The Importance of Relapse Prevention

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The Importance ofRelapse Prevention

• David L. Dunner, MD
• Center for Anxiety and DepressionUniversity of
  WashingtonSeattle, Washington

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(No Transcript)
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Course of Illness in Affectively Disordered
Patients Prior to and After Lithium Treatments
1960
1961
1962
1963
1964
1965
Mania
Mixed form and/or rapidmanic-depressive
alternations
Lithium administration
Depression
Lithium dosage increased
Baastrup PC and Schou M. Arch Gen Psychiatry.
196716162-172. From reference 2,
withpermission. A clear reduction in frequency
of attacks during lithium administration is
demonstrated.
4
Bipolar Disorders Relapse Prevention

• Bipolar disorders are recurrent
• Recurrence has clinical, medical, psychosocial,
  and economic effects
• Recurrence results in hospitalization
• Mania or depression (bipolar I)
• Depression (bipolar II)
• Recurrence results in cycle shortening

5
Bipolar Recurrence Clinical Effects

• ? Rate of substance abuse comorbidity
• ? Rate of alcoholism comorbidity
• ? Rate of suicide
• Possible treatment refractoriness

6
Bipolar Recurrence Medical Effects

• ? Risk of cardiac disease
• ? Risk of drug interactions

7
Mortality in Bipolar Disorder

• Excess mortality weighted averageof 16
  studies 2.28
• Suicide 4.7 - 52

Goodwin FK, Jamison KR. Manic-Depressive Illness.
New York, NYOxford University Press 1990.
8
Bipolar Recurrence Psychosocial Effects

• ? Rates of divorce, separation
• ? Possibility of jail/prison or hospitalization

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Bipolar Recurrence Economic Effects

• ? Job performance
• ? Medical treatment costs
• ? Psychiatric treatment costs

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Bipolar Disorders Are RecurrentRecurrence Rates
in Bipolar Disorders

• 45-100
• Short duration of observation
• Focus on hospitalized episodes
• Exclusion of episodes prior to study entry
• Inclusion of nonrecovered patients
• Combined episodes treated as single episodes
• High unipolar/bipolar patient ratios

Goodwin FK, Jamison KR. Manic-Depressive Illness.
New York, NYOxford University Press 1990.
11
Bipolar Disorders Are RecurrentRecurrence Rate
for Bipolar II Disorder

• 0.45 episodes of depression/ patient-year
  (placebo-treated bipolar II patients who had
  prior episodes)

Dunner et al. Arch Gen Psychiatry.
198239(11)1344-1345.
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Bipolar Disorders Relapse Prevention

• Bipolar disorders are recurrent
• Recurrence has clinical, medical, psychosocial,
  and economic effects
• Recurrence results in hospitalization
• Mania or depression (bipolar I)
• Depression (bipolar II)
• Recurrence results in cycle shortening

13
Bipolar Disorder Recurrence Rates for Bipolar
I Disorder

• About 4-5 episodes in 10 years
• About 80 of episodes involve mania
• Over 80 of manic recurrences required
  hospitalization
• Mean of 3.9 years from initial hospitalization
  to next episode

Dunner et al. Compr Psychiatry.
197920511-515.Winokur G, et al. Manic
Depressive Illness. St. Louis, MO CV Mosby
1969.Goodwin FK, Jamison KR. Manic-Depressive
Illness. New York, NYOxford University Press
1990.
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Bipolar Disorders Relapse Prevention

• Bipolar disorders are recurrent
• Recurrence has clinical, medical, psychosocial,
  and economic effects
• Recurrence results in hospitalization
• Mania or depression (bipolar I)
• Depression (bipolar II)
• Recurrence results in cycle shortening

15
Relationship Between Cycle Lengthand Number of
Episodes
Cycle Length (Months)
Episode
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Illness Course Issues in Bipolar Disorder

