WHAT’S REALLY NEW IN BIPOLAR
DISORDER, OCTOBER 2005
OR WHAT I THINK IS IMPORTANT
AND NEW
(AND SOME OLD STUFF TOO)
WHO AM I?
WHERE AM I?
MEDICAL DIRECTOR OF DAY HOSPITAL,
PALOMAR HOSPITAL, ESCONDIDO,
CALIFORNIA; PSYCHIATRIST, PSYCHIATRIC
CENTERS OF SAN DIEGO, ESCONDIDO
Pinnacle Of Career:
1. Admission to Medical School
2. Joining PCSD
$$$ DISCLOSURES $$$
RESEARCH,
LECTURES, CONSULTANT
• Lilly, Janssen, Wyeth-Ayerst, Servier, FHH
Foundation, Lundbeck, Organon, Alberta
Heritage Foundation Research, AstraZeneca, Biovail
• Inspiration: Dr. Ron Remick, Dr. Ernie
McCrank, My patients
MY DAILY AFFIRMATIONS
• Just for today…I won’t sit in my living
room all day in my underwear; I’ll move
the computer into the bedroom
HISTORICAL REVIEW
• Aretaeus
• Kraepelin
• Leonhard
• Goodwin
• Akiskal
• Gorman met McCrank
WHAT I LEARNED IN MY FIRST
RESEARCH PROJECT
• NOTHING IN LIFE OCCURS IN A
VACUUM, NOT EVEN HEART
DISEASE
MOOD DISORDERS ARE DISORDERS WITH
CYCLICAL CHANGES IN MOOD, ENERGY
AND BEHAVIOR
• It seems to me that it is more likely that
Mood Disorders are primarily energy
disorders with secondary mood and
behavior dimensions
DIAGNOSTIC ISSUES
• DSM IV puts primary emphasis on polarity (i.e.
•
history of mania or hypomania) rather than
cyclicity or recurrence
Depressive disorders are thus a meaningless
category because of: 1. Defined by “not bipolar”
2. Too heterogeneous, patient with 2 episodes in
lifetime vs. someone with episodes every 12 to
24 months
HIGHLY RECURRENT UNIPOLAR
DEPRESSION (Clinical Features)
•
•
•
•
•
•
•
Family history of Bipolar Disorder (BD)
Bipolar like age of onset (teens and 20’s)
High episode frequency (every 18-24 mo)
Represents 25-35% of unipolar cases
May convert to BD, but many don’t, unless
receiving antidepressants without mood
stabilizer
Patients respond to Li better than imipramine
No category for these patients in DSM IV
POTENTIAL BIPOLAR DIATHESIS
• Recurrent major depressive episodes
• Early age of onset (40% of patients before age 20 BD, of
•
•
•
•
•
•
•
remaining 60%, most have highly recurrent unipolar
depression)
Family history of BD
Atypical depressive symptoms
Brief depressive episodes
Psychotic Depressive episodes
Post Partum Depression
AD induced hypomania/mania
AD non-response or wear off
PNEMONIC FOR MANIC SYMPTOMS
- DIGFAST
• Distractibility
• Indiscretion (pleasurable activities)
• Grandiosity
• Flight of ideas
• Activity increase
• Sleep deficit (decreased need)
• Talkativeness (pressured speech)
ALL QUESTIONS POSED TO
BIPOLAR PATIENTS, ARE
BEST POSED TO THEIR
RELATIVES
…At Least When It Comes To Mania
Bipolar Disorder Symptoms are
Chronic and Predominantly Depressive
1% 2%
9%
6%
32%
53%
146 bipolar I patients
followed 12.8 years
Judd et al (2002) Archives of General
Psychiatry (59) 530-537
50%
% of Weeks
Asymptomatic
Depressed
Manic/hypoman
Cycling
/ mixed
ic
46%
86 bipolar II patients
followed 13.4 years
Judd et al (2003) Archives General
Psychiatry. (60) 261-269
ANTIDEPRESSANT (AD) TREATMENT
IN BIPOLAR VS. UNIPOLAR
DEPRESSION
• Ghaemi SN et. al.; Am J Psychiatry 161:163•
•
•
165,2004
Long term safety and effectiveness of AD’s is
well established for unipolar, but not BD
patients. Short term efficacy is clear.
