WHAT

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WHATS REALLY NEW IN BIPOLAR DISORDER, OCTOBER
2005

• OR WHAT I THINK IS IMPORTANT AND NEW
• (AND SOME OLD STUFF TOO)

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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
• Admission to Medical School
• Joining PCSD

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DISCLOSURES RESEARCH, LECTURES, CONSULTANT

• Lilly, Janssen, Wyeth-Ayerst, Servier, FHH
  Foundation, Lundbeck, Organon, Alberta Heritage
  Foundation Research, Astra-Zeneca, Biovail
• Inspiration Dr. Ron Remick, Dr. Ernie McCrank,
  My patients

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MY DAILY AFFIRMATIONS

• Just for todayI wont sit in my living room all
  day in my underwear Ill move the computer into
  the bedroom

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HISTORICAL REVIEW

• Aretaeus
• Kraepelin
• Leonhard
• Goodwin
• Akiskal
• Gorman met McCrank

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WHAT I LEARNED IN MY FIRST RESEARCH PROJECT

• NOTHING IN LIFE OCCURS IN A VACUUM, NOT EVEN
  HEART DISEASE

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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

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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

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HIGHLY RECURRENT UNIPOLAR DEPRESSION (Clinical
Features)

• Family history of Bipolar Disorder (BD)
• Bipolar like age of onset (teens and 20s)
• High episode frequency (every 18-24 mo)
• Represents 25-35 of unipolar cases
• May convert to BD, but many dont, unless
  receiving antidepressants without mood stabilizer
• Patients respond to Li better than imipramine
• No category for these patients in DSM IV

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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

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PNEMONIC FOR MANIC SYMPTOMS - DIGFAST

• Distractibility
• Indiscretion (pleasurable activities)
  
• Grandiosity
  
• Flight of ideas
  
• Activity increase
  
• Sleep deficit (decreased need)
  
• Talkativeness (pressured speech)

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ALL QUESTIONS POSED TO BIPOLAR PATIENTS, ARE BEST
POSED TO THEIR RELATIVES

• At Least When It Comes To Mania

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Bipolar Disorder Symptoms areChronic and
Predominantly Depressive
146 bipolar I patientsfollowed 12.8 years
86 bipolar II patientsfollowed 13.4 years
Judd et al (2002) Archives of General Psychiatry
(59) 530-537
Judd et al (2003) Archives General Psychiatry.
(60) 261-269
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ANTIDEPRESSANT (AD) TREATMENT IN BIPOLAR VS.
UNIPOLAR DEPRESSION

• Ghaemi SN et. al. Am J Psychiatry
  161163-165,2004
• Long term safety and effectiveness of ADs is
  well established for unipolar, but not BD
  patients. Short term efficacy is clear.
• Tricyclics are not as effective for recurrence
  as Li has been demonstrated
• This study compared modern and older ADs in
  Bipolar depression (41 patients) vs. Unipolar
  depression (37 patients)

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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 3.4Xs more
  frequent in BD depression
• Cycle acceleration, rapid cycling and response
  loss were not prevented by mood stabilizers
• In general, modern ADs did not have lower
  negative outcomes than Tricyclic's

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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 ADs for Bipolar depression

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A 52 WEEK OPEN-LABEL CONTINUATION STUDY OF Ltg.
IN THE TREATMENT OF BIPOLAR DEPRESSION

• McElroy SL et. al. J Clin Psychiatry 65204-210,
  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

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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

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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

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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

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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

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CARDIAC DISEASE AND DEPRESSION
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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 161564-566,2004
• 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

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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 DCed Pramipexole because of the
  emergence of hypomania (the only adverse effect
  drop-out)

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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

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GENERAL PRINCIPLES OF MANAGEMENT

• Use life charts to monitor illness
• Remember, it is basically a depressive disorder,
  even though all of the new meds are anti-manic
  drugs
• Issue is preventing recurrence
• ADs can induce mania and/or cycling
• Keep in mind high suicide risk with BD
• Never forget the therapeutic relationship

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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

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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

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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

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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.

