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 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

CARBAMAZEPINE
400 1000 mg/d Most effective for mixed states, rapid cycling SEs 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 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!

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 - 10 mg - 15 mg - 14.9 mg - 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

Baseline 0 :
Mean Change to Endpoint (LOCF)

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

-8.1
-14.8
Olanzapine Placebo

*
-20

**

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 -10

15 mg starting dose

Percent -20 Change from -30 Baseline in Y-MRS -40 Total

-50 -60

* * * *

Olanzapine Placebo 1 2 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
-5

Study I three weeks 29.58 27.56

Study II four weeks 30.8 25.5

Mean Change -10 (LOCF)

-15 -20

-9.9 *
Psychotic Non-psychotic

-10.7 -13.0 -15.9 **

*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
0 -5 Mean Change
Manic episode n=31

28.17

-10
-15

Mixed episode n=23

-15.39
-20

-13.96

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 n=21

25.62 n=21

Mean Change -5 in HAMD21 Total

-10

-6.81

-12.29 *
-15

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. *p=0.046 HAMD21 total score 20 at baseline

Y-MRS Total: Lithium Responders vs NonResponders

Study II four weeks Baseline: 27.67
0 -3 -6

29.38
Most Recent Lithium Response: Responder n=18 Non-responder n=24

Mean
Change

-9
-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: Responder n=11

-5

Mean Change -10

-11.73
-15

Non-responder n=21

-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 % Reporting
Olanzapine (n=125) Placebo (n=129)

Somnolence Dry mouth Dizziness Asthenia

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