Tricyclic’s are not as effective for recurrence as
Li has been demonstrated
This study compared modern and older AD’s in
Bipolar depression (41 patients) vs. Unipolar
depression (37 patients)
AD TREATMENT TRIAL
COMPARISON CONTINUED
• Short term non-response for BD at 51.3% vs. Unipolar at
•
•
•
•
•
31.6%
Manic switching less in BD patients taking mood
stabilizers (31.6% vs. 84.2%)
Cycle acceleration only occurred in BD depression
(25.6%), with new rapid cycling in 32.1% of patients
Late response loss, or tolerance was 3.4X’s more
frequent in BD depression
Cycle acceleration, rapid cycling and response loss were
not prevented by mood stabilizers
In general, modern AD’s did not have lower negative
outcomes than Tricyclic's
AD TREATMENT TRIAL
COMPARISON CONCLUSION
• An unfavorable cost/benefit ratio is
indicated for the use of AD therapy in the
treatment of Bipolar depression
• This studies distressing numbers are
significant, considering that many
clinicians, and even most guidelines are
suggesting both short and long-term use
of AD’s for Bipolar depression
A 52 WEEK OPEN-LABEL CONTINUATION
STUDY OF Ltg. IN THE TREATMENT OF
BIPOLAR DEPRESSION
• McElroy SL et. al.; J Clin Psychiatry 65:204-210,
•
•
2004
Bipolar depression is more frequent, lasts longer,
and is more difficult to treat than mania
Ltg is a novel anticonvulsant that has been
shown to be effective in the acute treatment of
Bipolar depression. This study is a 52 week,
open-label continuation of that original trial
A 52 WEEK OPEN-LABEL CONTINUATION
STUDY OF Ltg. IN THE TREATMENT OF
BIPOLAR DEPRESSION CONTINUED
• The study group were BD I patients with an
•
•
episode of Major Depression that had completed
a 7 week dbl. bld. Plc. Controlled Ltg.
intervention, and were then invited to enter this
study, receiving 100-500 mg./day of Ltg.
Of the 135 patients completing the acute study,
124 (92%) entered the continuation study
MADRS, CGI measures were applied at 4, 12,
24, 36, and 52 weeks
A 52 WEEK OPEN-LABEL CONTINUATION
STUDY OF Ltg. IN THE TREATMENT OF
BIPOLAR DEPRESSION CONTINUED
• Of the 124 patients entered, 77 had received Ltg and 47
•
•
•
•
had received placebo during the acute study
The mean duration of Ltg. exposure was 10.4 months,
and mean modal dose was 187 mg/d.
56% of the patients completed the trial
There was a significant and sustained improvement over
time. 84% achieved remission by week 4, and episodes
of mania/hypomania were reduced from the previous
year
Headache was the most common drug-related adverse
event
A 52 WEEK OPEN-LABEL CONTINUATION
STUDY OF Ltg IN THE TREATMENT OF
BIPOLAR DEPRESSION CONCLUSION
• Ltg was effective in 1 year of open label
treatment as adjunctive or monotherapy,
and provided sustained improvement
without mood destabilization
• The issue of remission is studied in many
psychiatric disorders, but it may be most
critical in BD
LAMOTRIGINE RASH
• Can cause severe skin reactions (i.e. Steven
•
•
Johnson Syndrome SJS, Toxic Epidermal
Necrolysis TEN)
Recent data from German Rash Registry show
only 1/10,000 (almost all neurology patients)
Registry lists many other agents (9 antibiotics, 4
anticonvulsants) ahead of Ltg
CARDIAC DISEASE AND
DEPRESSION
PRELIMINARY RANDOMIZED, DBL BLD, PLACEBO
CONTOLLED TRIAL OF PRAMIPEXOLE (MIRAPEX)
ADDED TO MOOD STABILIZERS FOR TREATMENT
RESISTANT BD DEPRESSION
• Goldberg et. al. Am J Psychiatry 161:564566,2004
• Pramipexole, a dopamine agonist, may have AD
properties. Efficacy and safety were assessed in
this study
• 22 depressed outpatients with non-psychotic BD
were randomly assigned to placebo or
Pramipexole at max. dose of 1.7 mg./d for 6
weeks. HDRS (response at 50% improvement)
and CGI were used
PRELIMINARY RANDOMIZED, DBL BLD, PLACEBO
CONTOLLED TRIAL OF PRAMIPEXOLE (MIRAPEX)
ADDED TO MOOD STABILIZERS FOR TREATMENT
RESISTANT BD DEPRESSION CONTINUED
• 83% of Pramipexole and 60% of placebo
patients completed the study
• Response rates in the Pramipexole and placebo
groups were 67% and 20% respectively
• Pramipexole patients also had greater mean
improvements in CGI scores
• One patient DC’ed Pramipexole because of the
emergence of hypomania (the only adverse
effect drop-out)
PRELIMINARY RANDOMIZED, DBL BLD, PLACEBO
CONTOLLED TRIAL OF PRAMIPEXOLE (MIRAPEX)
ADDED TO MOOD STABILIZERS FOR TREATMENT
RESISTANT BD DEPRESSION CONCLUSION
• Pramipexole appears to be effective and safe for
•
•
the treatment of Bipolar depression
Bipolar depression has emerged as one of the
most important and difficult conditions to treat.