• 90 have multiple recurrences
• Mean number of episodes is 9
• Length of time healthy decreases with age and
  more episodes
• If untreated, about 11 die because of suicide
• Recent evidence of unsatisfactory outcomes in
  about 50 of patients

Keller MB, et al. J Nerv Ment Dis.
1993181238-245.Tohen M, et al. Arch Gen
Psychiatry. 1990471106-1111.
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Principles of Bipolar Disorder Care

• Treat the illness, not just the episodes
• Help the patient learn about destabilizing
  factors
• Be empathetic, but blunt, about illness and
  denial
• Work to achieve recovery, not limited improvement
• Use regimens that yield excellent tolerability
  and adherence
• Acute episode drug needs are often different from
  maintenance, but they interact significantly

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Mood Stabilization

• Acute Maintenance
• Mania/
• Hypomania
• Depression

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Treatment of a Manic Episode

• Lithium
• Some anti-epileptic drugs
• Neuroleptics
• Typical
• Atypical
• ECT
• Other

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Treatment of Bipolar Depressive Episode

• Antidepressants
• Lithium
• MAOIs
• (TCAs)
• SSRIs
• Others
• Some anti-epileptic drugs
• Olanzapine
• ECT
• Psychotherapy

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Definitions of Mood Stabilizer

• Substance that is effective for 1 pole without
  inducing the other
• Substance that is effective for both poles of the
  illness
• Substance that is effective for both poles of the
  illness and for prophylaxis of recurrences

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Efficacy of Lithium Placebo-Controlled Studies
With Bipolar Patients
Duration (Months)
Lithium ( Relapses)
Placebo ( Relapses)
Study
Year
Baastrup Melia Cundall Coppen Stallone Prien
5 24 12 4-26 8-22 24
1970 1970 1972 1971 1973 1973
0 57 33 18 44 43
55 78 83 95 93 80
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Lithium Reduces Frequencyand Severity of Bipolar
Episodes
Lithium
Placebo
Stallone et al. Am J Psychiatry.
1973130(9)1006-1010.
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Lithium and Suicide

• Published studies 28
• Patients 17,000
• Suicide/suicide attempt rate
• 3.2 vs 0.37 per 100 patient-years
• After lithium discontinuation, rates of suicidal
  acts rose 7-fold, fatalities 9-fold

Tondo L, et al. Ann NY Acad Sci. 1997836339-351.
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Mood Stabilizers and Suicide
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Lithium Discontinuation Refractoriness

• Lithium responders who discontinued lithium
  failed to demonstrate a maintenance effect on
  restarting lithium
• 4 cases 13.6 from a series of 66 patients1
• Confirmed by 3 studies2-4
• Not confirmed by 2 studies5-6

1. Post RM, et al. Am J Psychiatry.
1992149(12)1727-1729.2. Post RM, et al.
Neuropsychobiology. 199327(3)132-137.3.
Kukopolus et al. 1995.4. Maj M, et al. Am J
Psychiatry. 1995152(12)1810-1811.5. Berghofer
A, et al. Acta Psychiatr Scand.
199693(5)349-354.6. Tondo L, et al. Ann N Y
Acad Sci. 1997836339-351.
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Lithium Prophylaxis at 24 Months(n101)

• Discontinued lithium 32
• Recurrence on lithium 20
• Lost to follow-up 14
• No recurrence 34
• Neuroleptics/antidepressants added 79

Vestergaard. APS. 199898(4)310-315.
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Relapse After Gradual vs Rapid Lithium
Discontinuation
1.0
Gradual Rapid
0.8
0.6
Probability of Remaining Euthymic
0.4
0.2
0.0
0
12
24
36
48
60
Time Off Lithium (Months)
Faedda GL, et al. Arch Gen Psychiatry.
199350(6)448-455.
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Predictors of Poor Long-TermResponse With Lithium

• Psychosis
• Substance abuse
• Rapid cycling
• More than 3 episodes
• Mixed mania (depression and mania)
• Poor compliance

