“AFTER ALL, THERE IS
NOTHING AS INTERESTING AS
PEOPLE, AND ONE CAN
NEVER STUDY THEM
ENOUGH”
VINCENT VAN GOGH
BIPOLAR DISORDERS
• Closely Kept Secrets
• New Treatments
EPIDEMIOLOGY OF
BIPOLAR DISORDER
• Prevalence is underestimated at 1%
• Prevalence is probably 2%
• Calgary est. 2%x890000=17,800 citizens
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
DIFFERENTIAL DIAGNOSIS
•
•
•
•
•
•
Schizophrenia, Schizoaffective disorder
Substance Abuse – Stimulants
Pseudo-Unipolar Disorder
Steroids, Ginseng, Valerian root
Syphilis, Hyperparathyroidism
Borderline, Narcissistic and Histrionic
Personality disorder
ADOLESCENCE
• Much more likely to be delusional and co
morbid for substance abuse
• More likely to be irritable and misdiagnosed
as conduct disorder
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
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?
SCREENING QUESTIONS
• Has anyone ever called you manic before?
DIGFAST
•
•
•
•
•
•
•
Distractibility
Indiscretion (pleasurable activities)
Grandiosity
Flight of ideas
Activity increase
Sleep deficit (decreased need)
Talkativeness (pressured speech)
DISTRACTABILITY
• Were you having trouble thinking or
concentrating?
• Was this because things around you or even
your thoughts were getting you off track?
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
INDISCRETIONS
this period that was unusual for you?
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?
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?
ACTIVITY INCREASE
• During that period, were you more active
than usual?
• Were you constantly starting new projects
and hobbies, working into the night?
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?
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?
CORROBORATION
• Denial and lack of insight rule the day
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
LITHIUM CARBONATE
• 900 – 1500 mg/d .8-1.3 mEq/L
• Most effective medication
• SE’s 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 SE’s”
CARBAMAZEPINE
• 400 – 1000 mg/d
• Most effective for mixed states, rapid
cycling
• SE’s – sedation, ataxia, aplastic anemia,
agranulocytosis
• Check CBC q3mo ?
VALPROATE
• 500 – 2000 mg/d; Highest blood level for
effect. Highest dose is 60 mg/kg/d
• SE’s – GI upset, weight gain, alopecia,
teratogenicity, liver problems
• Best for mixed states, rapid cycling,
secondary mania. Ineffective for depression
• Selenium for hair loss
• PCOD!
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
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:
– Mean modal daily dose:
Study I
Study II
Study I
Study II
•
DSM-IV Bipolar I Disorder, manic or mixed
•
Lorazepam use limited to initial study phase
- 10 mg
- 15 mg
- 14.9 mg
- 16.4 mg
* Study I -Tohen et al, Am J Psych 1999;
** Study II- Tohen et al, XI World Congress of Psychiatry, Hamburg Germany, 1999
Olanzepine Grp. Superior YMRS
Scores
Mean Change to
Endpoint (LOCF)
Baseline
0
:
Study I
three weeks
28.7
27.7
n=70
n=66
Study II
four weeks
28.8
29.4
n=54
n=56
-4.9
-10
-10.3
*
-20
-8.1
-14.8
**
Olanzapine
Placebo
Y-MRS Total score designated a priori as primary outcome measure.
*p=0.02, **p<0.001; LOCF
Antimanic Efficacy of Olanzapine Is
Significant Starting at the First Assessment
(Week 1 Y-MRS)
0
15 mg starting dose
-10
Percent -20
Change
from
-30
Baseline
in Y-MRS -40
Total
-50
*
*
*
Olanzapine
Placebo
*
-60
1
2
3
4
Week of Study
* p < .05. Response curve illustrates four week study of olanzapine (n=54) vs placebo
(n=56) for acute mania (four week study II)
Similar Y-MRS Improvement in
Non-Psychotic and Psychotic
Subjects
Baseline
:0
Study I
three weeks
29.58
27.56
Study II
four weeks
30.8
25.5
-5
Mean
Change -10
(LOCF)
-15
-9.9 *
Psychotic
Non-psychotic
-10.7
-13.0
-15.9 **
-20
*p=0.88; **p=0.41. No difference in mania improvement among olanzapinetreated subjects with and without psychotic features
Y-MRS Total:
Manic vs Mixed Episodes
Study II four weeks
Baseline:
29.19
28.17
0
Manic episode
n=31
-5
Mean
Change
-10
Mixed episode
n=23
-15
-15.39
-13.96
-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)
Symptoms‡
HAMD Improved During Olanzapine
Treatment
Baseline:
0
26.57
25.62
n=21
n=21
Mean
Change -5
in
HAMD21
Total
-6.81
-10
-12.29 *
Olanzapine
Placebo
-15
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.
*p=0.046 ‡HAMD21 total score 20 at baseline
Y-MRS Total:
Lithium Responders vs NonResponders
Study II four weeks
Baseline:
27.67
29.38
0
Most Recent
-3
Lithium Response:
Responder
n=18
-6
Mean
Change
-9
Non-responder
n=24
-12
-15
-18
-14.00
-15.88
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.
Y-MRS Total: Valproic Acid
Responders
vs Non-Responders
Study II four weeks
Baseline:
30.45
0
29.48
Most Recent
Valproic Acid
Response:
-5
Responder
n=11
Mean
Change -10
Non-responder
n=21
-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
Treatment-Emergent Adverse
Effects During Acute Mania
Trials
Event
Somnolence
Dry mouth
Dizziness
Asthenia
% Reporting
Olanzapine
(n=125)
Placebo
(n=129)
35%
22%
18%
15%
13%
7%
6%
6%
These four events were the only ones significantly more common (p<0.05) in
olanzapine-treated subjects
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.
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.
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
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
NEVER GIVE UP
It will help patient to be inspired by
us, rather than the other way around