Bipolar Disorder Diagnosis Updates

1
Bipolar Disorder DiagnosisUpdates
2
Increased Rates of Bipolar Disorder Diagnoses,
19962004

• National Hospital Discharge Survey (NHDS),
  19962004
• Trends in clinical diagnoses of children and
  adolescents admitted to inpatient psychiatric
  care
• Age Grouping
• Children 513 years
• Adolescents 1418
• Adults 19

Blader J, Carlson G. Biol Psychiatry.
200762(2)107-114.
3
Changes in US Rates for Psychiatric Disorders
(Primary Diagnoses) for Acute Care Inpatients,
19962004
P lt 0.01, significance of the linear trend,
Pearson correlation
Blader J, Carlson G. Biol Psychiatry.
200762(2)107-114.
4
National Trends in Increased Outpatient Diagnosis
of Bipolar Disorder
Based on the National Ambulatory Medical Care
Survey (NAMCS) Youth 019 years Adults 20
years
Bipolar Disorder Visit Rate,
0.6
Adults
0.5
Youth
0.4
0.3
Years
0.2
0.1
0.0
19961997
19981999
20002001
20022003
19941995

• Diagnosis of bipolar disorder for ADULTS
  increased 2X in the 10-year study period
• Diagnosis of bipolar disorder for YOUTH increased
  40X in the 10-year study period

Moreno C, et al. Arch Gen Psychiatry.
200764(9)1032-1039.
5
Lifetime and 12-Month Prevalence of Bipolar
Spectrum Disorder National Comorbidity Survey
Replication

• Nationally representative sample of 9,282 adults
  ( 20 years)
• Direct interviews, Version 3.0 World Health
  Organization Composite International Diagnostic
  Interview for assessment of DSM-IV lifetime and
  12-month Axis I disorders. February 2001April
  2003

• Subthreshold BPD is common, clinically
  significant, and underdetected
• 75 of subthreshold BPD lifetime cases received
  no medication

Merikangas K, et al. Arch Gen Psychiatry.
200764543-552.
6
Poor Prognosis of Childhood Onset Bipolar
Disorder
Duration From Disease Onset to First
Pharmacologic Treatment
20
16.8 years
N 420
15
11.5 years
10
Years Delay to First Treatment
4.6 years
5
2.6 years
0
12 Childhood (n 66)
13-18 Adolescence (n 157)
19-29 Adult (Early) (n 133)
30 Adult (Late) (n 75)
Age of Onset of Bipolar Symptoms
Leverich G, et al. J Pediatr. 2007150(5)485-490.
7
Poor Prognosis of Childhood Onset Bipolar
Disorder
Values represent mean SEM
Leverich G, et al. J Pediatr. 2007150(5)485-490.
8

• The average patient with bipolar disorder does
  not receive a proper diagnosis for nearly a
  decade after the onset of his or her first episode

Lish J, et al. J Affect Disord.
199431(4)281-294. Hirschfeld R, et al. J Clin
Psychiatry. 200364(2)161-174.
9
Diagnostic Challenges

• Poor documentation of prior history
• Vague diagnostic criteria
• Diagnostic criteria overemphasize episode
  characteristics
• Mixed episodes
• Depression is a common chief complaint during
  manic episodes
• Current affective state influences perceptions
  and reporting
• Absence of collateral informants
• Comorbid conditions are common
• Lack of validated biological markers
• Longitudinal factors

Sachs G. FOCUS. 20075(1)3-13.
10
Strategies to Improve Assessment and Diagnosis

• Utilize family or other collateral informants
• Identify the most extreme episode of mood
  elevation
• Systematically assess for all diagnostic features
  of mania/hypomania
• Assess irritability and lability during episodes
• Determine the degree of impairment
• Assess for potential general medical and
  substance use etiologies
• Assess longitudinal factors
• Determine age of first-episode onset
• Evaluate course to establish quality of
  inter-episode recovery
• Evaluate family history
• Review response prior to treatment
• Assess common conditions in differential
  diagnosis
• History
• Laboratories
• Assess common comorbidities
• Aim to estimate diagnostic confidence

Sachs G. FOCUS. 20075(1)3-13.
11
Endophenotypes What are They and Why are They
Important?