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Relationship of Acute Mania Response to Number of
Previous Affective Episodes
Placebo (n63) Lithium (n29) Divalproex sodium
(n62)
10 8 6 4 2 0
Improvement in SADSManic Syndrome
0 2 4 6 8 10 12 14 16
Cumulative Previous Episodes
Swann AC, et al. Am J Psychiatry.
1999156(8)1264-1266.
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Maintenance Treatment With Valproate, Lithium, or
Placebo (1 Year)
39
33
24
23
22
Percent
17
18
10
6
Bowden CL, et al. Arch Gen Psychiatry.
200057(5)481-489.
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Patients Without Relapse After 2.5 Years of
Prophylactic Treatment With Lithium vs
Carbamazepine
Percent
Greil W, et al. J Affect Disord.
199743(2)151-161.
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Problems of Current Mood Stabilizers

• Limited efficacy
• Toxicity
• Side effects renal, thyroid,
• hematologic, hepatic
• Monitoring
• Interactions
• Teratogenicity
• Weight gain
• Poor compliance
• Refractoriness

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Clozapine in Refractory Bipolar Disorder
10
Clozapine
8
Treatment as usual
6
4
2
Change (Months)
0
-2
-4
-6
BPRS
BRMS
CGI
SAPS
SANS
HDRS
Suppes T, et al. Am J Psychiatry.
1999156(8)1164-1169.
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Risperidone vs Haloperidol vs Placeboin Bipolar
Mania

Placebo


Risperidone
Haloperidol
Plt.05 risperidone vs placebo
Sachs, 1999.
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Similar YMRS Improvement in Nonpsychotic and
Psychotic Manic Patients Treated With Olanzapine
Study I 3 Weeks
Study II 4 Weeks
29.58
27.56
30.8
25.5
Baseline
Mean Change(LOCF)

-9.9
-10.7
-13.0
Psychotic

-15.9
Non-psychotic
P.88. P.41. No difference in mania
improvement among olanzapine-treated subjects
with and without psychotic features.1. Study I
Tohen MF, et al. Am J Psychiatry.
1999156(5)702-709. 2. Study II Tohen MF, et
al. Arch Gen Psychiatry. 200057(9)841-849.
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Treatment of Acute Bipolar I DepressionEfficacy
of Olanzapine
0

-5


Mean Change in MADRS Score


-10

Placebo (n377)
OLZ (n370)
-15



OLZ FLU (n86)
-20
0
2
4
6
8
Week
Plt0.05 vs OLZ FLU P lt0.05 vs OLZ.
OLZolanzapine FLUfluoxetine. Tohen et al. Ann
Meeting APA 2002 Philadelphia, Pa.
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Time to Relapse Into ManiaBased on
Hospitalization and/or Symptomatic Rating Scale
Criteria
100
plt.001
80
60
Probability of Remaining in Remission
40
Plt.001
Olanzapine
20
Placebo
0
0
50
100
150
200
250
300
350
400
Time to Manic Relapse (Days)
YMRS Total score ?15.
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Time to Relapse Into DepressionBased on
Hospitalization and/or Symptomatic Rating Scale
Criteria
100
plt.001
80
60
Probability of Remaining in Remission
40
20
Olanzapine
Placebo
0
0
50
100
150
200
250
300
350
400
Time to Depression Relapse (Days)
HAMD-21 Total score ?15.
40
Time to Relapse Into Mania or Depression Based on
Hospitalization and/or Symptomatic Rating Scale
Criteria
100
Olanzapine
plt.001
80
Placebo
60
Probability of Remaining in Remission
40
20
0
0
50
100
150
200
250
300
350
400
Time to Bipolar Relapse (Days)
Median Time 174 Days Olanzapine 22 Days Placebo
YMRS and/or HAMD-21 total scores ?15.
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Ziprasidone in Mania
Mania Rating Scale (LOCF)
Plt.01 vs placebo Plt.001 vs placebo





