1. “AFTER ALL, THERE IS NOTHING AS INTERESTING AS PEOPLE, AND ONE CAN NEVER STUDY THEM ENOUGH” VINCENT VAN GOGH

2. BIPOLAR DISORDERS
Closely Kept Secrets
New Treatments

3. EPIDEMIOLOGY OF BIPOLAR DISORDER
Prevalence is underestimated at 1%
Prevalence is probably 2%
Calgary est. 2%x890000=17,800 citizens

4. 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

5. DIFFERENTIAL DIAGNOSIS
Schizophrenia, Schizoaffective disorder
Substance Abuse – Stimulants
Pseudo-Unipolar Disorder
Steroids, Ginseng, Valerian root
Syphilis, Hyperparathyroidism
Borderline, Narcissistic and Histrionic Personality disorder

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

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

8. 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?

9. SCREENING QUESTIONS
Has anyone ever called you manic before?

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

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

12. 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

13. INDISCRETIONS
this period that was unusual for you?

14. 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?

15. 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?

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

17. 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?

18. 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?

19. CORROBORATION
Denial and lack of insight rule the day

20. 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

21. 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”

22. CARBAMAZEPINE
400 – 1000 mg/d
Most effective for mixed states, rapid cycling
SE’s – sedation, ataxia, aplastic anemia, agranulocytosis
Check CBC q3mo ?

23. 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!

24. ATYPICAL ANTIPSYCHOTICS
Olanzepine – mg/d; very effective; significant wt gain and lipid problems in some
Risperdal 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

25. 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 mg Study II mg
DSM-IV Bipolar I Disorder, manic or mixed
Lorazepam use limited to initial study phase
Background: 100+ psychiatrists in both inpatient and outpatient settings were interviewed in 1999 on their key goals of therapy in treating bipolar patients in manic or mixed episodes.
Key Point: Olanzapine’s efficacy for bipolar mania was demonstrated in two placebo-controlled registration trials. Both trials enrolled initially inpatient subjects in an acute manic or mixed episode, with or without psychotic features. Though the trials had very similar designs, there were two important differences:
· Study I lasted three weeks but study II lasted four weeks.
· Starting olanzapine dose was 10 mg in study I, but 15 mg
in study II, which appeared to produce more robust results.
Background: Both trials were multicenter studies; study I was conducted in and study II in These were double-blind, placebo-controlled, parallel group studies of 3 and 4 weeks duration. Subjects were initially inpatient, but responders could be discharged after one week. Medically unstable, organically impaired, or substance-dependent subjects were excluded. Patients in their first episode of mania were excluded from study II.
Patients were randomly assigned to therapy. After a two- to four-day screening period, qualified patients were assigned to either olanzapine or placebo. Following the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine 5 mg or placebo) within the allowed range of 1 to 4 capsules/day. Limited use of adjunctive lorazepam was allowed; the second study was the more restrictive: Max 2 mg/day for the first four days, max 1 mg/day for the next six days, none after day 10.
All randomized patients were included in statistical analyses; ANOVA was used for continuous variables and Fishers exact test for categorical ones; p values are two-tailed with protocol-specified significance level of 0.05.
Sources:
Study I (HGEH): Tohen M et al. Olanzapine versus placebo in the treatment of acute mania. Am J Psych 156: , 1999
Study II (HGGW): Tohen M et al. Olanzapine in the treatment of mania: a placebo-controlled four-week study poster presentation, XI World Congress of Psychiatry, Hamburg, Germany, 1999
* Study I -Tohen et al, Am J Psych 1999; ** Study II- Tohen et al, XI World Congress of Psychiatry, Hamburg Germany, 1999

26. Olanzepine Grp. Superior YMRS Scores
Study I three weeks
Study II four weeks
Baseline:
28.7
27.7
28.8
29.4
n=70
n=66
n=54
n=56
Mean Change to Endpoint (LOCF)
Key point: In both mania studies, olanzapine was superior to placebo for the reduction of manic symptoms. These studies demonstrated and replicated the finding that olanzapine is effective for treating manic or mixed episodes associated with bipolar disorder. This primary finding allowed application for an indication for the treatment of acute mania in the United States.
Background: Efficacy analysis included all subjects with baseline rating and at least one follow-up rating (study I, n=136; study II, n=110). In the three-week study I, olanzapine-treated patients improved by 10.3 points (36%) from baseline to endpoint, versus 4.9 points (18%) in the placebo group. In the four-week study II, olanzapine treated-patients improved by 14.8 points (51%) from baseline to endpoint, versus 8.1 points (28%) in the placebo group.
Non-medication treatments (eg, inpatient psychotherapies) were provided to both groups. * **
Y-MRS Total score designated a priori as primary outcome measure. *p=0.02, **p<0.001; LOCF

