder are:
1. Cancer
2. Cardiovascular disease
3. Osteoporosis
4. Eczema
Posttest Question 3