Keck PE Jr, Ice K. Presented at APA 2000 Annual
Meeting May 13-18, 2000Chicago, Illinois.
Abstract NR224.
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Short-Term Acute Bipolar ManiaClinical Trials
YMRS Young Mania Rating Scale CGI-BP CGI
bipolar version. Patients were diagnosed with
bipolar I disorder and were experiencing an acute
manic or mixed episode Starting dose. 1. Keck
et al. Am J Psychiatry. 20031601651 2. Data on
file, Otsuka America Pharmaceutical, Inc.
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Aripiprazole in Acute Mania Trial 1 Mean Change
From Baseline in YMRS
Placebo (n122 mean baseline 29.7)
Aripiprazole (n123 mean baseline 28.2)
Mean change from baseline
Days
Plt0.01 vs placebo. LOCF analysis. Keck et al.
Am J Psychiatry. 20031601651.
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Lamotrigine vs Placebo in Bipolar I Depression
(MADRS)
LOCF
Observed
0 -5 -10 -15 -20
0 -5 -10 -15 -20
Change from Baseline

Change from Baseline






PBO (n65) LTG 50 mg/day (n64) LTG 200 mg/day
(n63)








0 1 2 3 4 5 6 7 Time (Weeks)
0 1 2 3 4 5 6 7 Time (Weeks)
Plt.10Plt.05
Calabrese JR, et al. J Clin Psychiatry.
199960(2)79-88.
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Time to Intervention for Mania
LTG v. PBO, p 0.280 Li v. PBO, p 0.006 LTG
v. Li, p 0.092
Index Mania
Bowden et al., Arch. Gen. Psych. 2003
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Time to Intervention for Depression
LTG v. PBO, p 0.015 Li v. PBO, p 0.167 LTG
v. Li, p 0.355
Index Mania
Bowden et al., Arch. Gen. Psych. 2003
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Time to Intervention for a Mood Episode
LTG v. PBO, p 0.029 Li v. PBO, p 0.029 LTG
v. Li, p 0.915
12 Mon.
18 Mon.
Index Depressed
Calabrese et al., 2003 submitted
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Topiramate in Bipolar DisorderSummary of Open
Studies

• N Age Dosage Response
• Calabrese (monoth) 10 43 300 36
• McElroy 30 41 294 52
• Marcotte 44 45 200 52
• Chengappa 18 43 200 60
• Kusamakar 15 41 105 53
• Hussain 45 36 275 61
• Vieta 22 43 158 38
• Grunze (on-off) 11 42 172 73
• Sachs 14 37 100 36
• TOTAL 209 41 215 52

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Bipolar DisordersTreatments that Decrease Risk
of Recurrence

• Lithium
• Anticonvulsant mood stabilizers
  (lamotrigine,carbamazepine, divalproex)
• Olanzapine
• Possibly benzodiazepines (clonazepam)
• Possibly ECT
• Possibly clozapine

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Bipolar DisordersTreatments that Increase or Do
Not Alter Risk of Recurrence

• Tricyclic antidepressants
• Typical neuroleptics
• Gabapentin, topiramate
• Nonmood stabilizing anticonvulsants
• Alprazolam

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Bipolar Disorders Treatments Needing Research to
Determine Risk of Recurrence

• Atypical neuroleptics
• Risperidone
• (Olanzapine)
• Quetiapine
• Ziprasidone
• Aripiprazole

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Goals of Psychoeducation in Bipolar Patients

• Improve illness awareness
• Early identification of new episodes
• Enhance compliance
• Stress management
• Avoid substance abuse

Colom F, et al. Psychother Psychosom.
199867(1)3-9.
53
Principles of Bipolar Disorder Care

• Treat the illness, not just the episodes
• Help the patient learn about destabilizing
  factors
• Be empathetic, but blunt, about illness and
  denial
• Work to achieve recovery, not limited improvement
• Use regimens that yield excellent tolerability
  and adherence
• Acute episode drug needs are often different from
  maintenance, but they interact significantly

54
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