Transcript Bipolar Disorder: New Treatment Options

Bipolar Disorder:
New Treatment Options
Michael A. Chan, MD
Chair, Department of Psychiatry
Mount Carmel
Bipolar Disorder
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Significant Public Health Impact
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0.5 – 1.7% lifetime prevalence
6.4% lifetime prevalence “bipolar spectrum”¹
Suicide rate ~ 12%
Annual U.S. cost > $45.2 B²
6th leading cause of disability worldwide³
Co-morbid substance abuse (ETOH) ~70%
90% recurrence rate (median # episodes = 9)
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50% recurrence within one year of 1st episode
¹Judd LL, et al. J Affect Disord 2003 Jan;73(1-2):123-31
²Kleinman L, et al. Pharmacoeconomics 2003;21(9):601-22
³Woods SW. J Clin Psych 2000;61(suppl 13):38-41.
Bipolar Disorder
 Often
misdiagnosed or undiagnosed:
 35-60%
have depression first¹
 May have several depressive episodes
prior to manic episode²
 Many will not report mania/hypomania
 May progress to psychosis
 Lag between symptom onset and first
treatment with mood stabilizer³
¹Goodwin FK, Jamison KR. Manic-Depressive Illness 1990:56-73;NY: Oxford Univ Press
²Lish JD, et al. J Affect Disord. 1994;31:281-294.
³Goldberg JF, Ernst CL. J Clin Psych. 2002 Nov;63(11):985-91.
Bipolar Disorder:
Clues to Diagnosis
 History
of mania
 Family history of bipolar disorder
 Earlier age of onset¹
 Multiple episodes
 Abrupt onset and termination of
depressive episodes
 Worsening with antidepressant
treatment²
¹Lish JD, et al. J Affect Disord. 1994 Aug;31(4):281-94.
²Ghaemi SN, et al. J Clin Psychiatry. 2000;61:804-808.
Bipolar Disorder:
DSM-IV Criteria for Manic Episode
 Abnormally
and persistently elevated,
expansive, or irritable mood > 1 week
 3* or more activation symptoms:
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Distractibility, Increased risk-taking, Grandiosity,
Fast/racing thoughts, Activity increased, Sleep
decreased, Talkativeness (“DIG FAST”)
 Marked
social/occupational impairment
 Not due to drugs or medical condition
*Four, if primarily irritable
Bipolar Disorder:
DSM-IV Criteria for Depression
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5 or more of following present > 2 weeks:
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depressed mood most of day, nearly every day
decreased interest or pleasure in activities most of day,
nearly every day
increased/decreased appetite & weight
increased/decreased sleep
psychomotor agitation/retardation
decreased energy
guilt/worthlessness
poor concentration
recurrent thoughts of death/suicide
“SIG: E-CAPS”
Bipolar Patients Are Symptomatic
Almost Half Their Lives
9%
6%
32%
Weeks asymptomatic
Weeks manic/hypomanic
53%
N=146
Weeks depressed
12.8-year follow-up
Weeks cycling/mixed
Judd et al. Arch Gen Psychiatry 2002;59:530-537
Bipolar II Patients Are Symptomatic
Most Of Their Lives
1.3%2.3%
46.1%
50.3%
N=86
13.4-year follow-up
Weeks asymptomatic
Weeks hypomanic
Weeks depressed
Weeks cycling/mixed
Judd LL, et al. Arch Gen Psychiatry 2003;60:261-269.
