“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