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AFTER ALL, THERE IS NOTHING AS INTERESTING AS
PEOPLE, AND ONE CAN NEVER STUDY THEM ENOUGH
VINCENT VAN GOGH
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BIPOLAR DISORDERS

• Closely Kept Secrets
• New Treatments

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EPIDEMIOLOGY OF BIPOLAR DISORDER

• Prevalence is underestimated at 1
• Prevalence is probably 2
• Calgary est. 2x89000017,800 citizens

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COMORBID DISORDERS

• Substance Abuse At least 61
• Alcohol, Cocaine, THC
• Effect More mixed and rapid cycling, poorer
  response to Lithium, slower time to recovery, and
  more lifetime hospitalizations
• Narcissistic PD
• Borderline PD
• 20-30 OCD, Panic Disorder

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DIFFERENTIAL DIAGNOSIS

• Schizophrenia, Schizoaffective disorder
• Substance Abuse Stimulants
• Pseudo-Unipolar Disorder
  
• Steroids, Ginseng, Valerian root
  
• Syphilis, Hyperparathyroidism
• Borderline, Narcissistic and Histrionic
  Personality disorder

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ADOLESCENCE

• Much more likely to be delusional and co morbid
  for substance abuse
• More likely to be irritable and misdiagnosed as
  conduct disorder
  

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PRECIPITANTS

• 60 of first episodes precipitated by
  psychosocial, physical, or drug causes
  30 of second episodes
• None of fourth episodes
  
• Illness starts as exogenous and becomes more
  endogenous
• Concept of kindling

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SCREENING QUESTIONS

• Have you ever had a period of a week or so when
  you felt so happy and energetic that your friends
  told you that you were talking too fast or that
  you were behaving differently and strangely?
• Has there been a period when you were so hyper
  and irritable that you got into arguments with
  people?

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SCREENING QUESTIONS

• Has anyone ever called you manic before?

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DIGFAST

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

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DISTRACTABILITY

• Were you having trouble thinking or
  concentrating?
• Was this because things around you or even your
  thoughts were getting you off track?

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INDISCRETION

• During the period we were talking about, how were
  you spending your time?
• Were you doing things that caused trouble for you
  or your family?
• Were you doing things that showed a lack of
  judgment, such as driving too fast, running red
  lights, or spending too much?
• Were you doing sexual things during this

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INDISCRETIONS

• this period that was unusual for you?

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GRANDIOUSITY

• During this period did you feel so confidant that
  you felt you could conquer the world?
• What was your best idea when you felt that way?
  
• Did you feel that you had special powers or
  abilities?
  
• Did you feel more religious than normal for you?

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FLIGHT OF IDEAS

• During this period did you have so many thoughts,
  or were they so fast, that you could barely keep
  up to them?
• Did it feel like your thoughts were racing?

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ACTIVITY INCREASE

• During that period, were you more active than
  usual?
• Were you constantly starting new projects and
  hobbies, working into the night?

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SLEEP DEFICIT

• During that period, did you need less sleep?
• Did you ever stay up all night doing all kinds of
  things, like working on projects or phoning
  people?
• Did your sleep duration become reduced and still
  you had lots of energy?

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TALKATIVENESS

• During this period, were you talking more than
  usual for you?
• Were you talking so much that people had to
  interrupt you to speak to you?
• Were you using the phone more than usual for you?

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CORROBORATION

• Denial and lack of insight rule the day

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TREATMENT OPTIONS

• Hospitalization for mania, severe depression
• Mood stabilizers, antipsychotics and
  antidepressants
  
• ECT most effective treatment
  
• Supportive psychotherapy and CBT
• Lifestyle change
  
• Substance abuse treatment

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LITHIUM CARBONATE

• 900 1500 mg/d .8-1.3 mEq/L
• Most effective medication
  
• SEs include teratogenicity, tremor, renal
  dysfunction, acne, hypothyroidism, gastric upset,
  cardiac conduction problems, cognitive impairment
  
• Serum TSH, Cr, EKG, electrolytes pre and TSH, Cr
  q6mo.
• Mogen Schou rule, Always treat SEs

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CARBAMAZEPINE

• 400 1000 mg/d
• Most effective for mixed states, rapid cycling
  
  
• SEs sedation, ataxia, aplastic anemia,
  agranulocytosis
  
• Check CBC q3mo ?

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VALPROATE

• 500 2000 mg/d Highest blood level for effect.
  Highest dose is 60 mg/kg/d
• SEs GI upset, weight gain, alopecia,
  teratogenicity, liver problems
  
• Best for mixed states, rapid cycling, secondary
  mania. Ineffective for depression
• Selenium for hair loss
• PCOD!

