The diagnosis and treatment of bipolar mixed states

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The diagnosis and treatment of bipolar mixed
states

• Eduard Vieta, MD, PhD

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Disclosure Eduard Vieta, MD, PhD
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Ferdinand VI of Spain (1713-1759)
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Andrés Piquer
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Treatments Assayed for Bipolar Disorder During
the XVIII Century in His Majesty Ferdinand VI of
Spain

• Donkey milk
• Turtle soup with frogs, calf and snakes
• Enemas
• Lime tea with cherries
• Mother-of-pearl dust
• Fumaria

• Head baths
• Deer antler jelly with tender vipers
• Violet
• Diet
• Borage potion
• Pimpernel
• Agrimony

Piquer, 1759 Vieta Barcia, 2000
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Classification of Mixed states

• Depression with racing thoughts
• Excited depression
• Depressive-anxious mania
• Improductive mania
• Inhibited mania
• Manic stupor
• 
  Kraepelin, 1921

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Symptom domains in maniaand mixed mania
Manic Mood and Behaviour
Dysphoric or Negative Mood and Behaviour

• Euphoria
• Grandiosity
• Pressured Speech
• Impulsivity
• Excessive Libido
• Recklessness
• Diminished Need for Sleep

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

Cognitive Symptoms

• Racing Thoughts
• Distractibility
• Poor Insight
• Disorganization
• Inattentiveness
• Confusion

Psychotic Symptoms

• Delusions
• Hallucinations
• Sensory Hyperactivity

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Discriminatory Depressive Symptoms in Dysphoric
Mania

• Depressed mood
• Irritability
• Mood lability
• Anhedonia
• Hopelessness/helplessness
• Suicidal ideation and/or attempt
• Guilt
• Fatigue

Akiskal et al. J Affect Disord 2000
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Affective states in 908 patients during 7 years
of follow-up

Percentage of total visits
Depression
Hypomania
Euthymia
Mixed Hypomania
Suppes et al, Arch Gen Psychiatry, 2005
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Distribution of the number of lifetime MOODS-SR
manic / hypomanic items
Patients ()
30
Bipolar disorder
Recurrent major depression
20
10
0
45
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
0-4
Number of manic / hypomanic spectrum items
Recurrent major depression, n117 bipolar
disorder, n106MOODS-SR, Mood Spectrum-Self
Report questionnaire
Cassano et al 2002
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Mixed states are the best proof of the need of a
dimensional approach to complement the
categorical diagnosis

• Tonality of mood more important than polarity
• Mixed states too restrictively defined in DSM-IV
• A dimensional module should be included in the
  upcoming DSM-V and ICD-11 classifications
• Depressive mixed states poorly studied because of
  limited potential economic benefit

Henry et al, 2007 Vieta Phillips, 2007
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NOT EASY!
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Rates of Mixed States
Study Patients (N) Percent Winokur et al
(1969) 61 16 Kotin Goodwin (1972)
20 65 Himmelhoch et al (1976)
84 31 Akiskal Puzantian (1979)
60 25 Nunn (1979) 112
36 Prien et al (1988) 103
67 Post et al (1989) 48
46 DellOsso et al (1991) 108
45 McElroy et al (1995) 71
40 Cassidy et al (1998) 273
14 Akiskal et al (1998)
104 37 Dilsaver et al (1999)
105 40 Total 1149 43
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The EMBLEM Study
NETHERLANDS 41 Invs 168 Pts
NORWAY 7 Invs 30 Pts
FINLAND 10 Invs 34 Pts
BELGIUM 11 Invs 78 Pts
DENMARK 6 Invs 23 Pts

• 14 Countries
• 530 Investigators
• 3536 Patients
• 833 (24) Mixed

UK IRELAND 35 Invs 203 Pts
GERMANY 116 Invs 535 Pts
SWITZERLAND 12 Invs 95 Patients
PORTUGAL 20 Invs 74 Pts
FRANCE 126 Invs 795 Pts
SPAIN 32 Invs 312 Pts
ITALY 56 Invs 555 Pts
GREECE 58 Invs 634 Pts
Haro JM, et al. Acta Psychiatrica Scand, 2006
Goetz I, et al. Bipolar Disord, 2007 Vieta et
al, J Affect Disord, 2007.
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Mixed episodes are difficult to treat
plt0.0001 vs. manic plt0.0001 vs. manic and
plt0.05 vs. depressed
Kupfer et al. 2000
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Mixed Episodes Carry More Chronicity
35
32
30
25
22
20
Remaining Ill at 1 Year
15
10
7
5
0
Pure Mania
Pure Depression
Mixed
Index Episode
N 155.