Bipolar Disorder:
Subtypes
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Mixed Mania
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Rapid Cycling
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> 4 episodes/year
Bipolar II
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Simultaneous mania and depression
May be > 40% prevalence of episodes*
Hypomania (< 4 days duration) alternating with
depression
Secondary Mania
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e.g., drugs, tumor, CVA, lupus, endocrine,
infectious, Huntington’s, Wilson’s
*Akiskal HS, et al. J Affect Disord
2000 Sep;59 Suppl 1:S5-S30
Treatment:
APA Practice Guidelines 2002
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Acute mania/mixed mania:
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Acute depression:
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1st line: lithium or valproate or antipsychotic*
1st line severe: lithium or valproate + antipsychotic*
1st line: lithium or lamotrigine
1st line severe: lithium + antidepressant
Maintenance
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lithium or valproate:
Alternatives: lamotrigine, carbamazepine, oxycarbazepine
Atypical antipsychotics “may be considered”
*APA recommends atypical antipsychotics > typical antipsychotics
Treatment:
Mood Stabilizers
Lithium*
Depakote* (divalproex sodium)
Lamictal* (lamotrigine)
Tegretol (carbamazepine)
Trileptal (oxcarbazepine)
Neurontin (gabapentin)
Topamax (topiramate)
Gabitril (tiagibine)
Keppra (levetiracetam)
*FDA-approved
Mood Stabilizers:
Lithium
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Advantages:
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50+ years worldwide experience (FDA-approved 1970)
effective in euphoric mania and hypomania
inexpensive
reduces suicide rate¹‚²
Disadvantages:
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slow onset ~ 14 days
narrow therapeutic index
non-response in > 50% (usually bipolar subtypes)
frequent side effects (polyuria, tremor, GI symptoms) and
non-compliance
discontinuation associated with high relapse rate³
¹Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52.
²Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73.
³Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.
Mood Stabilizers:
Lithium
 Predictors
of response to Lithium:
 euphoric
mania
 good inter-episode functioning
 family history of Bipolar Disorder (and of
Lithium response¹)
 mania/depression/euthymia sequence vs.
depression/mania/euthymia²
¹Duffy A, et al. J Clin Psych. 2002 Dec;63(12):1171-8.
²Kleindienst N, Greil W. Neuropsychobiology. 2002;42 Suppl 1:2-10.
Mood Stabilizers:
Divalproex
 Advantages:
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extensive experience (FDA-approved for epilepsy 1983; for
bipolar mania 1995)
rapid onset (1-4 days)
loading dose strategy¹ well-tolerated:
 20 mgs/kg
 77% moderate to marked response
effective in Bipolar subtypes
effective for psychotic symptoms²
plasma levels (50-125 mcg/ml)
less cognitive impairment than lithium³
¹McElroy SL, Keck PE. Neuropsychobiol. 1993;27(3):146-9.
²McElroy SL, et al. J Clin Psych. 1996 Apr;57(4):142-6.
³Zajecka J, et al. J Clin Psych. 1996 Aug;57(8):356-9.
Mood Stabilizers:
Divalproex
 Disadvantages:
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sedation
transient hair loss
weight gain
tremor
GI upset
dose-related thrombocytopenia
rare hepatotoxicity, pancreatitis