• What is an endophenotype?
• Internal, intermediate phenotype that fills the
  gap between genes and distal disease
• An endophenotype represents
• Upstream traits underlying clinical phenotypes
• Downstream biological consequences of genes
• Why are endophenotypes important?
• Endophenotypic markers may help to differentiate
  bipolar
• disorder from other psychiatric disorders
• An understanding of these markers may help to
  explain the
• heterogeneity of symptoms
• These markers may help to define patients at high
  risk for
• development of manic or hypomanic episodes

Hasler G, et al. Biol Psychiatry.
200660(2)93-105.
12
Possible Bipolar Disorder Endophenotypes

• Brain Function Endophenotypes
• Attention deficits
• Deficits in verbal learning and memory
• Cognitive deficits following tryptophan depletion
• Circadian rhythm instability
• Dysmodulation of motivation and reward
• Brain Structure Endophenotypes
• Anterior cingulate volume reduction
• Early-onset white matter abnormalities
• Symptom Provocation Endophenotypes
• Sensitivity to sleep deprivation
• Sensitivity to psychostimulants
• Sensitivity to cholinergic drugs

Hasler G, et al. Biol Psychiatry.
200660(2)93-105.
13
Mental Health America. Available at
http//www.mentalhealthamerica.net/go/information/
get-info/bipolar-disorder/bipolar-disorder-and-afr
ican-americans. Accessed April 2008.
Diagnostic Challenges Ethnic/Cultural
Considerations
Most African Americans with bipolar disorder are
going undiagnosed and untreated

• Contributing Factors
• A mistrust of health professionals
• Higher prevalence of hallucinations
• Cultural barriers between many doctors and their
  patients
• Reliance on family and religious community rather
  than mental health professionals during times of
  emotional distress
• A tendency to talk about physical problems rather
  than discuss mental symptoms, or to mask symptoms
  with substance abuse or other medical conditions
• Socioeconomic factors that can limit access to
  medical and mental health care
• Misunderstanding and stigma about mental illness

14
Ethnic/Cultural Considerations Effectiveness of
MDQ

• An examination of the performance of the Mood
  Disorders Questionnaire (MDQ) as a screening
  instrument in a population of predominantly
  African American patients attending primary care
  clinics
• Sensitivity 61.9 Specificity 69
• Positive predictive value 16.8 Negative
  predictive value 94.7
• Overall level of correct classification 68.4
• Conclusion the MDQ has a low specificity in
  primarily African American trauma-exposed
  patients attending primary care clinics, hence
  the important need for thorough assessment of
  mood symptoms in this patient population,
  particularly in association with trauma and/or
  substance abuse

Graves R, et al. Bipolar Disord.
20079(4)318-323.
15
Ethnic/Cultural Considerations STEP-BD

• Data collected from the first 2000 patients of
  the STEP-BD
• Illness characteristics, treatment history, and
  functioning in sample of European American (n
  1686), African American (n 65), and Latino (n
  77) patients
• African Americans greater likelihood of
  psychosis and fewer psychiatric prescriptions
  than European Americans
• Latinos greater alcohol comorbidity, fewer
  psychiatric prescriptions and specialty treatment
  visits, and more frequent religious service
  attendance than European Americans
• Depression, manic episode severity, and
  functional outcomes were similar across groups
• Conclusion Members of ethnic minority groups
  receive less intensive mental health treatment
  compared with European Americans

Gonzalez J, et al. Psychopharmacol Bull.
200740(1)31-46.
16
Comorbidities and Bipolar Disorder
17
Mortality and Severe Mental Illness

• Osby et al studied gt 15,000 patients with bipolar
  disorder diagnosis (Sweden)1
• Standardized mortality ratios (SMRs) (all causes)
  in the bipolar patients was 2.5 for males, 2.7
  for females (values greater than 1.0 indicate
  greater risk than general population)
• Most frequent cause of death for bipolar patients
  
• Cardiovascular disease 31
• Suicide 19
• Cancer 14
• Patients with severe schizophrenia, bipolar
  disorder, and depression lose 25 or more years of
  life expectancy, with most of the premature
  deaths due to cardiovascular disease3

1. Osby U, et al. Arch Gen Psychiatry.
200158(9)844-850. 2. Angst F, et al. J Affect
Disord. 200268(2-3)167-181. 3. Newcomer J,
Hennekens C. JAMA. 2007298(15)1794-1796.
18
Heart Disease Is the Primary Cause of Death in
Persons With Mental Illness
60
50
40
Percentage of Deaths
30
20
10
0
MO
OK
RI
TX
UT
VA
Heart Disease
Cancer
Cerebrovascular
Chronic Respiratory
Accidents
Diabetes
Influenza/Pneumonia
Suicide
Average data from 19962000 includes
schizophrenia and BPD Colton C, Manderscheid R.
Prev Chronic Dis. Available at http//www.cdc.gov/
pcd/issues/2006/apr/05_0180.htm. Accessed March
2008.
19
Cardiovascular Disease (CVD) Risk Factors

