Early and Accurate Diagnosis of Bipolar Disorder

1
MEASURE Resource Module 2005

• Section 1
• Early and Accurate Diagnosis of Bipolar Disorder

2
Objective

• To emphasize the importance of an accurate
  diagnosis of bipolar disorder in identifying
  appropriate clinical, pharmacological, and
  psychosocial treatment

3
Accurate Diagnosis
4
Bipolar Terminology

• Mania
• A distinct period of abnormally and persistently
  elevated, expansive, or irritable mood, lasting
  at least 1 week with a significant decline in
  function
• Hypomania
• A distinct period of persistently elevated,
  expansive, or irritable mood, lasting at least 4
  days, that is clearly different from the usual
  non-depressed mood, without a significant decline
  in function

• Young LT. J Psychiatry Neurosci. 20042987-88.
• American Psychiatric Association Diagnostic and
  Statistical Manual of Mental Disorders, Fourth
  Edition, Text Revision. Washington, DC American
  Psychiatric Association 2000.

5
Bipolar Terminology (cont.)

• Mixed Episode
• The criteria are met both for a manic episode and
  for a major depressive episode
• Cyclothymia
• Alternating mood states that do not meet full
  criteria for depressive, manic, or mixed episode
  for at least 2 years
• Bipolar NOS
• A mood episode that does not meet specific
  criteria for any specific bipolar disorder

• Young LT. J Psychiatry Neurosci. 20042987-88.
• American Psychiatric Association Diagnostic and
  Statistical Manual of Mental Disorders, Fourth
  Edition, Text Revision. Washington, DC American
  Psychiatric Association 2000.

6
Symptom Domainsof Bipolar Disorder
Dysphoric or Negative Mood and Behavior
Manic Mood and Behavior

• Euphoria
• Grandiosity
• Pressured speech
• Impulsivity
• Excessive libido
• Recklessness
• Social intrusiveness
• Diminished need for sleep

• Depression
• Anxiety
• Irritability
• Hostility
• Violence
• Suicide

BIPOLARDISORDER
Cognitive Symptoms
Psychotic Symptoms

• Racing thoughts
• Distractibility
• Disorganization
• Inattentiveness

• Delusions
• Hallucinations

Slide courtesy of Keck PE Jr. adapted from
Goodwin FK, Jamison KR. Manic-Depressive Illness.
Oxford University Press New York, NY 1990.
7
Spectrum of Bipolar Disorders

• Bipolar I
• Bipolar II
• Major depression with a strong family history of
  bipolar disorder
• Hypomania
• Antidepressant-induced mania and hypomania
• Cyclothymia
• Rapidly changing mood swings
• NOS
• Secondary mania, due to other illnesses or drugs

Adapted from American Psychiatric Association.
Practice Guideline for the Treatment of Patients
with Bipolar Disorder. 2nd ed. Washington, DC
2002.
8
Bipolar Disorder The Ingredients
MANIA
MANIA
HYPOMANIA
MIXED EPISODE
NORMALMOOD
SUBSYNDROMAL DEPRESSION
DEPRESSION
Hypomania is a milder form of mania with similar
yet less severe symptoms and less overall
impairment. Mixed Episode is an episode that
simultaneously presents symptoms of both
depression and mania.
Stahl SM. Essential Psychopharmacology. New York,
NY Cambridge University Press 2000.
9
Gradations of Mixedness
Depressive Mixed States1
Dysphoric Mania
Mixed Mania
Full Mania
Full Mania
2 Mania Symptoms
Mania MDE
2 Depressive Symptoms
Full MDE
Full MDE
MDE major depressive episode 1 Benazzi F.
Psychiatry Res. 2004127247-257. 2 Maj M, et al.
Am J Psychiatry. 20031602134-2140. 3 Akiskal
HS, et al. J Affect Disord. 200585245-258.
Agitated depressions? 2,3
10
Differentiation of Bipolar Disorder and ADHD
Geller B, et al. J Affect Disord.
19985181-91. DelBello MP, et al. Bipolar
Disord. 2001353-57.
11
Lifetime Comorbid Axis I Diagnoses in Bipolar
Patients
80
70
60
50
All BP
Percent
40
BP I
30
BP II
20
10
0
None
1 or more
2 or more
3 or more
McElroy SL, et al. Am J Psychiatry.
2001158420-426.
12
Screening ToolsThe Mood Disorder Questionnaire

• Important symptoms
• Hyper or more energetic than usual
• Predominately or thematically irritable
• Distinctly self-confident, positive or
  self-assured
• Less sleep than usual
• More talkative or speaking faster than usual
• Racing thoughts
• Easily distracted
• Problems at work and socially
• More interest in sex
• Taking unusual risks
• Excessive spending

13
Screening Tools The Mood Disorder Questionnaire
(cont.)

• The Mood Disorder Questionnaire (MDQ)
• Derived from DSM-IV criteria and clinical
  experience
• Initial validation study of MDQ in psychiatric
  outpatients
• (N 198)
• Sensitivity 73 and Specificity 90 for
  Bipolar I and II
• Validation study of MDQ in general population (N
  711)
• Sensitivity 28 and Specificity 97 for
  Bipolar I and II
• MDQ as screening tool (13 questions)
• Positive MDQ ? 7 yes responses Negative MDQ ?
  7 yes responses
• Rapid screening tool 10 minutes or less
• Patients can self-administer MDQ while in the
  waiting area
• Does not require trained evaluators
• Easily used in primary care settings

Hirschfeld RMA, et al. J Clin Psychiatry.
20036453-59.
14
Misdiagnosis in Bipolar Disorder
15
Misdiagnosis of Bipolar Disorder

• 2000 NDMDA initial diagnosis (69)

60
60
50
Depression
Anxiety
40
Percent
Schizophrenia
30
Cluster B
26
20
Alcohol abuse
18
17
10
14
0
NDMDA National Depressive and Manic-Depressive
Association N 400 Hirschfeld RM, et al. J
Clin Psychiatry. 200465(suppl 15)5-9.
16
Physicians Diagnoses Among Patients Who
Screened Positive for Bipolar Disorder on MDQ

• Bipolar II
• Recurrent hypomania major depression
• Female male 21
• Diagnostic challenges
• Hypomania not experienced as abnormal
• Prior hypomania often not reported