• Keller MB et al. JAMA. 19862553138-3142.

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Long-term Characteristics of Mixed States

• Female preponderance (DellOsso et al, 1991
  Perugi et al, 1997 Akiskal et al, 1998)
• Frequent in children and adolescents (Birmaher
  Axelson 2006)
• Alcohol neuropsychiatric comorbidity
  (Himmelhoch et al, 1976)
• More past depressive than manic episodes (Perugi
  et al, 2000 Colom et al, 2006)
• Family history more often depressive than manic
  (DellOsso et al, 1991 Perugi et al, 2000)
• High switch risk to depression (Salvatore et al,
  2007)
• High suicide risk (Dilsaver et al, 1993
  Strakowski et al, 1996 Goldberg et al, 1998)
• Includes agitated depression (Benazzi, 2004)
• May respond better to antipsychotics than to
  antidepressants (Vieta, 2005)

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Response to lithium and divalproate in pure and
mixed mania
SADS-C Criteria

Mania

Improvement vs. Comparator
0.18
6.94
5.08
plt0.05
Swann et al. 1997
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Risperidone in Bipolar Mixed States
During 3 week double-blind phase
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Risperidone in the treatment of bipolar subtypes
plt0.001 vs. baseline
Vieta et al. 2001
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Olanzapine in patients with a Mixed Episode
vs Placebo3 weeks
vs Placebo4 weeks
vs Valproate3 weeks
vs Risperidone 3 weeks
vs Placebo3 weeks
Cotherapy vs Mono6 weeks
vs Haloperidol
Adol
38.5
n5
-5.92
of Patients
-7.46
-7.42
n12
Mean Change in YMRS Score
-8.39
16.7
n54
n12
-9.56
n2
-9.96
n23
n50
n25
-12.92
-12.88
-13.6
-14.0
-13.96
n121
n56
n90
n95
n23
Remission Rates
-19.66
p.378
n61
Olanzapine
Placebo
plt.001
p.588
p.274
p.184
p.203
plt.001
OLZ Li or VPA
Haloperidol
Valproate
Li or VPA
Risperidone
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Time to Relapse (Any Mood Episode)
Mixed Index Episode
Manic Index Episode
plt.001
plt.001
n144
n76
n88
n45
Tohen M et al. Presented at 24th CINP Meeting
June 20-24, 2004 Paris, France.
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Time to Manic Relapse
Tohen M et al. Presented at 24th CINP Meeting
June 20-24, 2004 Paris, France.
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Time to Depressive Relapse
Manic Index Episode
Mixed Index Episode
p.001
p.002
n144
n76
n88
n45
Tohen M et al. Presented at 24th CINP Meeting
June 20-24, 2004 Paris, France.
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Time to Mixed Relapse
Mixed Index Episode
Manic Index Episode
n144
n88
n76
n45
plt.001
p.48
Tohen M et al. Presented at 24th CINP Meeting
June 20-24, 2004 Paris, France.
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Quetiapine in rapid cycling bipolar disorder
Maximum and endpoint doses according to index
episode
N14 rapid cycling bipolar patients Follow-up
112 days Mixed n3
Vieta et al. 2002
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Adjunctive quetiapine as a long-term treatment
for bipolar I disorder
Stabilisation treatment phase
Randomised treatment phase Up to 104 weeks
Enrolment

12 to 36 weeks
Up to 7 days

Quetiapine plus mood stabiliser
Stabilisation quetiapine plus mood stabiliser
Placebo plus mood stabiliser