possible Polycystic Ovarian Syndrome
plasma level monitoring
Mood Stabilizers:
Lamictal
 FDA-approved
for maintenance
treatment of Bipolar I Disorder
 Black box warning for serious rash
(includes Stevens-Johnson Syndrome and
toxic epidermal necrolysis)
 Slow
titration necessary
 Interaction with other AEDs (especially
valproic acid and carbamazepine)
Lamictal:
Efficacy in Bipolar Disorder
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Placebo controlled 18-month trials of
lamotrigine and lithium – pooled analysis
 8-16 week open label treatment with
lamotrigine or lithium before randomization:
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N = 191 for placebo
N = 280 for lamotrigine (100-400 mgs/d)
N = 167 for lithium (0.8-1.1 mEq/L)
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18-month maintenance treatment phase
 Both lamotrigine and lithium superior to
placebo in preventing any mood episode
Goodwin GM, et al;J Clin Psych 2004 Mar;65(3):432-441
Bowden CL, et al;Arch Gen Psych 2003 Apr;60(4):392-400
Calabrese JR, et al;J Clin Psych 2003 Sep;64(9):1013-1024
Treatment:
Atypical Antipsychotics
 Clozaril
(clozapine)
 Risperdal* (risperidone)
 Zyprexa* (olanzapine)
 Seroquel* (quetiapine)
 Geodon* (ziprasidone)
 Abilify* (aripiprazole)
*FDA-approved
Atypical Antipsychotics
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Comparable efficacy on positive symptom
 Better efficacy for improving cognitive and
affective (“negative”) symptoms
 Less risk of extrapyramidal symptoms
______________________________________
“Brightening” effects related to receptor
actions that differ from one agent to another
 Appropriate dosing is key for optimal benefits
with any atypical
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Antipsychotic Receptor Binding
Haloperidol
Profiles
Olanzapine
D1
A1
Clozapine
M D1
5HT1A
D1
D2
D2
H1
5HT2A
5HT2A
M
5HT2A
A1
A2
D2
H1
A2
Quetiapine
5HT1A
A1
D1 D2
5HT2A
Risperidone
5HT1A
D1 D2
A2 H1
A1
A1
H1
Ziprasidone
A1
A2
5HT1A
D2
5HT1A
Receptor:
D1
A1, 2 = a1, a2 adrenergic
D1,2 = dopamine
5HT2A
H1 = histamine
5HT1A, 2A = serotonin
M = muscarinic
Goldstein 1999
5HT2A
Atypical Antipsychotics
 High
5HT2:DA blockade (aripiprazole: unique
mechanism)
 5HT-2a
antagonism:
 Mesolimbic:
does not reverse
antipsychotic action at D2 receptors
 Nigrostriatal: reverses enough D2
blockade to EPS
 Mesocortical:
DA enough to improve
cognition
Atypical Antipsychotics
 Receptor
actions that improve mood
and cognition:
 5HT2a
antagonism (CLZ/RIS/OLZ/QTP/ZIP/ARI)
 5HT2c antagonism (RIS/OLZ/ZIP)
 5HT1a agonism (CLZ/QTP/ZIP/ARI)
 5HT/NE reuptake blockade (ZIP)
Atypical Antipsychotics
Proper dosing:
Drug
Initial launch
Current
Risperidone
16 mgs
4-8 mgs
Olanzapine
10 mgs
15-20 mgs
Quetiapine
200-300 mgs
600-800 mgs
Ziprasidone
40-80 mgs
120-160 mgs
Aripiprazole
20-30 mgs
5-10 mgs
Evaluation of Mania
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Young Mania Rating Scale items*:
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Elevated mood
Increased motor activity
Sexual interest
Sleep
Irritability
Speech
Language
Content
Disruptive/aggressive behavior
Appearance
Insight
*Possible Score = 0-60
Antipsychotics:
Olanzapine
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FDA-approved for acute mania (2000) and
bipolar maintenance (2004)
 First-line treatment for mania per APA 2002
Practice Guidelines (along with lithium &
divalproex)