Dx with bipolar disorder Dx with depression but
not bipolar disorder Neither bipolar disorder
nor depression Dx
3158 MDQ positive individuals
MDQ Mood Disorder Questionnaire Hirschfeld
RM, et al. J Clin Psychiatry. 200465(suppl
15)5-9.
17
Bipolar Disorder Is Frequently Misdiagnosed

• Only 1 in 5 patients with bipolar disorder is
  correctly diagnosed by a physician
• Those incorrectly diagnosed are likely to be more
  impaired, female, and poorer
• Delay of treatment may reduce the efficacy of
  certain pharmacological agents (eg, lithium)
• 1 in 3 is misdiagnosed as having unipolar
  depression, perhaps due to the prevalence of the
  depressive phase of the illness

These data are based on MDQ positive scores, not
clinical diagnosis of bipolar disorder Hirschfeld
RMA, et al. J Clin Psychiatry. 20036453-59.
18
Risks of Misdiagnosis in Bipolar Disorder

• Incorrect diagnosis increases the risk of suicide
  in bipolar disorder

19
Consequences of Delayed Initiationof Mood
Stabilizers

• More suicide attempts
• Greater psychosocial impairment
• More comorbidities
• More hospitalizations
• More inappropriate treatments
• Cycle acceleration

Goldberg JF, Ernst CL. J Clin Psychiatry.
200263985-991.
20
Factors Associated With SuicideAttempts in
Bipolar Illness
Course of Illness
Increased Cycling Severity of Depression
Comorbidities
Suicide Attempts
Genetic
Suicidal (D) and (M), Severity of Mania, More
time III (Prosp.), Early Onset
Axis I Anxiety and Eating Disorders,
Comorbidities, Axis II A, B, C
Family HX Depression, Bipolar, Alcohol, Other
Psych. Illnesses
Drug Abuse, Alcohol Abuse, PTSD
Suicide and Drug Abuse
Problems with Health Ins., and Access to Health
Care
Death of Imp. Other, Lack of Confidence
Occupational, Financial and Health Care
Adversities
Social
Occupational, Financial, Legal and Housing
Problems
Loss of Social Support, Social Role Demands,
Problems with Spouse (most recent episode)
Post RM, et al. Bipolar Disord. 20035310-319.
21
Increased Risk for Suicide Attempts With Delayed
Mood Stabilizer Initiation
14
12
12.2
10
8
Years of Delay to Mood Stabilizer
6
4
4.8
2
0
Suicide Attempt
No Suicide Attempt
OR 7.3 (95 CI 1.632.6 P .01)
Goldberg JF, Ernst CL. J Clin Psychiatry.
200263985-991.
22
Implications of Inappropriate Treatment
Lifetime Risk of Developing Mania/Hypomaniaor
Rapid Cycling While Taking Antidepressants

• Naturalistic chart review of 85 depressed
  patients
• 56 misdiagnosed as unipolar depression
• Antidepressants used earlier and more often than
  mood stabilizers
• Naturalistic study of 38 patients with bipolar
  disorder in a psychiatric clinic misdiagnosed and
  (mis)treated as having unipolar depression

100
N 38
80
55
60
Patients ()
40
23
20
0
Mania/Hypomania
RapidCycling
Ghaemi SN, et al. J Clin Psychiatry.
200061804-808.
23
Antidepressant-induced Mania and Hypomania

• One-quarter to one-third of bipolar patients
  using antidepressants may be susceptible to
  antidepressant-induced manias
• Patients with previous antidepressant manias
• Patients who have a strong family history of
  bipolar disorder
• Patients whose illness began in adolescence
• Patients with exposure to multiple antidepressant
  trials

Goldberg JF, Truman CJ. Bipolar Disord.
20035407-420.
24
Bipolar and Unipolar Depression
25
Bipolar Depression

• About 90 of people who experience a manic
  episode will also experience a depressive
  episode1
• Depression may be the first affective episode in
  more than 50 of patients with bipolar disorder2
• Frequently long-lasting, severe, and disabling
• Mean duration of bipolar depressive episodes is
  longer than manic episodes3
• More than 20 of bipolar depressive episodes run
  a chronic course3

1. Goodwin FK, Jamison KR. Manic-Depressive
Illness. Oxford University Press New York, NY
1990. 2.
Roy-Byrne P, et al. Acta Psychiatr Scand Suppl.
19853171-34. 3. Keller MB, et al. JAMA.
19862553138-3142.
26
Depression Constitutes a Majority of Symptomatic
Time Spent With Affective Symptoms
NIMH Collaborative Depression Study 146
patients followed every 6 months over 1220 years
Euthymia
5.9
9.3
Depression
9.4
52.7
Dysthymia
13.5
8.9
Subsyndromal
Elevated
Cycling
25 present with manic symptoms
10 years correct dx
Correct treatment
Onset of Symptoms
75 present with depressive symptoms
Adapted from Judd LL, et al. Arch Gen
Psychiatry. 200259530-537.
27
Clues That Unipolar Depression May Be Bipolar
Depression

• Early age of onset
• Postpartum mood disorders
• Seasonal mood changes
• Hypersomnia and/or psychomotor slowing
• Severe anhedonia
• Depression with catatonia and/or psychotic
  features
• Bipolar family history
• Pharmacological-induced mania or hypomania
• History of recurrent but brief depressive episodes

Marchand WR. Hosp Physician. 20033921-30.
Geller B, Luby J. J Am Acad Child Adolesc
Psychiatry. 1997361168-1176. Akiskal HS, et
al. J Affect Disord. 19835115-128.
28
Unipolar vs Bipolar Depression
Symptoms

• Bipolar depression
• Psychic anxiety
• Fatigue
• Fewer physical complaints
• Psychomotor retardation
• Hypersomnia
• Anger attacks

• Unipolar depression
• Somatic anxiety
• Appetite disturbances
• Physical complaints
• Irritability

Bowden CL. J Affect Disord. 200584117-125. Mitch
ell PB, et al. J Clin Psychiatry.
200162212-216. Perlis RH, et al. J Clin
Psychiatry. 200566159-166.
29
Prevalence of Anger Attacks During Depressive
Episodes of Bipolar Disorder

• Distinct autonomic phenomenon
• Younger age of onset of depressive symptoms
  coincided with increased percent of anger attacks
• Anger attacks were significantly more common
  among bipolar (62) than unipolar (26) depressed
  patients
• The presence of anger attacks emerged as a
  significant predictor of bipolarity