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ATYPICAL ANTIPSYCHOTICS

• Olanzepine 2.5-20 mg/d very effective
  significant wt gain and lipid problems in some
• Risperdal - .5-4.0 mg/d more EPS and increased
  prolactin in some
• Clozapine - For truly refractory patient, but can
  be remarkably effective. Slow response, serious
  SE profile and significant wt gain

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Olanzepine Efficacy for Mania Two
Placebo-Controlled Studies

• Both double-blind, placebo-controlled, inpatient
• Study I 3 weeks
• Study II 4 weeks
• Olanzapine dosage 5-20 mg/day
• Starting daily dose Study I - 10 mg Study II -
  15 mg
• Mean modal daily dose Study I - 14.9 mg Study
  II - 16.4 mg
• DSM-IV Bipolar I Disorder, manic or mixed
• Lorazepam use limited to initial study phase

Study I -Tohen et al, Am J Psych 1999
Study II- Tohen et al, XI World Congress of
Psychiatry, Hamburg Germany, 1999
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Olanzepine Grp. Superior YMRS Scores
Study Ithree weeks
Study IIfour weeks
28.7
27.7
28.8
29.4
Baseline
n70
n66
n54
n56
Mean Change to Endpoint (LOCF)


Y-MRS Total score designated a priori as primary
outcome measure.p0.02, plt0.001 LOCF
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Antimanic Efficacy of Olanzapine Is Significant
Starting at the First Assessment (Week 1 Y-MRS)
0
15 mg starting dose
-10
PercentChangefromBaselinein Y-MRSTotal
-20

-30

-40


-50
Placebo
-60
1
2
3
4
Week of Study
p lt .05. Response curve illustrates four week
study of olanzapine (n54) vs placebo (n56) for
acute mania (four week study II)
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Similar Y-MRS Improvement in Non-Psychotic and
Psychotic Subjects
Study I three weeks
Study II four weeks
29.58
27.56
30.8
25.5
Baseline
MeanChange(LOCF)

-9.9
-10.7
-13.0
Psychotic

-15.9
Non-psychotic
p0.88 p0.41. No difference in mania
improvement among olanzapine-treated subjects
with and without psychotic features
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Y-MRS TotalManic vs Mixed Episodes
Study II four weeks
Baseline
28.17
29.19
0
Manic episoden31
-5
Mean Change
-10
Mixed episoden23
-13.96
-15
-15.39
-20
There was no difference in antimanic response
(Y-MRS Total beginning to endpoint improvement,
four-week study II) between olanzapine-treated
patients in manic or mixed episodes (p.681)
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In Patients Presenting with Depressive
SymptomsHAMD Improved During Olanzapine
Treatment
26.57
25.62
Baseline
n21
n21
Mean Change in HAMD21 Total
Olanzapine

Placebo
In patients with depressive symptoms,
olanzapine-treated patients had a statistically
significantly greater mean improvement in HAMD21
total scores compared to placebo-treated patients
in this four-week study II acute mania trial.
p0.046 HAMD21 total score ?20 at baseline
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Y-MRS Total Lithium Responders vs Non-Responders
Study II four weeks
27.67
29.38
Baseline
0
Most Recent Lithium Response
-3
Respondern18
-6
Mean Change
-9
Non-respondern24
-12
-14.00
-15
-15.88
-18
There was no difference in antimanic response
(Y-MRS Total beginning to endpoint improvement,
four-week study II) between olanzapine-treated
patients with history of good vs poor response to
lithium treatment for mania (p.641)
Baker RW et al. Bipolar Disorders Conference.
Phoenix, Arizona, January 2000.
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Y-MRS Total Valproic Acid Respondersvs
Non-Responders
Study II four weeks
30.45
29.48
Baseline
0
Most RecentValproic AcidResponse
-5
Mean Change
Respondern11
-10
Non-respondern21
-11.73
-15
-14.67
-20
There was no difference in antimanic response
(Y-MRS Total beginning to endpoint improvement,
four-week study II) between olanzapine-treated
patients with history of good vs poor response to
valproate treatment for mania (p.546)
Baker RW et al. Bipolar Disorders Conference.
Phoenix, Arizona, January 2000
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Treatment-Emergent Adverse Effects During Acute
Mania Trials
Event
Reporting
Placebo(n129)
Olanzapine (n125)
Somnolence Dry mouth Dizziness Asthenia
35 22 18 15
13 7 6 6

• These four events were the only ones
  significantly more common (plt0.05) in
  olanzapine-treated subjects

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Persisting Improvement in Depression Ratings
During Extended Olanzapine Treatment
Weeks of Open-Label Therapy
0
10
20
30
40
50
0
-1
MeanChange inHAMD21Total Score(LOCF)
-2
-3
-4
-5
-6
-7
A significant improvement in depressive symptoms
as measured by the HAMD21 was observed from
baseline (12.17) to endpoint (mean change
-5.77, plt.001). Tohen MF et al, European
Neuropsychopharmacol 9(Suppl5)S247, 1999
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GABAPENTIN

• Anticonvulsant, least effective new drug
• Most helpful with anxiety, insomnia, pain
• May cause persistent sedation
• Excreted by kidneys only, no drug interaction
• 1200 to 4000 mg/d.

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LAMOTRIGINE

• Anticonvulsant, best for Bipolar depression
• Improved cognition, excellent tolerance, serious
  autoimmune rash
• Valproate interaction
• 12.5 to 25 mg/wk increments. Dose range of 75 to
  300mg/d.

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TOPYRAMATE

• May augment other medications?
• Significant cognitive ill effect and paresthesiae
• BUT SIGNIFICANT WEIGHT LOSS, AND NEVER
  UNDERESTIMATE LOOKING GOOD !!!!!!
• 50 mg qhs, increase by 50 mg/wk. in divided doses
  to maximum of 200 mg bid

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THYROID AUGMENTATION

• TSH is not reliable indicator of subclinical
  hypothyroidism in mood disorder patients
• T3 and T4 in lower range of normal cause
  cognitive impairment, relapse and lethargy
• Supplemental T4 caused 10/11 Li refractory to
  respond
• Large study showed no bone density effect of high
  dose T4 treatment

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NEVER GIVE UP

• It will help patient to be inspired by us, rather
  than the other way around