• Allison D, et al. J Clin Psychiatry.
  199960(4)215-220
• Fagiolini A, et al. Bipolar Disord.
  20057(5)424-430
• McElroy S, et al. J Clin Psychiatry.
  200263(3)207-213
• Hennekens C, et al. Am Heart J.
  2005150(6)1115-1121
• Davidson S, et al. Aust N Z J Psychiatry.
  200135(2)196-202
• Ucok A, et al. Psychiatry Clin Neurosci.
  200458(4)434-437
• Herran A, et al. Schizophr Res.
  200041(2)373-381

• Goff D, et al. Schizophr Res. 200580(1)45-53
• Dixon L, et al. J Nerv Ment Dis.
  199987(8)496-502
• Cassidy F, et al. Am J Psychiatry.
  1999156(9)1417-1420
• Kilbourne A. Bipolar Disord. 20046(5)368-373
• Allebeck P. Schizophr Bull. 198915(1)81-89
• Koro C, et al. Arch Gen Psychiatry.
  200259(11)1021-1026

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Clinical Identification of the Metabolic
SyndromeAny 3 of the Following 5 Criteria

• Obesity
• Waist greater than 40 inches in men or 35 inches
  in women
• High-density lipoprotein cholesterol (HDL-C)
• Less than 40 mg/dL in men 50 mg/dL in women
• Fasting triglycerides
• Greater than 150 mg/dL
• Blood pressure
• Greater than 130 mm Hg systolic or 85 mm Hg
  diastolic
• Fasting blood glucose
• Greater than 100 mg/dL

Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 2001285(19)2486-2497. Grundy S, et al.
Circulation. 2005112285-290.
21
Obesity and Bipolar Disorder in the General
Population
No Mood Disorder
30
Mood Disorder
25


20
15
Percent Obese Class I-III
10
5
0
Total
Males
Females
P lt 0.05
McIntyre R, et al. Can J Psychiatry.
200651(5)274-280.
22
Impact of Obesity on Recurrence (Adherence?) in
Bipolar Disorder
1.0
Non-obese (n 79) Obese (n 46)
0.8
0.6
Cumulative Proportion Remaining Well
0.4
0.2
Log-rank Chi-square 5.54 df 1 P lt 0.02
0.0
0
20
40
60
80
100
120
Weeks in Preventive Treatment
Obese patients had shorter time to recurrence of
depression than non-obese patients
Fagiolini A, et al. Am J Psychiatry.
2003160(1)112-117.
23
Contribution of Lifestyle to the Metabolic
Syndrome in Bipolar Disorder

• High prevalence of substance abuse nicotine
  dependence
• Poor diet
• Lack of exercise
• Chronic stress

Taylor V, MacQueen G. J Clin Psychiatry.
200667(7)1034-1041.
24
Stress/Hypothalamic-Pituitary-Adrenal (HPA) Axis

• HPA axis hyperactivity prominent in BPD
• ? basal level of cortisol
• Abnormal response to physical and psychological
  stressors
• Chronic elevation of glucocorticoids
• Impedes insulin mediated glucose uptake
• Promotes deposition of body fat
• Formation of atherosclerotic plaques
• ? Visceral fat

Taylor V, MacQueen G. J Clin Psychiatry.
200667(7)1034-1014.
25
Immune Function

• Bipolar disorder (both mania and depression) is
  associated with increased production of
  pro-inflammatory cytokines
• IL-8
• TNF-?
• IL-6
• C-reactive protein
• IL-6 stimulation of the HPA axis stimulation of
  cortisol

OBrien S, et al. J Affect Disord.
200690(2-3)263-267. Taylor V, MacQueen G. J
Clin Psychiatry. 200667(7)1034-1014.
26
Type 2 Diabetes and Bipolar Disorder

• Depression - risk factor for development of type
  2 diabetes
• HPA hyperactivity chronic elevation of
  glucocorticoids
• Impaired glucose tolerance
• Insulin resistance

1. Cassidy F, et al. Am J Psychiatry.
1999156(9)1417-1420. 2. Regenold W, et al. J
Affect Disord. 200270(1)19-26. 3. Ruzickova M,
et al. Can J Psychiatry. 200348(7)458-461. 4.
Kilbourne A, et al. Bipolar Disord.
20046(5)368-373.
27
We Are Not Yet Measuring Health Consistently
Enough
Frequency of Baseline Assessment for Weight and
Metabolic Parameters Prior to Initiating
Treatment With an SGA
Personal and family hx
Height and body weight
Waist circumference
Blood pressure
Fasting blood glucose
Fasting lipid profile
Percent of Respondents
gt 80 of the time
50-80 of the time
lt 50 of the time
Buckley P, et al. Schizophr Res. 200579281-288.
28
Undertreatment of Hypertension, Dyslipidemia, and
Diabetes in Schizophrenia
Percent
UNTREATED
TREATED
Hypertension
Hyperlipidemia
Diabetes
N 1460 CATIE subjects
Nasrallah H, et al. Schizophr Res.
200686(1-3)15-22.
29
ADA/APA Consensus Conference on Obesity,
Diabetes, and Antipsychotic Medications