Beyond Ltg., the choices are complex and poorly
supported by sufficient data
Larger randomized and controlled studies are
now needed to further assess this study
GENERAL PRINCIPLES OF
MANAGEMENT
• Use life charts to monitor illness
• Remember, it is basically a depressive
disorder, even though all of the new med’s
are anti-manic drugs
• Issue is preventing recurrence
• AD’s can induce mania and/or cycling
• Keep in mind high suicide risk with BD
• Never forget the therapeutic relationship
WHAT IS THE THERAPEUTIC
RELATIONSHIP?
• The psychodynamic features of the
•
•
pharmacotherapy relationship can never be
overlooked
Without attention to elements such as
transference, pharmacotherapy can have
reduced value
As in all therapeutic relationships, a working
alliance must be established to allow the
treatment to proceed with greatest effectiveness
WHAT IS THE THERAPEUTIC
RELATIONSHIP, CONTINUED?
• The pharmacotherapeutic alliance can be tested
•
and strengthened when: discussing goals of
treatment; discussing side effects; the potential
for abuse with this patient; the clinicians
availability for the resolution of medication and
non-medication difficulties
Attention to the therapeutic alliance also
involves: consistency; availability; willingness to
discuss; and explain alternatives
WHAT IS THE THERAPEUTIC
RELATIONSHIP, CONTINUED?
• Transference issues include: Idealization initially with the
•
•
physician being authoritative and knowledgeable, and a
provider of coherent and non-judgmental explanation,
with no confrontation of looking inward or need to face
past and present painful experiences
Unfortunately, the inconsistent and sometimes limited
results of the medication, can be more than
disappointing to the hopeful patient
Some times the initial positive transference can lend
itself to the undermining of psychotherapy, and even
splitting. If under-recognized, it can undermine all of the
treatment
WHAT IS THE THERAPEUTIC
RELATIONSHIP, CONTINUED?
• Counter-transference needs to be
recognized and understood
• Issues like: discouragement; the desire for
treatment to proceed more quickly or with
less pain; to control the patient; or to give
some thing tangible to the patient during
a hopeless or helpless impasse.
TREATMENT OF BREAKTHROUGH
DEPRESSION
• Li has modest effect
• Lamotrigine (Ltg) has more robust effect
• Olanzapine very small effect (perhaps
through non-specific anti-anxiety, antinsomnia effect)
• Quetiapine has large effect, that appears
to be specific for depression (?study data)
HOW DO YOU DISTINGUISH BIPOLAR
FROM BORDERLINE AND FACTITIOUS
DISORDER?
• Bipolar Spectrum Disorder has
considerably more denial
• Bipolar Spectrum Disorder has much less
interest in any treatment, but particularly
psychotherapy
WHY IS THERE SO
MUCH DISABILITY
IN BIPOLAR
DISORDER?
Seroquel is not yet indicated
in Canada for the treatment of
bipolar disorder
Information presented within may contain
data not supported by the current product
monograph. Please consult the product
monograph for prescribing information.