Perlis RH, et al. J Affect Disord.
200479291-295.
30
Unipolar vs Bipolar Depression
Course of Illness
Bipolar Unipolar
Age at onset 1519 2530
Number of episodes Higher Lower
Cycle length Shorter Longer
Goodwin FK, Jamison KR. Manic-Depressive Illness.
New York Oxford University Press 1990. Sadock
BJ, Sadock VA. Comprehensive Textbook of
Psychiatry, 7th ed. New York Lippincott Williams
Wilkins 2000 1385-1431.
31
Unipolar?Bipolar Polarity Conversion
74 initially unipolar depressed hospitalized
adolescent/young adult patients followed for 15
years in the Chicago Follow-up Study
Hypomania only
Percent Developing Mania or Hypomania
Mania only
0
Approx. Number of Years After Index
Hospitalization
Goldberg JF, et al. Am J Psychiatry.
20011581265-1270.
32
Bipolar vs Unipolar DepressionLong-Term Outcome
Remission at 10-YearFollow-up ()
(n 17)
(n 72)
(n 34)
Bipolar Disorder
Unipolar Depression (psychotic)
Unipolar Depression (non-psychotic)
P lt 0.01
Goldberg JF, Harrow M. J Affect Disord.
200481123-131.
33
Psychosocial Impairment
35
32.2
30
26.9
25
23.1
22.4
20
Unipolar depression
Percent With Disruption
19.9
Bipolar depression
15
16.5
10
5
0
Work/school
Social/leisure
Family life
P lt 0.001
P lt 0.0001
P lt 0.0001

• Greater functional impairment

Marked or extreme over past 4 weeks Hirschfeld
RM. Eur Neuropsychopharmacol. 200414(suppl
2)S83-S88.
34
Psychosocial Impairment Unmet Needs
50
45
43.3
40
40.6
35
Due to depressive
30
symptoms
Percent With Disruption
30.4
25
Due to manic
20
symptoms
19.1
18.1
15
12.7
10
5
0
Work/school
Social/leisure
Family life
P lt 0.001
P lt 0.0001
P lt 0.0001
marked or extreme over past 4 weeks
Hirschfeld RM. Eur Neuropsychopharmacol.
200414(suppl 2)S83-S88.
35
Systematic Treatment Enhancement Program for
Bipolar Disorder (STEPBD)

• Early onset of mood symptoms in BD have been
  associated with
• Poor outcome
• Greater rates of comorbid anxiety disorders
• Substance abuse
• Higher incidence of suicide attempts
• Violence
• Rapid cycling
• Early onset of BD may predict a more severe
  disease course
• One third of bipolar patients had symptom onset
  prior to 13 years of age

Perlis RH, et al. Biol Psychiatry.
200455875-881.
36
Steps to Avoid Misdiagnosis of Patients
Presenting With Depressive Symptoms

• Ask about a history of mania or hypomania
• Ask about family history of bipolar disorder
• Involve family members or significant others in
  the evaluation process
• Administer a screening instrument for bipolar
  disorder, eg, the Mood Disorder Questionnaire

Hirschfeld RM, et al. J Clin Psychiatry.
200465(suppl 15)5-9.
37
Scales Used to Diagnose/Assess Depression and/or
Bipolar Depression

• Screening Tools
• BDI-II Beck Depression Inventory (2nd ed.)
• BSDS Bipolar Spectrum Diagnostic Scale
• MDQ Mood Disorder Questionnaire
• PHQ-9 Patient Health Questionnaire
• Quantitative Rating Scales
• BDRS Bipolar Depression Rating Scale
• CGI Clinical Global Impressions
• HAM-A Hamilton Rating Scale for Anxiety
• HAM-D Hamilton Rating Scale for Depression
• MADRS Montgomery-Asberg Depression Rating Scale

38
Developing a Rating Scalefor Bipolar Depression

• Need for a diagnostic scale specific to the
  patient population of bipolar depressive symptoms
• Need for more sophisticated means of assessing
  the symptom differences
• To advance both research and clinical goals
• Bipolar Depression Rating Scale (BDRS) is
  currently being developed

Berk M, et al. Acta Psychiatr Scand Suppl.
2004110(s422)39-45.
39
Summary

• Misdiagnosis can result in inappropriate
  treatment, aggravated course and future treatment
  resistance
• Utilizing screening tools such as the MDQ can
  help differentiate bipolar disorder from unipolar
  depression and decrease the risk of misdiagnosis
• Characteristics of bipolar depression include
  early age of onset, psychic anxiety, fatigue,
  psychomotor retardation, hypersomnia, and anger
  attacks
• Early and accurate treatment may reduce the risks
  of suicide, psychosocial impairment, and
  comorbidities

Adapted from Akiskal HS, et al. J Affect Disord.
200585245-258.
40
MEASURE Resource Module 2005

• Section 2
• An Update on Clinical Trialsin Bipolar Disorder

41
Objective

• To discuss the standards of care as well as
  current research on pharmacotherapeutic
  strategies for treating bipolar depression

42
Modern History of Bipolar Disorder
1921 Distinguished manic-depression from
schizophrenia 1949 Lithium antimanic effects
reported 1962 Bipolar terminology
introduced 1970s Lithium approved by FDA for
acute mania and maintenance therapy 1978
First inclusion of bipolar disorder in
DSM 1980s Traditional carelithium,
neuroleptics, ECT 1990s Lamotrigine,
depakote, and carbamazepine as mood
stabilizers (?? class effect) 2000 Role
of atypical antipsychotics/monotherapy of 2nd
generation antipsychotics (?? class effect)
DSM Diagnostic and Statistical Manual of Mental
Disorders ECT electroconvulsive therapy
43
Few Therapies With Bipolar Disorder Indications
2005 Physicians Desk Reference. Available at
http//www.pdr.net. Accessed July 25, 2005.
44
Lithium Efficacyin Bipolar Depression

• Lithium gt placebo in early placebo-controlled
  studies, but
• All crossover designs
• Lithium stopped abruptly in placebo groups,
  resulting in worse outcomes
• Mixed samples of bipolar and unipolar depressed
  patients
• In randomized studies, lithium minimally better
  than placebo and inferior to tricyclic
  antidepressants (TCAs)