• Evaluate metabolic risks in patients when
  initiating treatment with antipsychotic
  medications
• Baseline screening
• Personal/family history, weight (BMI), waist
  circumference, blood pressure, fasting plasma
  glucose, fasting plasma lipids
• Regular monitoring
• 4 weeks, 8 weeks, 12 weeks, quarterly, annually
• Refer to specialist care
• Provide education

Diabetes Care. 200427(2)596-601.
30
Metabolic Abnormalities and Atypical
Antipsychotic Medication
? increased effect no effect D discrepant
results
Adapted from Diabetes Care. 200427(2)596-601.
31
Substance Use Disorders and Overweight/Obesity in
Bipolar I Disorder Preliminary Evidence for
Competing Addictions

• Data from 36,984 individuals (gt 15 years old) in
  the 2002 Canadian Community Health Survey
• Overweight and obesity were defined as BMI of
  25.0-29.9 and 30.0 kg/m2, respectively.

Comorbid Conditions in Bipolar I Disorder
60
60
54

• The results demonstrate that individuals with
  bipolar I disorder exhibit an inverse
  relationship between comorbid overweight/obesity
  and substance use disorders
• Comorbid addictive disorders may compete for
  identical brain reward systems

50
50
39
40
40
Rate of Substance Dependent ()
Rate of Overweight/Obesity ()
30
30
21
20
20
13
10
10
0
0
Overweight/ Obese
Nonoverweight/ Obese
Substance Dependent
Nondependent
P lt 0.01
McIntyre R, et al. J Clin Psychiatry.
200768(9)1352-1357.
32
Effects of Co-Occurring Cannabis Use Disorders on
the Course of Bipolar Disorder Following a First
Hospitalization for Mania

• This study examined the co-occurrence of cannabis
  use disorders with bipolar disorder to determine
  how the sequence of the onsets of both disorders
  is associated with their subsequent outcomes
• In a 5-year follow-up period
• 33 patients had onset of cannabis use disorder
  prior to onset of bipolar disorder (Cannabis
  First)
• 36 had onset of bipolar disorder prior to the
  onset of cannabis use disorder (Bipolar First)
• 75 had bipolar disorder only (Bipolar Only)
• When evaluated by simple survival analysis, the
  Cannabis First group showed higher rates and more
  rapid recovery than did the 2 other groups, which
  did not differ. However, when adjusted for
  potential mediator variables (eg, age at onset,
  gender), these differences did not persist

Strakowski S, et al. Arch Gen Psychiatry.
200764(1)57-64.
33
Co-Occurring Cannabis Use Disorders and Bipolar
Disorder
Recovery from Cannabis Use Disorder
100

• Bipolar First group experienced more time in
  manic and mixed states during follow-up compared
  with other groups
• Both comorbid groups displayed more rapid
  cycling during follow-up compared with Bipolar
  only
• Percentage of weeks in a depressive episode was
  correlated with weeks of cannabis abuse symptoms
• Percentage of time in remission was inversely
  associated with percentage of weeks with
  cannabis abuse symptoms

90




80




70

60
Patients Recovered,
50
P lt 0.001
40

Bipolar First Cannabis First
30
20
10
0
0 20 40 60 80 100 120
140 160 180 200 220 240
260 Follow-up Time (weeks) Asterisk indicates
censored data (subjects dropped out of the study
prior to recovery)

• Most patients experienced a period of abstinence
  (albeit brief) from cannabis following
• hospitalization, a window in which aggressive
  drug abuse treatment might reduce rates of
  recurrence and new cases of cannabis use
  disorder in bipolar illness

Strakowski S, et al. Arch Gen Psychiatry.
200764(1)57-64.
34
General Principles in Treatment of Comorbidity
in Bipolar Disorder

• Address bipolar disorder and its comorbidities
  concurrently
• Use medications that treat both disorders
• Use medication with least abuse potential and
  least toxicity
• Use doses that optimize efficacy, but minimize
  side effects
• Most treatment of psychiatric comorbidities is
  off label
• Maximize the use of nonpharmacologic treatment
• Patients with comorbidities are at greater risk
  for medication nonadherence