Study Overview
• Eight-week, multicenter, double-blind,
•
•
•
randomized, fixed-dose, placebo-controlled
monotherapy study
Study population: outpatients with DSM-IV
bipolar I or bipolar II disorder, with or without
rapid cycling, in a major depressive episode
Study groups: quetiapine 600 mg/d, quetiapine
300 mg/d, placebo
Conducted at 39 centers in the United States
Calabrese et al, APA 2004
MADRS: Change From
Baseline
Study Week
1
2
3
4
5
6
7
8
Mean Change From Baseline
0



-5
Quetiapine 600 mg (n=170)
Quetiapine 300 mg (n=172)
Placebo (n=169)
§
-10
§
§
§
§
§
§
-15
§
§
§
§
§
§
§
§
§
-20
§p<0.001
vs placebo
ITT, LOCF
Calabrese et al, APA 2004
Response Rate
(50% decrease in MADRS)
70
Quetiapine 600 mg (n=170)
Quetiapine 300 mg (n=172)
Placebo (n=169)
60
§
§
§
% Patients
§
50
§
§
§
§
§
§
§
§
40
§
§
30
†
20
10
0
1
2
3
4
5
6
7
8
Study Week
†p<0.01 §p<0.001
vs placebo
ITT, LOCF
Calabrese et al, APA 2004
Remission Rate
(MADRS 12)
60
Quetiapine 600 mg (n=170)
Quetiapine 300 mg (n=172)
Placebo (n=169)
% Patients
50
§
§
§
§
§
§
§
§
†
40
§
§
§
30
§
§
20
10
0
1
2
3
4
5
6
7
8
Study Week
†p<0.01 §p<0.001
vs placebo
ITT, LOCF
Calabrese et al, APA 2004
Effect Size: Change in
MADRS
Large (0.8)
Quetiapine 600 mg
0.75
Quetiapine 300 mg
0.64
Medium (0.5)
Small (0.2)
AstraZeneca data on file
HAM-A: Change From
Baseline
Study Week
1
2
3
4
5
6
7
8
Mean Change From Baseline
0
-1



-2
Quetiapine 600 mg (n=170)
Quetiapine 300 mg (n=172)
Placebo (n=169)
-3
*
-4
-5
§
†
-6
-7
†
§
§
§
§
§
-8
§
§
§
§
-9
§
§
§
-10
*p<0.05 †p<0.01 §p<0.001
ITT, LOCF
Macfadden et al, APA 2004
Pittsburgh Sleep Quality Index (PSQI):
Change From Baseline
Mean Change From Baseline
0
Quetiapine
600 mg
n=170
Quetiapine
300 mg
n=172
Placebo
n=169
-1
-2
-3
-4
-5
§
-6
§
-7
§p<0.001
vs placebo
ITT, LOCF
Calabrese et al, APA 2004
Quality of Life (Q-LES-Q):
Change From Baseline
Mean Change From Baseline
15
§
§
10
5
0
Quetiapine
600 mg
Quetiapine
300 mg
§p<0.001
vs placebo
Placebo
ITT, LOCF
Calabrese et al, APA 2004
Efficacy Summary
• Quetiapine was found to be effective
for a broad range of depressive and
anxiety symptoms
• Quetiapine was found to be effective
in improving quality of sleep
• Quetiapine was found to be effective
in improving quality of life
Common Adverse Events
(>10% patients and 2x placebo rate)
Quetiapine
600 mg
n=180
Quetiapine
300 mg
n=179
Placebo
n=180
Dry mouth (%)
40.6
44.1
7.8
Sedation (%)
32.2
29.6
6.1
Somnolence
(%)
24.4
27.4
8.3
Dizziness (%)
22.8
16.8
8.3
Constipation
(%)
11.1
11.7
4.4
Adverse
Event
Safety, LOCF
Calabrese et al, APA 2004
Treatment-Emergent Mania
10
% Patients
8
6
4
2
0
Quetiapine
600 mg
n=180
Quetiapine
300 mg
n=179
Placebo
n=180
Treatment-emergent mania: adverse event of mania,
or YMRS 16 at 2 consecutive visits or last visit
ITT, LOCF
Calabrese et al, APA 2004
Change in Weight
Quetiapine
600 mg
Quetiapine
300 mg
Placebo
Mean change
(kg)
1.6
1.0
0.2
>7% increase
in weight (%)
11
10
3
Safety, LOCF
Serum Glucose (Fasting)
Quetiapine Quetiapine
600 mg
300 mg
Placebo
Baseline
mg/dL
86
87
87
Endpoint
mg/dL
92
90
90
Safety, LOCF
Sexual Adverse Events
20
% Patients
15
10
5
0
Quetiapine
600 mg
n=180
Quetiapine
300 mg
n=179
Placebo
n=180
Safety, LOCF
Safety Summary
• The rate of treatment-emergent mania with
•
•
•
•
quetiapine was no greater than with placebo
Common adverse events included dry mouth,
sedation/somnolence, and dizziness
Quetiapine was associated with minimal weight
change
Quetiapine was not associated with significant
change in serum glucose levels
The safety profile of quetiapine in this population
was consistent with previous studies
Pearls
• Screen for bipolar disorder in every
depressed and anxious patient
• Early diagnosis and treatment will lead to
improved quality of life and will slow the
progression of
bipolar disorder through the life cycle;
• Atypical agents such as quetiapine
(Seroquel) are effective
mood stabilizers
EXCELLENT BOOKS
• “An Unquiet Mind”, by Kay Jamieson, PH.D.
• “A Brilliant Madness”, by Patty Duke
• “Plato Not Prozac! Applying Eternal Wisdom To
•
•
•
•
Everyday Problems”, by Lou Marinoff PH.D.
“The Moral Animal”, by Robert Wright
“Mind Over Mood”, Greenberger et al.
“Agitated Depression”, Koukopolis, Clinics of
North America
“Creating True Peace” Thich Nhat Hahn