Fieve RR, et al. Am J Psychiatry.
1968125487-491 Goodwin FK, et al. Arch Gen
Psychiatry. 196921486-496 Stokes PE, et al.
Lancet. 197111319-1325 Goodwin FK, et al. Am J
Psychiatry. 197212944-47 Mendels J, et al.
Arch Gen Psychiatry. 197226154-157 Noyes R Jr,
et al. Compr Psychiatry. 197415187-193 Baron
M, et al. Arch Gen Psychiatry. 1975321107-1111
Watanabe S, et al. Arch Gen Psychiatry.
197532659-668 Mendels J, et al. Lancet.
19761966 Donnelly EF, et al. J Consult Clin
Psychol. 197644233-237 Worrall EP, et al. Br J
Psychiatry. 1979135255-262.
45
Bipolar Depression Lithium With Antidepressants
(N 117)
70
Li PBO
60
Li PAR
50
Li IMI
Percent Reduction of HAMD Score
40
30
20
10
0
Li ? 0.8 mEq/L
Efficacy Overall

• Greater relapse prevention in mania vs depression
• Switch rate 0 paroxetine 3 placebo 7
  imipramine
• Mean Li level 0.78 mEq/L

Li lithium, IMI imipramine, PAR paroxetine,
PBO placebo
Nemeroff CB, et al. Am J Psychiatry.
2001158906-912.
46
Theories Why Lithium May Reduce Suicide Rates
Due to therapeutic monitoring increased
interaction with health care providers (more
socialization)
General mood-stabilizing effect
Effects on limbic dopamine activity
Specific anti-suicide effect theorized
Lithium
Decreased impulsive and aggressive features
Effects on limbic serotonin related activity
Note 13-fold reduction rate in suicide on lithium
vs no lithium treatment This is a long-term
benefit
Baldessarini RJ, et al. Ann NY Acad Sci.
200193224-38. Ernst CL, Goldberg JF. Harv Rev
Psychiatry. 20041214-41.
47
Time to Relapse of Any Mood Episode in Patients
Receiving Valproate, Lithium, or Placebo
1
Valproate
Lithium
0.8
Placebo
0.6
Survival
0.4
0.2
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Weeks
No significant difference in time to relapse was
found in bipolar I patients receiving maintenance
therapy with valproate, lithium, or placebo.
Bowden CL, et al. Arch Gen Psychiatry.
200057481-489.
48
Prophylaxis With Divalproex, Lithium, or
Placebo Additional Analyses
Double-blind1-year outcome
(n 372)
Recovery
Divalproex(n 187)
(n 571)
Open treatment 12 weeks
Acute episode within 3 months
Lithium(n 91)
Placebo(n 94)
McElroy SL, et al. Poster presented at IPS, 2003.
49
Divalproex Maintenance Period 59 Greater Than
Lithium
Mean number of days in the maintenance periodfor
subjects who were treated with the same
medicationin the open phase and maintenance phase
250
206.9
200
59
130.3
150
Mean Number of Days
100
50
0
Lithium
Divalproex
P 0.019
McElroy SL, et al. Poster presented at IPS, 2003.
50
Adding a Second Mood Stabilizer vs Adding an
Antidepressant
25
Hamilton Rating Scale for Depression
Two mood stabilizers Mood stabilizer
and paroxetine
(16)
20
Young Mania Rating Scale Two mood
stabilizers Mood stabilizer and
paroxetine
(11)
(15)
15
(11)
(12)
Score
(11)
(11)
(11)
10
(11)
(11)
(11)
n 27
(10)
(10)
(10)
5
0
Baseline
1
2
3
4
5
6
Duration of Treatment (weeks)
Parenthetical numbers indicate numbers of the
remaining 27 subjects, but the data points
include imputed (last observation carried
forward) data on dropouts. Medications used are
valproate lithium Young LT, et al. Am J
Psychiatry. 2000157124-126.
51
Lamotrigine in Bipolar Depression
Placebo
Lamotrigine 50 mg
Lamotrigine 200 mg
60
54
51
51
48
45
50

41
37
40
29
26
Responders ()
30
20
10
0
HAM-D-17
MADRS
CGI-I
Response defined as 50 reduction on the
17-item HAM-D or MADRS scale or a rating of very
much improved or much improved on the CGI-I scale
P lt 0.05 vs. placebo P lt 0.1 vs. placebo
Calabrese JR, et al. J Clin Psychiatry.
19996079-88.
52
Lamotrigine in Bipolar Depression (cont.)
Week
0
0.5
1
2
3
4
5
6
7
0
-2
P lt .05 vs placebo
-4
-6
-8
MADRS Change From Baseline

-10

-12



-14



Placebo (N 65)
-16
Lamotrigine 50 mg/d (N 64)

-18
Lamotrigine 200 mg/d (N 63)
-20
Dose gt 50 mg/d in lamotrigine 200 mg/d group only
after week 3
Calabrese JR, et al. J Clin Psychiatry.
200263(suppl 3)5-9.
53
Adverse Events From Lamotrigine Maintenance Trials

P lt 0.05 Li vs PBO P lt 0.05 Li vs LTG
Goodwin GM, et al. J Clin Psychiatry.
200465432-441.
54
Treatment Guidelines
55
First-line Treatments for Bipolar Depression
2002 APA Treatment Guidelines

• Lithium or lamotrigine are first-line treatments
  for bipolar depression
• Antidepressant monotherapy is not recommended
  (Category I)
• Lithium plus an SSRI is not considered a
  first-line treatment
• New controlled studies have recentlyemerged

American Psychiatric Association. Practice
Guidelines for the Treatment of Patients with
Bipolar Disorder. 2nd ed. Washington, DC 2002.
Category I Recommended with substantial
clinical confidence. Category II Moderate
confidence.
56
2004 Expert Consensus GuidelinesTreatment Acute
Bipolar Depression

• Lamotrigine monotherapy rated first line for
  every presentation except psychotic depression
• Lamotrigine or lithium rated first line as
  initial medication for severe nonpsychotic
  depression, depression with antidepressant-induced
  mania, and rapid cycling
• New controlled studies have recently emerged

Keck PE Jr, et al. Postgrad Med Special Report.
2004 (December)1-120.
57
2004 Expert Consensus GuidelinesTreatment Acute
Bipolar Depression (cont.)

