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“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: Study I - 10 mg
Study II - 15 mg– Mean modal daily dose: Study I - 14.9
mgStudy 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
Olanzepine Grp. Superior YMRS Scores
Y-MRS Total score designated a priori as primary outcome measure.*p=0.02, **p<0.001; LOCF
-10.3
-14.8
-4.9
-8.1
-20
-10
0
OlanzapinePlacebo
Study Ithree weeks
Study IIfour weeks
28.7 27.7 28.8 29.4Baseline: n=70 n=66 n=54 n=56
*
**
Mea
n C
han
ge
to
En
dp
oin
t (L
OC
F)
Antimanic Efficacy of Olanzapine Is Significant Starting at the First Assessment
(Week 1 Y-MRS)
-60
-50
-40
-30
-20
-10
0
PlaceboOlanzapine
1
*
**
*
* p < .05. Response curve illustrates four week study of olanzapine (n=54) vs placebo (n=56) for acute mania (four week study II)
15 mg starting dose
Week of Study
2 3 4
PercentChange
fromBaselinein Y-MRS
Total
-20
-15
-10
-5
0
Similar Y-MRS Improvement in Non-Psychotic and Psychotic
Subjects
*p=0.88; **p=0.41. No difference in mania improvement among olanzapine-treated subjects with and without psychotic features
MeanChange(LOCF)
Study Ithree weeks
Study IIfour weeks
**
*
Non-psychoticPsychotic
-9.9-10.7
-15.9
-13.0
29.58 27.56 30.8 25.5Baseline:
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)
Y-MRS Total:Manic vs Mixed Episodes
-20
-15
-10
-5
0
Mean Change
Manic episoden=31
Mixed episoden=23
Baseline: 28.17 29.19
-15.39-13.96
Study II four weeks
In Patients Presenting with Depressive Symptoms‡
HAMD Improved During Olanzapine Treatment
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
-12.29
-6.81
-15
-10
-5
026.57 25.62Baseline:
n=21 n=21
*OlanzapinePlacebo
Mean Change
in HAMD21 Total
-18
-15
-12
-9
-6
-3
0
Mean
Change
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)
Respondern=18
Non-respondern=24
Most Recent
Lithium Response:
Y-MRS Total: Lithium Responders vs Non-
Responders27.67 29.38
-14.00-15.88
Baseline:Study II four weeks
Baker RW et al. Bipolar Disorders Conference. Phoenix, Arizona, January 2000.
Y-MRS Total: Valproic Acid Responders
vs Non-Responders
-20
-15
-10
-5
0
-11.73
-14.67
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)
30.45 29.48
Mean Change
Baseline:Study II four weeks
Respondern=11
Non-respondern=21
Baker RW et al. Bipolar Disorders Conference. Phoenix, Arizona, January 2000
Most RecentValproic Acid
Response:
Treatment-Emergent Adverse Effects During Acute Mania
Trials
These four events were the only ones significantly more common (p<0.05) in olanzapine-treated subjects
Event % ReportingPlacebo(n=129)
SomnolenceDry mouthDizzinessAsthenia
35%22%18%15%
13%7%6%6%
Olanzapine (n=125)
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