27. Percent Change from Baseline in Y-MRS Total
Antimanic Efficacy of Olanzapine Is Significant Starting at the First Assessment (Week 1 Y-MRS)
15 mg starting dose
-10
Percent Change from Baseline in Y-MRS Total
-20 *
-30 *
-40 *
Olanzapine *
Key point: Prompt onset of mood-stabilizing effects in mania may be relevant to safety, patient functioning, and length of hospitalization. In the placebo-controlled mania studies, ratings of mania were done at weekly intervals. In study II, with a starting olanzapine dose of 15 mg, efficacy was prompt and superiority over placebo was noted at the first assessment, one week. Olanzapine can have prompt anti-manic effects.
Background: In study II, the starting dose was 10 mg. YMRS improvement was noted at each assessment starting at week 1, which was statistically significant within group but separated from placebo only at the third assessment. The more robust effects evident in the study with a 15 mg starting dose suggest that this is the appropriate starting dose for patients similar to those in these trials: Acutely manic inpatients, relatively physically healthy, treated with monotherapy.
In placebo-controlled trials, the earliest separation of valproic acid from placebo on the primary efficacy measure (Mania Rating Scale) was at day 10 (Bowden et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 271: , 1994). Some have suggested that high-dose “loading” techniques may produce quicker results with lithium or valproic acid, but time-to-separation from placebo is not available for these techniques.
-50
Placebo
-60 1 2 3 4
Week of Study
* p < Response curve illustrates four week study of olanzapine (n=54) vs placebo (n=56) for acute mania (four week study II)

28. Similar Y-MRS Improvement in Non-Psychotic and Psychotic Subjects
Study I
three weeks
Study II
four weeks
Baseline:
29.58
27.56
30.8
25.5
Mean Change (LOCF)
-9.9 *
Key point: While olanzapine’s efficacy for psychosis is well known, it is important to note its wider effects for mania. This graph compares improvement in Y-MRS for the 2 studies between subjects with and without baseline psychotic features. Improvement was statistically similar across the 2 groups in both studies, suggesting that olanzapine is not limited in usefulness to psychotic patients, but has broad anti-manic effects.
Background: Baseline mean Y-MRS total scores for olanzapine-treated subjects:
with psychosis (n) w/o psychosis (n)
Study I
Study II
-10.7
-13.0
Psychotic **
-15.9
Non-psychotic
*p=0.88; **p=0.41. No difference in mania improvement among olanzapine-treated subjects with and without psychotic features

29. Y-MRS Total: Manic vs Mixed Episodes
Study II four weeks
Baseline:
29.19
28.17 -5
Manic episode n=31
Mean
Change
-10
Mixed episode n=23
Key point: Olanzapine is useful across a broad range of mania subtypes. A multicenter comparison of lithium and valproic acid revealed that patients with mixed or depressive mania did not respond as well to lithium, and those with more classic mania did not respond as well to valproic acid.
This slide from study II illustrates that mania improved similarly between those subjects diagnosed at baseline with manic episode and those in a mixed episode. Therefore, it appears that olanzapine will be useful in both subgroups.
Background: Similarly in study I, there was no significant difference in mean Y-MRS change from baseline between patients with pure and mixed mania treated with olanzapine. However, only 17% of subjects in that study were in a mixed state.
A secondary analysis of the valproic acid vs lithium vs placebo study in acute mania demonstrated that “depressive symptoms were associated with poor antimanic response to lithium,” and suggested better relative efficacy with valproic acid for depressive mania and lithium for classic mania. By contrast, olanzapine appears to have comparable efficacy in both groups.
Reference: Swann AC et al. Depression during mania, treatment response to lithium or divalproex. Arch Gen Psych 54:37-42,1997
-15
-13.96
-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)