 Superior to placebo¹
 Equivalent to lithium²
 Superior efficacy (vs. placebo) as add-on to
lithium or valproate ³
 Superior to divalproex4
1. Tohen M, et al. Am J Psych. 1999 May;156(5):702-9.
2. Berk M, et al. Int Clin Psychopharmacol. 1999 Nov;14(6):339-43.
3. Tohen M, et al. Arch Gen Psych. 2002 Jan;59(1):62-9.
4. Tohen M, et al. Am J Psych. 2003 Jul;160(7):1263-71.
Antipsychotics:
Risperidone
 FDA-approved
for acute mania (2003)
 Superior to placebo (equivalent to haloperidol)
as add-on to mood stabilizer (lithium or
divalproex)¹
 Equivalent
to lithium or haloperidol
monotherapy²
¹Sachs, et al. Am J Psych 2002 Jul;159(7):1146-54
²Segal J, et al. Clin Neuropharm 1998 May-Jun;21(3):176-80
Antipsychotics:
Quetiapine
 FDA-approved
for acute mania up to 12
weeks (2004)
 2 monotherapy and 2 adjunct therapy
studies completed*
 Superior efficacy on YMRS, PANSS,
CGI (including Response and Remission
rates on YMRS) for 3 of 4 studies
*Data on file, AstraZeneca Pharmaceuticals LP, Wilmington, DE
Presented at 16th Annual U.S. Psychiatric & Mental Health Congress. Nov 6-9, 2003. Orlando, FL
Quetiapine:Safety Summary
Monotherapy/Adjunct Therapy
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No clinically significant changes observed on ECG
parameters (including QTc)
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No clinically significant changes in glucose levels
(random test) from baseline to endpoint
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No other laboratory abnormalities occurred
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No clinically significant change observed in blood
pressure (including orthostatic)
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No difference from placebo in EPS or prolactin levels
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No difference from placebo in withdrawal due to
adverse events
Antipsychotics:
Ziprasidone
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FDA-approved for mania August 2004
 3-week, double-blind, randomized trial (DSMIV mania/mixed mania)
 N = 210
 Ziprasidone 40-80 mgs B.I.D. vs. placebo
 Outcome: SADS (MRS), PANSS, CGI-I, CGIS, GAF
 Ziprasidone superior from day 2 on all
primary and most secondary efficacy
measures
Keck PE, et al. Am J Psych. 2003 Apr; 160(4):741-8.
Antipsychotics:
Aripiprazole
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FDA-approved for mania October 2004
 3-week, multi-center, double-blind,
randomized trial (acute mania/mixed mania)
 N=262
 aripiprazole 30 mgs vs. placebo
 Outcome: YMRS change from baseline and
response rate ( > 50%)
 aripiprazole superior from day 4:
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YMRS (-8.2 vs. –3.4)
YMRS response (40% vs. 19%)
Similar discontinuation rate, weight, prolactin, QTc
Keck PE, et al. Am J Psych. 2003 Sep; 160(9):1651-8.
Atypical Antipsychotics:
Metabolic Abnormalities
DRUG
WEIGHT GAIN
DIABETES
RISK
WORSENING
LIPID PROFILE
CLOZAPINE
+++
+
+
OLANZAPINE
+++
+
+
RISPERIDONE
++
D
D
QUETIAPINE
++
D
D
ARIPIPRAZOLE
+/–
–
–
ZIPRASIDONE
+/–
–
–
(+) = increase; (–) = no effect; D = discrepant results
Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes.
Diabetes Care. 2004 Feb. 27(2):596-601.
Atypical Antipsychotics:
Case Reports Summary*
New Onset DM
DKA/Coma
Deaths
Clozapine
242
80
25
Olanzapine
225
100
23
Risperidone
131
36
5
Quetiapine°
69
21
11
Ziprasidone
1
1
0
Aripiprazole
?
?
?
*Data from MedWatch and Koller et al. Am J Med. 2001;111:716-23/ Koller et al. Pharmaotherapy. 2002;22:841-52.
°J Clin Psychiatry 2004;65:857-863
Literature reports through July 2003 and post-marketing surveillance date through August 2002
Comparative Side Effect Profile of
Atypical Neuroleptics
Drug:
EPS:
Weight
Gain:
Sedation: Prolactin:
Aripiprazole
0/+
0
0
0
Clozapine
0
+++++
+++++
0
Olanzapine
++
++++
++
++
Quetiapine
0
++
+++
0
Risperidone
+++
+++
+
+++
Ziprasidone
++
0
+
+
Benefits of Lower EPS
 “Negative”
symptom benefits
 Cognitive benefits
 Decreased dysphoria
 Improved compliance
 Lower risk for tardive dyskinesia
Tandon R, Jibson MD. Annals Clin Psychiatry 2002;14(2):123-9.