• Antidepressants plus lithium rated first line for
  severe nonpsychotic depression despite the
  controversy
• Atypical antipsychotic and an antidepressant
  rated first line for psychotic bipolar
  depression, but second line for severe
  nonpsychotic depression

Keck PE Jr, et al. Postgrad Med Special Report.
2004 (December)1-120.
58
Treatment Guidelines

• Guidelines help avoid non-evidence-based
  treatment decision
• As new studies emerge, guidelines can become
  outdated

Fountoulakis KN, et al. J Affect Disord.
2005861-10.
59
Guidelines for Acute Mania
AP antipsychotic Cbz carbamazepine ECT
electroconvulsive therapy Li lithium Olz
olanzapine Quet quetiapine Risp
risperidone Vp valproate.
Fountoulakis KN, et al. J Affect Disord.
2005861-10. Keck PE Jr, et al. Postgrad Med
Special Report. 20041-120.
60
Guidelines for Acute Bipolar Depression
AD antidepressant Cbz carbamazepine ECT
electroconvulsive therapy La lamotrigine Li
lithium Olz olanzapine Quet quetiapine
Risp risperidone Vp valproate.
Fountoulakis KN, et al. J Affect Disord.
2005861-10. Keck PE Jr, et al. Postgrad Med
Special Report. 20041-120.
61
Guidelines for Bipolar Maintenance
Arip aripiprazole Cbz carbamazepine ECT
electroconvulsive therapy La lamotrigine Li
lithium OCBz oxcarbamazepine Olz
olanzapine Quet quetiapine Risp
risperidone Vp valproate Zipr ziprasidone.
Fountoulakis KN, et al. J Affect Disord.
2005861-10. Keck PE Jr, et al. Postgrad Med
Special Report. 20041-120.
62
Proportion of Use of Each Classof Medications
for Bipolar Patients
Bipolar I
Bipolar II
70
60
50
40
Percent
30
20
10
0
Benzo-diazepine
Adequate Mood Stabilizer
Stimulant
Antipsychotic
Antidepressant

• STEP Study

Simon NM, et al. J Clin Psychopharmacol.
200424512-520.
63
Monotherapy for Bipolar Disorder Adverse Events
Atypical Antipsychotics

• Olanzapine
• Weight gain, somnolence, diabetes, hyperlipidemia
• Risperidone
• EPS, ? prolactin, weight gain
• Quetiapine
• Somnolence, hypotension, weight gain
• Ziprasidone
• Akathisia, ? QTc
• Aripiprazole
• Akathisia, insomnia, nausea

Dose related EPS. Adverse effects with
moderate/high frequencies listed. Bold face
indicates marked significance. EPS
extrapyramidal syndrome Akathisia is noted in
all atypical antipsychotics Adapted from
Nasrallah HA, et al. Ann Clin Psychiatry.
200113215-227. Adapted from Halbreich UM, et
al. Psychoneuroendocrinology. 20032853-67.
64
Monotherapy for Bipolar Disorder Adverse Events
(cont.)
Mood Stabilizers

• Lithium
• Polyuria, tremor, weight gain, hypothyroidism
• Valproate
• Weight gain, somnolence, gastrointestinal, memory
  impairment
• Lamotrigine
• Rash, drug interactions
• Carbamazepine
• Enzyme induction, rash, leukopenia

Common benign and rare serious. Adverse effects
with moderate/high frequencies listed. Bold face
indicates marked significance. Adapted from
Nasrallah HA, et al. Ann Clin Psychiatry.
200113215-227. Adapted from Halbreich UM, et
al. Psychoneuroendocrinology. 20032853-67.
65
Pharmacotherapyof Bipolar Depression
66
Inadequate Response to Initial Strategy for
Bipolar Depression

• Optimize dose and duration of trial although the
  benefit of optimization has never been studied
• Given a partial response in nonpsychotic bipolar
  depression, experts recommended adding (not
  switching) medication
• If initial treatment was a mood stabilizer or
  atypical antipsychotic, add lamotrigine or an
  antidepressant

Keck PE Jr, et al. Postgrad Med Special Report.
2004 (December)1-120.
67
Medications With at Least One Randomized,
Controlled Trial for Bipolar Depression
Risk of serious side effects associated with
rapid titration. Doses used for maintenance
treatment may be lower. Adapted from Goldberg
JF, et al. Bipolar Disord. 2003.
68
Medications With at Least One Randomized,
Controlled Trial for Bipolar Depression (cont.)
Adapted from Calabrese JR, et al. Am J
Psychiatry. 20051621351-1360 Adapted from
Tohen MF Jr, et al. Arch Gen Psychiatry.
2003601079-1088. Erratum in Arch Gen
Psychiatry. 20046176. US Food and Drug
Administration. Available at http//www.fda.gov/c
der/foi/appletter/2004/20825s009ltr.pdf.
Accessed December 1, 2004.
69
Mood Stabilizers Acrossthe Bipolar Spectrum
1 or more randomized, controlled trials
Ghaemi SN, et al. Bipolar Disord.
20035421-433.Goodwin GM, et al. J
Psychopharmacol. 200317149-173.Baldessarini
RJ, et al. Bipolar Disord. 20035169-179.
70
Atypical Antipsychotics Acrossthe Bipolar
Spectrum
1 or more randomized, controlled trials
Ghaemi SN, et al. Bipolar Disord.
20035421-433.Goodwin GM, et al. J
Psychopharmacol. 200317149-173.Baldessarini
RJ, et al. Bipolar Disord. 20035169-179.
71
Bipolar DepressionOlanzapine-Fluoxetine
Combination (OFC)
Placebo (n 355)
-2
Olanzapine (n 351)
-4
Olanzapine-fluoxetine combination (n 82)
-6
-8
Visitwise Improvement From Baseline in MADRS
(LOCF)

-10

-12



-14



-16


-18





-20
0
1
2
3
4
5
6
7
8
Week

P lt .05 vs placebo

P lt .05 vs olanzapine
Tohen MF Jr, et al. Arch Gen Psychiatry.
2003601079-1088. Erratum in Arch Gen
Psychiatry. 20046176.
72
Bipolar DepressionOFC MADRS Item Analyses
Source