30. Mean Change in HAMD21 Total
In Patients Presenting with Depressive Symptoms‡ HAMD Improved During Olanzapine Treatment
Baseline:
26.57
25.62
n=21
n=21
Mean Change in HAMD21 Total
Key point: Olanzapine does not precipitate depressive symptoms during acute mania treatment, and in fact, average depression ratings declined. What about patients with significant baseline depressive symptoms? In study II, a large number of subjects had depressive mania. Forty-two subjects had baseline Hamilton ratings in the moderately to severely depressed range, ie, HAMD >20. A post-hoc analysis in this group showed that improvement on olanzapine was significantly greater than on placebo. Olanzapine did not induce depression, and the group with significant baseline depressive symptoms improved during olanzapine treatment.
Background: Will a drug that improves depressive symptoms in manic patients carry the risks of an antidepressant? In the treatment of bipolar patients, antidepressant drugs are thought to pose a risk for precipitating or exacerbating mania. Mania precipitation has been reported among antipsychotic drugs such as risperidone, and in a number of anecdotal reports for olanzapine. It can be difficult to interpret uncontrolled case reports because of issues of natural history of illness and confounding factors such as withdrawal from other treatments. These placebo-controlled trials offered the opportunity to assess whether olanzapine worsened mania, in a group that presumably would be at high risk if worsening were an issue. Y-MRS worsening occurred more often on placebo than olanzapine, arguing that rather than worsening mania, olanzapine may diminish likelihood of exacerbation.
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

31. Y-MRS Total: Lithium Responders vs Non-Responders
Study II four weeks
Baseline:
27.67
29.38
Most Recent
Lithium Response: -3
Responder n=18 -6
Mean
Change -9
Non-responder n=24
Key point: With the availability of an additional mood stabilizer for mania, it is clinically relevant whether its usefulness will extend to patients with incomplete response to their current primary mood stabilizer. While the placebo-controlled trials of olanzapine do not definitively answer the question, study II did collect information on recent results of mood- stabilizer trials for its subjects. As the slide illustrates, the magnitude of improvement was similar between those with past good response to lithium and those with past poor response. This provides hope that olanzapine will be useful for some patients with incomplete response to lithium.
Background: Study I did not record information on past treatment response adequate to address this question. In study II, investigators recorded, when known, the results of the most recent treatment with lithium, which was not necessarily in the present episode.
Baker RW et al. Mania impairment during olanzapine treatment is comparable across patient subtypes. Bipolar Disorders Conference. Phoenix, Arizona, January 19-21, 2000
-12
-15
-14.00
-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.

32. Y-MRS Total: Valproic Acid Responders vs Non-Responders
Study II four weeks
30.45
29.48
Baseline:
Most Recent Valproic Acid Response: -5
Mean
Change
Responder n=11
-10
Non-responder n=21
-11.73
Key point: This slide illustrates that the magnitude of improvement was similar between those with past good response to valproic acid and those with past poor response. This provides hope that olanzapine will be useful for some patients with incomplete response to valproic acid.
Background: Study I did not record information on past treatment response adequately to address this question. In study II, investigators recorded, when known, the results of the most recent treatment with valproic acid, which was not necessarily in the present episode.
Baker RW et al. Mania impairment during olanzapine treatment is comparable across patient subtypes. Bipolar Disorders Conference. Phoenix, Arizona, January 19-21, 2000
-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

33. 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%
Key point: Olanzapine was well-tolerated; these are the only 4 treatment-emergent adverse events that were significantly more common on olanzapine than on placebo.
Background: Somnolence was the most commonly reported treatment-emergent adverse event. Arguably this “adverse event” was clinically helpful to the symptoms of mania, especially as sleep deprivation may worsen mania. The incidence of somnolence in this study was substantially higher than the 16-26% observed on olanzapine in large-scale schizophrenia trials. Given characteristically increased energy and decreased need for sleep in mania, one is tempted to speculate that the incidence of “somnolence” is increased in part by patients’ misinterpretation of normalizing sleep, energy, and alertness.
These four events were the only ones significantly more common (p<0.05) in olanzapine-treated subjects

34. Weeks of Open-Label Therapy Mean Change in HAMD21 Total Score (LOCF)
Persisting Improvement in Depression Ratings During Extended Olanzapine Treatment
Weeks of Open-Label Therapy 10 20 30 40 50 -1
Mean Change in HAMD21 Total Score (LOCF) -2 -3 -4
Key point: On average depressive symptoms also improved rapidly and then remained stable during open label treatment with olanzapine.
Background: Average baseline depression rating was modest, and remained low throughout the study. About one-third of subjects were treated with adjunctive fluoxetine; as a group they had improved from baseline prior to fluoxetine prescription and continued to improve afterward. Compared to subjects not taking fluoxetine, those on olanzapine-fluoxetine combination had some increase in rates of certain side effects such as insomnia and nausea.
Tohen MF et al. Long-term olanzapine treatment: Efficacy and safety in manic patients with and without psychotic features. European Neuropsychopharmacol 9(Suppl5):S247, 1999 -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, p<.001). Tohen MF et al, European Neuropsychopharmacol 9(Suppl5):S247, 1999

35. 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.

36. 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.

37. 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

38. 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

39. NEVER GIVE UP
It will help patient to be inspired by us, rather than the other way around