Enrolment
Visit S1

Stabilisation treatment phase entry

Visit 23 Final visit
Visit 1 Randomisation
Vieta E, Suppes T, et al. ECNP. Vienna. 2007.
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Quetiapine plus lithium or valproate in the
long-term treatment of bipolar disorder time to
recurrence of a mood event
1.0
Quetiapine plus lithium or divalproex (n646)
0.9
Placebo plus lithium or divalproex (n680)
0.8
0.7
0.6
Proportion of patients event free
0.5
0.4
0.3
0.2
HR 0.30 95 CI 0.24, 0.37 plt0.0001
0.1
0.0
0
10
20
30
40
50
60
70
80
90
100
110
Time (weeks)
ITT population
Vieta E, Suppes T, et al. ECNP. Vienna. 2007.
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Incidence of Mood, Mania, or Depression Event by
Index Episode
Index episode Index episode Index episode
Manic Depressed Mixed
Mood event QTP 19.5 PLA 49.6 QTP 17.4 PLA 47.4 QTP 21.0 PLA 54.0
Manic event QTP 12.8 PLA 30.2 QTP 6.0 PLA 12.2 QTP 7.8 PLA 24.3
Depressed event QTP 6.6 PLA 19.4 QTP 11.4 PLA 35.2 QTP 13.2 PLA 29.6
Outcome
Time to next mood episode hazard ratio
plt0.0001 vs placebo ITT population
Vieta et al 2007 Suppes et al, 2007.Study 126
127
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Ziprasidone in Manic and Mixed Episodes
Change in MRS Score (LOCF)
Mixed Episode
Manic Episode









Mean dose 122 mg/day
Pooled Studies Plt0.05, Plt0.01 Potkin S et al.
APA 2004.
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Aripiprazole in mixed mania(Pooled data from 3
placebo-controlled trials)
YMRS
p0.044
Jody et al. 2004
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Electroconvulsive therapy
Mania Harin et al. 1993
Mixed Episodes Ciaparelli et al. 2001
Rapid Cycling Kho. 2002
Bipolar Depression Grunhaus et al. 2002
Valenti et al. 2008
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Psychoeducation and prevention of mixed and
depressive episodes
N120
Relapsed Patients
p0.0006
p0.003
p0.01
Colom et al. 2003
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Sub-threshold mixed symptoms predict
Antidepressant-Related Mania
YMRS Items higher in the ADRM group 2 motor
activity 6 speech 8 thought content.
Frye et al. Presented at the ASBD 2006, Melbourne
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Antidepressants in mixed bipolar depression
findings from the STEP-BD

• 335 bipolar depressed patients with at least 2
  concurrent manic symptoms from the first 2000
  STEP-BD participants
• Adjunctive antidepressant use was associated with
  significantly higher mania symptom severity at
  3-month follow-up
• No significant effect of antidepressants on
  recovery likelihood

Goldberg et al, 2007
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Problems regarding the initial treatment of
bipolar disorders
Firstprescribeddrug class()
Antidepressant monotherapy twice as common as
mood stabilizers
Sedative
Lithium
Antidepressant
Anticonvulsant
Antipsychotic
n7,760 (63 of 12,237 received monotherapy)
based on Commercial and Medicare claims.
Baldessarini R, et al. Psychiatr Serv
200758(1)85-91.
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EMBLEM Study Antidepressant Medication
Rosa et al, submitted
a before b after change in oral medication
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Summary of the APA guidelines for mixed bipolar
episodes

• Treatment of Mixed Episodes
• Severe lithium or divalproate antipsychotic
• Mild lithium, divalproate or olanzapine
• Resistant carbamazepine/oxcarbazepine,
  clozapine, ECT

Hirschfeld et al. 2002
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Recommendations for the treatment of mixed
bipolar episodes

• General rules
• Predominant symptoms/subtype
• Screening and treatment of physical and
  psychiatric co-morbidities (i.e. substance abuse)
• Discontinue antidepressants and use BZD if severe
  anxiety
• Assess suicide risk and provide support

Vieta. 2005
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Recommendations for the treatment of mixed
bipolar episodes

• Specific treatment
• Low/moderate doses of atypical antipsychotics
• Combination with divalproate (or carbamazepine?)
• Lithium still has a role
• Avoid antidepressants except in very particular
  cases
• ECT often necessary

Vieta. 2005
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Conclusions

• Effective for mixed mania
• Divalproate
• Olanzapine
• Aripiprazole
• Ziprasidone
• Possibly effective for mixed mania
• Lithium
• Carbamazepine
• Oxcarbazepine
• Quetiapine
• Risperidone
• Clozapine
• ECT

• Not effective for mixed mania
• Lamotrigine
• Topiramate
• Gabapentin
• Antidepressants
• Possibly effective for mixed depression
• Quetiapine
• Olanzapine
• ECT

ADVICE COMBINATION!
Vieta. 2005
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THANK YOU!
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