Apparent sadness
Review

Reported sadness

Inner tension


Reduced sleep


Olanzapine fluoxetine
Reduced appetite

Olanzapine
Reviewer Memo
Placebo
Concentration difficulties

Lassitude

Inability to feel

Pessimistic thoughts
Suicidal thoughts
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
P lt .05 Olanzapine vs placebo P lt .05 OFC
vs placebo P lt .05 OFC vs Olanzapine Tohen MF
Jr, et al. Arch Gen Psychiatry.
2003601079-1088. Erratum in Arch Gen
Psychiatry. 20046176.
Mean Change From Baseline MADRS Items (LSM)
Slide Modified
Memo
73
Bipolar Depression Mood Stabilizer Plus
Risperidone and/or Paroxetine
Risperidone (n 10)
24
Paroxetine (n 10)
22
Risperidone paroxetine (n 10)
20
Paroxetine
18
P ns
16
Risperidone paroxetine
14
HAM-D Score
12
Risperidone
10
8
6
4
2
0
2
0
1
3
4
5
6
7
8
9
10
11
12
Week
Shelton R, Stahl S. J Clin Psychiatry.
2004651715-1719.
74
Time to Relapse Into Mania or DepressionWith
Olanzapine vs Placebo
Tohen M, et al. Olanzapine versus placebo for
relapse prevention in bipolar disorder,
(Abstract) Presented at 156th Annual Meeting of
the American Psychiatric Association. San
Francisco, CA, 2003
75
Bipolar DepressionQuetiapine Monotherapy
Study Week
1
2
4
3
6
5
7
8
0
Placebo (n 169)
Quetiapine 300 mg (n 172)
-5
Quetiapine 600 mg (n 170)

Mean Change From Baselinein MADRS Total Score

-10








-15






P lt 0.001 vs placebo (ITT, LOCF)
-20
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
76
Bipolar Depression QuetiapineMADRS Item
Analyses

Apparent Sadness


Reported Sadness


Inner Tension


Reduced Sleep

Reduced Appetite

Quetiapine 600 mg (n 170) Quetiapine 300 mg (n
172) Placebo (n 169)
Conc. Difficulties


Lassitude

Inability to Feel


Pessimistic Thoughts


Suicidal Thoughts

0
10
20
30
40
50
60
70
80
Mean Change in Score
P lt 0.05 P lt 0.01 P lt 0.001 vs placebo ITT,
LOCF
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
77
Common Adverse Events (gt 10 patients and 2x
placebo rate)
Dropouts due to sedation or somnolence 10.9
mostly within 7 days.
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
78
Observed Magnitudeof Antidepressant Effect
1.2
BP I
1.0
QUET 600
QUET 300
0.8
BP II
LTG 200
0.6
OFC
Effect Size
0.4
LTG 50
OLA
0.2
0
OFC
OLA
LTG 50
QUET 300
QUET 600
LTG 200
QUET 600
QUET 300
Effect size (ES) improvement over
placebo/pooled SD. small lt 0.4 moderate
0.40.79 large gt 0.79. Combined ES for
quetiapine 0.66/0.80
Calabrese JR. Issues in treating bipolar
depression. Paper presented at APA 2005 Annual
Meeting May 22, 2005 Atlanta, Georgia.
79
Safety and Tolerability
80
Metabolic Syndrome and Serious Mental Illness

• Recent reports by the FDA, ADA, APA, AACE, and
  NAASO have raised concerns regarding obesity,
  diabetes, and dyslipidemia as adverse effects of
  atypical antipsychotic agents1
• In addition, the metabolic syndrome appears to be
  more common in patients with schizophrenia and
  bipolar disorder
• Monitoring is now recommended1,2

AACE American Association of Clinical
Endocrinologists NAASO North American
Association for the Study of Obesity. 1 American
Diabetes Association. Diabetes Care. 200427596.
2 Buse JB. J Clin Psychiatry. 200263(suppl
4)37-41.
81
Incidence of Selected Serious Adverse Effects
With Boxed Warnings in Prescribing
Information SJS Stevens-Johnson Syndrome TEN
Toxic Epidermal Necrolysis. 1. Physicians Desk
Reference. 59th ed. Montvale, NJ Medical
Economics Co 2005. 2. Pellock JM. Epilepsia.
198728(suppl 3)S64-S70. 3. Leppik I.
Contemporary Diagnosis and Management of the
Patient With Epilepsy. Newtown, PA Handbooks in
Health Care 2001130.
82
Antipsychotic Safetyand Tolerability Concerns

• Second-generation
• Weight gain
• Sedation
• Diabetes
• Cardiac
• Akathisia
• Hyperprolactinemia
• NMS
• Cerebrovascular

Warning in prescribing information
83
Fixed-Effect Model of Clinical Response in
Randomized, Controlled Trials of Antidepressants
Versus Placebofor the Treatment of Bipolar
Depression
Favors placebo Favors antidepressant
0.1 0.2 0.5 1.0 2.0
5.0 10.0
aSignificance test for heterogeneity (?2 10.51,
df 3, P 0.01 I2 71.4). Significance test
for overall effect (z 5.60, P lt
0.00001). Gijsman HJ, et al. Am J Psychiatry.
20041611537-1547.
84
Bipolar DepressionDivalproex Monotherapy
Week
Subjects Responding
1
2
3
4
5
6
7
8
50
0

-2
40
Placebo (n 22)
-4
30
Percentage of Patients
-6
Mean ? From Baseline HAM-D
20
-8

10
DVP (n 22)

-10
0
-12
DVP
Placebo
P 0.051 vs placebo P 0.052 vs placebo
P lt 0.035 vs placebo
Sachs GS, et al. Presented at American College
of Neuropsychopharmacology Annual Meeting May
2001 Honolulu, HI. Davis LL, et al. Expert Rev
Neurother. 20044349-362.
85
Carbamazepine Extended-release Capsules Improve
Depressive Symptoms in Patients With Mixed
Episodes
MIXED
Moderate
Placebo n 67
Change -2.25
Mild
Change -4.77
Carbamazepine extended-release capsules n 80
MANIC
Placebo n 146
Change -0.70
Non-depressed
Change -1.72
Carbamazepine extended-release capsules n 134
P lt .05 compared to placebo following ANCOVA
with baseline score as covariate. Data on file,
Shire Pharmaceuticals. Wayne, PA.
86
Do the SSRIs Destabilizethe Course of Bipolar
Disorder?
SSRI PBO vs DVP SSRI P lt 0.05 DVP vs PBO
P lt 0.05
Gyulai L, et al. Neuropsychopharmacology.
2003281374-1382.
87
Why Do Antidepressants Appear More Effective Than
They Are?