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TREATMENT OF BREAKTHROUGH DEPRESSION

• Li has modest effect
• Lamotrigine (Ltg) has more robust effect
• Olanzapine very small effect (perhaps through
  non-specific anti-anxiety, ant-insomnia effect)
• Quetiapine has large effect, that appears to be
  specific for depression (?study data)

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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

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• WHY IS THERE SO MUCH DISABILITY IN BIPOLAR
  DISORDER?

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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.

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Dosing Schedule
Day
8-56
5-7
4
3
2
1
600
400
300
200
100
50
Quetiapine 600 mgat bedtime
Quetiapine 300 mgat bedtime
300
300
300
200
100
50
Placebo at bedtime
Calabrese et al, APA 2004
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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
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MADRS Change From Baseline
Study Week
1
2
4
3
6
5
7
8

Mean Change From Baseline















plt0.001 vs placebo
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HAM-D Change From Baseline
Study Week
1
2
4
3
6
5
7
8

Mean Change From Baseline















plt0.001 vs placebo
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HAM-D Item 1 Change From Baseline
Study Week
1
2
4
3
6
5
7
8

Mean Change From Baseline















ITT, LOCF
plt0.01 plt0.001 vs placebo
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Response Rate (?50 decrease in MADRS)















plt0.01 plt0.001 vs placebo
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Remission Rate (MADRS ?12)














plt0.01 plt0.001 vs placebo
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Effect Size Change in MADRS
Large (0.8)
Quetiapine 600 mg
0.75
Quetiapine 300 mg
0.64
Medium (0.5)
Small (0.2)
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HAM-A Change From Baseline
Study Week
1
2
4
3
6
5
7
8

Mean Change From Baseline















plt0.05 plt0.01 plt0.001
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Pittsburgh Sleep Quality Index (PSQI) Change
From Baseline
Quetiapine 600 mg n170
Quetiapine 300 mg n172
Placebo n169
Improvement
Mean Change From Baseline


plt0.001 vs placebo
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Quality of Life (Q-LES-Q) Change From Baseline


Improvement
Mean Change From Baseline
Quetiapine 600 mg
Placebo
Quetiapine 300 mg
plt0.001 vs placebo
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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

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Common Adverse Events (gt10 patients and 2x
placebo rate)
Adverse Event Quetiapine 600 mg n180 Quetiapine 300 mg n179 Placebo n180
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
Safety, LOCF
Calabrese et al, APA 2004
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Treatment-Emergent Mania
Patients
Quetiapine 600 mg n180
Placebo n180
Quetiapine 300 mg n179
Treatment-emergent mania adverse event of mania,
or YMRS ?16 at 2 consecutive visits or last visit
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Change in Weight
Quetiapine 600 mg Quetiapine 300 mg Placebo
Mean change (kg) 1.6 1.0 0.2
gt7 increase in weight () 11 10 3
Safety, LOCF
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Serum Glucose (Fasting)
Quetiapine 600 mg Quetiapine 300 mg Placebo
Baseline mg/dL 86 87 87
Endpoint mg/dL 92 90 90

Safety, LOCF
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Sexual Adverse Events
Patients
Quetiapine 600 mg n180
Placebo n180
Quetiapine 300 mg n179
Safety, LOCF
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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

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Conclusions

• Quetiapine was found to be effective and well
  tolerated as monotherapy in bipolar depression
  with a rapid onset of action
• Quetiapine improves a broad range of mood and
  anxiety symptoms
• Quetiapine was found to be effective in improving
  the quality of sleep and quality of life in
  patients with bipolar depression

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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 ofbipolar disorder through the life
  cycle
• Atypical agents such as quetiapine (Seroquel) are
  effectivemood stabilizers

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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