Prolactin Elevation*
 Loss
of libido
 Anorgasmia/Ejaculation difficulty
 Amenorrhea
 Gynecomastia
 Galactorrhea
 Osteoporosis
*DA blockade in tubero-infundibular tract
Treatment:
Antidepressants
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Appropriate use and effectiveness is
controversial
 Antidepressant-induced mania in 20-40%
with all antidepressant classes (TCAs >
others)¹‚²
 Increased risk of switching³:
 Previous antidepressant-induced mania
 Bipolar family history
 Exposure to multiple antidepressant trials
¹Stoll AL, et al. Am J Psych 1994 Nov;151(1):1642-45
²Calabrese JR, et al. Eur Neuropsychopharm 1999 Aug;9 Suppl 4:S109-12
³Goldberg
JF, et al. Bipolar Disord 2003 Dec;5(6):407-20
Treatment:
Antidepressants
 Conflicting
evidence for efficacy against
depressive relapse:
 Protective?:
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Altshuler L, et al¹ (retrospective, 39 pts, 1 year):
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35% relapse rate with antidepressant continuation
68% relapse rate with antidepressant discontinuation
Altshuler L, et al² (prospective, 84 pts, 1 year):
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36% relapse rate with antidepressant continuation
70% relapse rate with antidepressant discontinuation
¹Altshuler L, et al. J Clin Psychiatry. 2001;62:612-16.
²Altshuler L, et al. Am J Psychiatry. 2003;160:1252-62.
Treatment:
Antidepressants
 No
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benefit?:
Frankle WG, et al¹ (retrospective, 50 pts, 30
weeks):
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No difference in length of depressive episode
regardless of antidepressant status
Ghaemi S, et al² (open, randomized 33 pts, 1
year):
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Relapse rate 50% within 20 weeks regardless of
antidepressant status
¹Frankle WG, et al. Psychol Med. 2002 Nov;32:1417-23.
²Ghaemi S, et al. San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2003.
Treatment:
Antidepressants
 Antidepressants
can be safe and
effective*
 Review
of 12 randomized, controlled trials
in Bipolar Depression (1,088 patients):
Antidepressants more effective than placebo
 Switch rate 3.8% for antidepressants and 4.7%
for placebo
 Tricyclics had 10% switch rate vs. 3.2% for all
other antidepressants
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*Gijsman HJ, et al. Am J Psychiatry 2004; 161:1537-1547.
Treatment:
Antidepressants
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Recommendations for Bipolar depression*:
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Augment mood stabilizer with antidepressant,
unless:
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“ultra-rapid” cycler (>4 episodes/week)
History of antidepressant-induced cycle acceleration
History of multiple episodes antidepressant-induced
mania despite mood stabilizer treatment
Continue maintenance antidepressant if stable
for 2 months
*Post RM. Current Psychiatry. 2004 July. 3(7):40-49.
Treatment
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Electroconvulsive treatment¹‚²:
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Phototherapy (bright light treatment)
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superior to pharmacotherapy
bilateral ECT superior to unilateral ECT
psychotic depression predicts better response
effective in depressed and manic phases
> 300 case reports of ECT during pregnancy
Benefit as monotherapy³ or augmentation4
especially if seasonal component
Sleep deprivation
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5
improvement in 40-60% (may last weeks)
some risk of hypo-mania
¹UK ECT Review Group. Lancet. 2003 Mar 8;361(9360):799-808; ²Kho KH, et al. J ECT. 2003 Sep;19(3):139-47;
³Levitt AJ, et al. J Affect Disord. 2002 Sep;71(1-3):243-8; 4Loving RT, et al. Depress Anxiety. 2002;16(1):1-3;
5Giedke H, Schwarzler F. Sleep Med Rev. 2002 Oct;6(5):361-77.
Treatment
 Psychotherapy
issues:
 acceptance
of illness
 effect of illness on relationships
 effect on employment
 enhance compliance (>50% non-compliance:
M>F, white>non-white, combination
therapy>monotherapy, substance abusers)*
 identify
precipitants to mood episodes
 manage/reduce stress
*Keck PE, et al. Psychopharm
Bull 1997;33(1):87-91
Summary
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Bipolar disorder:
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Significant public health impact
Highly recurrent
Must look to find
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Usually presents in depressed phase
Subtypes exist and are less lithium-responsive
First-line treatment:
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Mood stabilizers
Atypical antipsychotics
Bipolar Disorder:
New Treatment Options
Michael A. Chan, MD
Chair, Department of Psychiatry
Mount Carmel