• Negative studies go unpublished, which inflates
  reported effect sizes
• Old studies took credit for switching
• Antidepressants work acutely, but have been
  ineffective in randomized clinical trials
• May be effective for short term but not long term

Ghaemi SN, et al. J Clin Psychiatry.
200162565-569. Kraemer HC, et al. Int
Psychogeriatr. 19981043-51. Calabrese JR, et
al. Eur Neuropsychopharmacol. 19999S109-S112.
88
Bipolar Depression and Antidepressants General
Guidelines and Risks

• Always use mood stabilizer in bipolar I patients,
  even while depressed
• Promptly wean the antidepressant if evidence of
  hypomania or mania emerges
• Antidepressants may trigger mania (mood
  destabilization) or accelerate mood cycle
• Up to 33 of patients with bipolar disorder may
  be susceptible to antidepressant-induced manias
• Possibly less efficacious in BP than UP
  depression
• Few standard antidepressants have been studied in
  bipolar depression

Dantzler A, Osser DN. Psychiatr Ann.
199929270-284. Frances AJ, et al. J Clin
Psychiatry. 199859(suppl 4)73-79. Goldberg JF,
Ernst CL. J Clin Psychiatry. 200263985-991. Gold
berg JF, Truman CJ. Bipolar Disord.
20035407-420. Möller HJ, et al. J Affect
Disord. 200167141-146.
89
The Consequences of Inappropriate Treatment of
Bipolar Depression

• Misdiagnosis can result in inappropriate
  treatment, aggravated course and future treatment
  resistance
• Naturalistic study of 32 patients with bipolar
  disorder in a psychiatric clinic, all of whom had
  been misdiagnosed and (mis)treated as unipolar
  depressives
• 55 developed a manic/hypomanic episode on
  antidepressants
• 23 developed new or accelerated rapid cycling

Rapid cycling occurs when a person experiences
four or more mood swings or episodes in a
twelve-month period. An episode can consist of
depression, mania, hypomania or even be a mixed
state. Rapid cycling in children can be ultra
rapid in contrast to adults.
Ghaemi SN, et al. J Clin Psychiatry.
200061804-808.
90
Summary

• Evidence-based treatment for bipolar depression
  includes lithium, lamotrigine, and
  antidepressants
• Quetiapine and OFC are emerging as viable
  alternatives for bipolar depression
• Monotherapy standard antidepressants may cause
  problems in terms of mood destabilization in
  bipolar depression
• Using antidepressants in bipolar depression is
  better than nothing, but not better than using
  lithium or a mood stabilizer
• Some novel antipsychotics may have a role in
  treating bipolar depression as monotherapy while
  stabilizing mania
• Goal is to stabilize depression without causing
  mania and minimizing side effects

91
Patient Case 1

• Treatment-related Side Effectsin the Bipolar
  Patient Screening and Management

92
Treatment-related Side Effectsin the Bipolar
Patient History

• 34-year-old female complaining of feeling
  depressed for one month
• Daily depressed mood Distractible
• Increased sleep Decreased energy
• Increased appetite Racing thoughts
• Anhedonia Physical agitation
• No suicidal ideation
• No new work-related or interpersonal stressors
• Six previous depressive episodes beginning at age
  12

93
Treatment-related Side Effectsin the Bipolar
Patient History (cont.)

• Currently taking venlafaxine failed sertraline,
  paroxetine, and fluoxetine in the past
• Three prior manic episodes (never diagnosed)
• Racing thoughts
• Pressured speech
• Overconfidence
• Overspending
• Hypersexual behavior
• No psychiatric hospitalizations, no suicide
  attempts, no psychotic symptoms

94
Treatment-related Side Effectsin the Bipolar
Patient History (cont.)

• No past medical history, no known drug allergies
• Married for 10 years, no children, gainfully
  employed in computer webpage design industry
• Positive psychiatric family history (maternal)
• Bipolar disorder in a cousin
• Suicide in a cousin
• Depression in an aunt and a cousin
• Medical history
• Coronary artery disease in her father and uncle

95
Treatment-related Side Effectsin the Bipolar
Patient Examination

• Normal physical examination
• BP 110/70 mm Hg
• Pulse 75 bpm
• BMI 23 kg/m2
• Mood depressed affect depressed and anxious
• Thought content normal thought process logical
• No suicidal ideation
• MADRS 22 (moderately depressed)
• YMRS 15 (mildly manic)

96
Treatment-related Side Effectsin the Bipolar
Patient Laboratory Tests

• Fasting blood sugar 90 mg/dL
• Total cholesterol 188 mg/dL
• Creatinine 0.9 mg/dL
• Liver function tests WNL
• TSH 2.4 mIU/L
• Free T4 8.9 ng/dL

97
Treatment-related Side Effectsin the Bipolar
Patient Clinical Course

• Venlafaxine discontinued lithium initiated with
  titration to therapeutic level of 0.8 (900 mg
  qHS)
• Incomplete resolution of mood symptoms and
  insomnia after 3 months
• Olanzapine added and titrated to 10 mg qHS in 2
  weeks with resolution of mood symptoms at 1 month
• Significant weight gain (10 lbs in 2 months) and
  metabolic changes (increased FBS and cholesterol)
• Olanzapine discontinued given metabolic issues
  and family history of heart disease

98
Treatment-related Side Effects in the Bipolar
Patient Clinical Course (cont.)

• Risperidone initiated and titrated to 2 mg QD
  with stable mood
• Akathisia with anxiety and agitation risperidone
  reduced to 1 mg
• Manic symptoms (racing thoughts and nervous
  energy) at lower dose
• Risperidone 2 mg with propranolol 10 mg BID with
  improvement of mood symptoms
• Risperidone discontinued due to oversedation with
  propranolol
• Aripiprazole initiated and titrated to 15 mg QHS
  with resolution of mood symptoms
• Insomnia and akathisia (agitation and physical
  restlessness)
• Aripiprazole was reduced to 10 mg with resolution
  of akathisia
• Insomnia managed with low dose benzodiazepine prn
• Maintenance on lithium 900 mg QD and aripiprazole
  10 mg QHS

99
Treatment-related Side Effectsin the Bipolar
Patient Key Messages

• Bipolar depression is frequently misdiagnosed as
  major unipolar depression
• Atypical antipsychotics appear to have similar
  efficacy in controlling mood symptoms
• Side-effect profiles can vary among various
  agents
• Patients should be monitored closely for EPS,
  akathisia, parkinsonism, hyperlipidemia, and
  hyperglycemia, as well as metabolic side effects
  and weight gain

100
Patient Case 2

• Bipolar Depression Focus on Accurate
  Diagnosis/Differentiation From Unipolar
  Depression

101
Bipolar Disorder Focus on Diagnosis History

• 22-year-old female complaining of feeling high
  for one week
• Erratic behavior Pressured speech
• Grandiosity Overspending
• Intrusive in social setting Sexually
  inappropriate
• Insomnia
• Started on venlafaxine 150 mg QD 2 months prior
  for depressed mood, severe fatigue, excessive
  sleepiness, and weight gain
• Rapid response to antidepressant (1 week)

102
Bipolar Disorder Focus on Diagnosis History
(cont.)

• Moody and labile as a child
• Easily upset by teasing
• Suicide gesture (wrist scratched superficially)
  at 16
• Very active in school activities
• Hypersexual behavior
• Past medical history (age)
• Adenoidectomy (5), broken leg (10), gonorrhea
  (20), migraine headaches
• Currently taking venlafaxine, tryptan, oral
  contraceptive allergic to penicillin

103
Bipolar Disorder Focus on Diagnosis History
(cont.)

• Works as a salesperson in department store
• Drinks socially experimented with marijuana
  smokes 1 pack/day
• Positive family history
• Mother anxiety and postpartum depression
• Brother polydrug abuser with an arrest
• Grandmother bipolar disorder with
  hospitalization
• Great aunt suicide

104
Bipolar Disorder Focus on Diagnosis Examination

• Normal physical exam except for cardiac click
• Mood irritable affect appropriate
• Speech pressured thoughts scattered
• No delusions or hallucinations (some grandiosity)
• No suicidal or homicidal ideas (SI in past)
• Insight limited judgment impaired
• MMSE 28 (missed points on concentration and
  attention)
• YMRS 28 HAM-D 9

105
Bipolar Disorder Focus on Diagnosis Laboratory
Tests

• CBC within normal limits
• LFTs slightly elevated
• Electrolytes within normal limits
• TSH normal
• Urine screen no drugs or abuse

106
Bipolar Disorder Focus on Diagnosis Clinical
Course

• Admitted with diagnosis of bipolar disorder, NOS
  (drug-induced mania)
• Quetiapine added to venlafaxine and titrated to
  500 mg/day at bedtime
• Reduced grandiosity, pressured speech, insomnia,
  irritability, and intrusiveness
• YMRS fell to 12 over two weeks
• Side effects included mild headache, dry mouth,
  and sedation
• Discharged with euthymic mood and appropriate
  affect
• Monthly outpatient appointments with
  psycho-educational, supportive, and behavioral
  therapy

107
Bipolar Disorder Focus on Diagnosis Key
Messages

• Bipolar depression is frequently misdiagnosed as
  unipolar depression leading to inappropriate
  treatment
• Clues to help distinguish bipolar from unipolar
  depression include
• Early age at initial presentation Family
  history
• Erratic response to antidepressant Substance
  abuse
• Past hypomanic behavior
• Combination therapy with an antidepressant and
  mood stabilizer/anti-manic drug is an approach to
  bipolar depression

108
Patient Case 3

• Bipolar Diagnosis and Treatment in Children and
  Adolescents

109
Childhood Bipolar Disorder History

• 17-year-old male, accompanied by parents, feeling
  sad and down for past 3 weeks
• Decreased motivation/energy Decreased
  concentration
• Increased sleep (1214 hr/d) Increased appetite
  (4 lb gain)
• Tired throughout the day Passive suicidal
  ideation
• Increased irritability/sensitivity
• Similar episodes over past year lasting 4 weeks
• Behavioral issues as a toddler/child
• Defiant, lack of focus Sloppy, incomplete work
• Restless Preferred playing alone

110
Childhood Bipolar Disorder History (cont.)

• Obsessions and compulsions beginning at age 12
• Intrusive thoughts about germs with ritualistic
  behaviors
• Caused problems at school and home, never sought
  treatment
• Increasingly irritable behavior over past 2 years
• Temper tantrums Racing thoughts
• Violent outbursts Physically restless
• Hyper and energized Increased libido
• One recent episode of feeling great following a
  4-week depression
• Increased energy, clear thinking, decreased
  sleep, increased mood, social, outgoing

111
Childhood Bipolar Disorder History (cont.)

• Experimented with tobacco, alcohol, and cannabis
  (denies regular use)
• Positive family history
• Alcoholism grandparents
• Bipolar disorder grandfather
• Depression/anxiety mother
• Suicide maternal aunt

112
Childhood Bipolar Disorder Mental Status
Examination

• Well developed, athletic appearing white male
• Affect constricted Mood depressed
• Movements slowed eyes downcast with poor eye
  contact
• Thoughts linear speech slow and halting with
  delayed responses
• Endorsed all neurovegetative symptoms of
  depression
• Denied manic symptomatology
• Denied psychotic thinking

113
Childhood Bipolar Disorder Clinical Course

• Diagnosis of bipolar spectrum disorder
• Lamotrigine started at 25 mg QD and titrated to
  200 mg over 12 weeks
• Depression remitted in 2 weeks
• After 1 year of lamotrigine, patient noted a
  definitive improvement in his symptoms
• Only 1 brief depression (l week), no manic
  symptoms
• Cognitive therapy for OCD symptoms
• Positive effect in reducing obsessions and
  compulsions

114
Childhood Bipolar Disorder Key Messages

• Reverse neurovegetative symptoms of depression
  occur in about 1/3 of bipolar depressed episodes
• History consistent with cyclothymia with onset of
  depression at 16typical for bipolar disorder
• Brief recurrent depressions (at least 4 in one
  year) and hypomania consider rapid cycling
• Mixed episodes are a common presentation in
  children with bipolar disorder

115
Childhood Bipolar Disorder Key Messages (cont.)

• Mania in children and adolescents is more likely
  irritable than euphoric and elated (adults)
• Comorbid psychiatric illness is common in
  childhood bipolar disorder
• ADHD Oppositional defiant disorder
• OCD Conduct disorder
• Anxiety disorders (overanxious, separation,
  agoraphobia, panic, social phobia, and simple
  phobia)
• Given history of recurrent depression,
  lamotrigine was given
• Cognitive therapy preferable to SSRI for OCD,
  given history of rapid cycling

116
Patient Education Tools
117
The Mood Disorder Questionnaire (MDQ)
118
Bipolar Spectrum Diagnostic Scale (BSDS)
119
Mood Tracking Diary
120
Frequently Asked Questions