UpgradingUpgrading
Your BrainYour Brain
MadeMade
EasyEasy
New Treatment Options for
Patients with Bipolar
Disorders
Terence A. Ketter, M.D.
Disclosure InformationDisclosure Information
Research Support / Consultant / SpeakerResearch Support / Consultant / Speake...
OverviewOverview
 Mood Stabilizers
– A - Lithium, divalproex, carbamazepine
– B - Lamotrigine
 New Anticonvulsants
– Oxc...
Agents Approved for Bipolar I Disorder in the U.S.Agents Approved for Bipolar I Disorder in the U.S.
Acute Mania
Year Drug...
Overview of 20 Acute Mania StudiesOverview of 20 Acute Mania Studies
Response Rates
5 Combination
Therapy Studies
15 Monot...
Summary of 15 Acute Mania Monotherapy StudiesSummary of 15 Acute Mania Monotherapy Studies
Response Rates
Atypical Antipsy...
22
36
25
29
24
25
19
29
11
35
4
35
8
25
0%
10%
20%
30%
40%
50%
60%
Q T P
600mg
Q TP
300mg
LTG
200mg
OFC LTG
50mg
Li Pax Li...
Response Rates
Pope HG, et al. Arch Gen Psychiatry 1991;48:62-8. Bowden CL, et al. JAMA 1994;271:918-24.
PercentResponders...
Acute Antimanic Effect Size Increases with Serum
Valproate Concentration in Controlled Studies
Allen MH et al., Am J Psych...
Response Rates
PercentResponders
(≥50%SADS-CMRSdecrease)
*p < 0.05 vs placebo
Divalproex Placebo
0
10
20
30
40
50
60
34%
4...
Baseline MRS 26.6 for both Placebo and Divalproex ER
Placebo (n = 177)
Divalproex ER 3065 mg/d, 95.9 ug/mL (n = 187)
-14
-...
Divalproex ER Dosing RegimenDivalproex ER Dosing Regimen
 Initiated at 25mg/kg/day, rounded up to nearest 500mg
 Additio...
Divalproex ERDivalproex ER
Mean Doses & LevelsMean Doses & Levels
 Target serum valproate level 85 – 125 ug/mL
Time
Dose
...
Adverse Effect DiscontinuationsAdverse Effect Discontinuations
and Serum Valproate Levelsand Serum Valproate Levels
Group
...
VPA + Antipsychotic Superior to Antipsychotic
Monotherapy
* 20 mg/kg/day
Muller-Oerlinghausen et al., J Clin Psychopharmac...
Response Rates
Percentresponders
(≥50%YMRSdecrease)
22%
42%
P<0.01
Extended-Release
Carbamazepine
Placebo Extended-Release...
Design N Finding N Finding
Monotherapy vs PBO 443 CBZ > PBO 1-2
- -
Monotherapy vs NL/Li 173 CBZ = NL/Li 3-6
90 OXC = NL/L...
7-Week Double-Blind Oxcarbazepine
vs Placebo Monotherapy in Acute Pediatric Mania
Wagner KD, et al. Am J Psychiatry 2006:1...
Weight Gain During Maintenance TreatmentWeight Gain During Maintenance Treatment
Divalproex Lithium Placebo
0
5
10
15
20
2...
Bipolar Disorder Symptoms areBipolar Disorder Symptoms are
Chronic and Predominantly DepressiveChronic and Predominantly D...
Polarity of Index Episode Predicts Polarity ofPolarity of Index Episode Predicts Polarity of
Relapse: Relapses on PlaceboR...
Controlled Trials in Acute Bipolar DepressionControlled Trials in Acute Bipolar Depression
Better than Placebo
Imipramine1...
Course and Subtype Depressive
Burden
Switch
Risk
Antidepressant
Risk:Benefit Ratio
Rapid Cycling Bipolar I Higher Higher L...
Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward.
Davis LL, et al. J Affective Disord 2005...
Oligomenorrhea and HyperandrogenismOligomenorrhea and Hyperandrogenismaa
with Valproatewith Valproate
**p <0.002 Joffe H, ...
“Unfortunately, there’s no cure -
there’s not even a race for a cure.”
AEDs Marketed in the U.S.AEDs Marketed in the U.S.
Year Drug
1981 Clorazepate
1993 Felbamate
1993 Gabapentin
1994 Lamotrig...
Placebo Controlled Gabapentin Trials
Diagnosis N Dose Finding
Bipolar Disorder - Ineffective as Primary Treatment
Mania (a...
"Read the instructions very, very, very, very carefully."
Gradual Lamotrigine Titration Crucial toGradual Lamotrigine Titration Crucial to
Reduce Risk of RashReduce Risk of Rash
1
...
“If you remember,
I did mention possible side-effects.”
Ketter TA, et al. J Clin Psychiatry 2005;66:642-5.
Slower Titration and Dermatology PrecautionsSlower Titration and Dermat...
Ginsberg L, et al. 156th Annual Meeting of American Psychiatric Association; San Francisco, Calif; May 17-22, 2003.
Weight...
Calabrese et al. J Clin Psychiatry. 1999;60:79-88.Calabrese et al. J Clin Psychiatry. 1999;60:79-88.
Last Observation Carr...
16-Week Randomized Open Adjunctive Therapy of16-Week Randomized Open Adjunctive Therapy of
Treatment Resistant Bipolar Dep...
Goodwin et al. J Clin Psychiatry 2004;65:432-41.
Lamotrigine and LithiumLamotrigine and Lithium
Effective in Bipolar I Pro...
Some patients considered intervention-free for depression could have had intervention for mania.
Goodwin et al. J Clin Psy...
Some patients considered intervention-free for mania could have had intervention for depression.
Goodwin et al. J Clin Psy...
6-Week Lamotrigine Versus Gabapentin Versus
Placebo in Treatment Resistant Mood Disorders
Lamotrigine Gabapentin Placebo
0...
Lamotrigine Effective in Rapid Cycling BPII
41%
46%
18%
*
* p < 0.05.
Calabrese JR, et al. J Clin Psychiatry 2000;61:841-5...
Lamotrigine Ineffective in Acute Mania
44%
42%
46%
*
* p < 0.05 vs PBO.Similar percentages of patients had MRS increases w...
Lamotrigine Stabilizes Mood From Below Baseline?Lamotrigine Stabilizes Mood From Below Baseline?
Ketter TA, Calabrese JR. ...
”Being on a diet does not give you the right to
go berserk in a donut shop."
Placebo Controlled Topiramate Trials
Diagnosis N Dose Finding
Bipolar Disorder - Ineffective as Monotherapy in Adult Mania...
Weight Loss with Zonisamide in Obesity
Gadde KM, et al. JAMA. 2003;289:1820-5.
Obese (No psychiatric disorder) Obese Euthy...
Primary Therapies for Bipolar Disorders
 Divalproex - Mania, ± maintenance, ± rapid cycling
 Carbamazepine - Mania, ± ma...
New Anticonvulsants Not (Yet) Proven
Effective in Mania
 Oxcarbazepine - B, underpowered active-comparator monotherapy
st...
“I’m going to prescribe something that works like
aspirin, but costs much, much more.”
Suppes T, et al. Am J Psychiatry 1999;156:1164-9.
12-Month Randomized Adjunctive Clozapine in12-Month Randomized Adjunctiv...
Smulevich AB, et al. Eur Neuropsychopharmacol 2005;15:75-84.Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65.
Young ...
Yatham LN, et al. Br J Psychiatry 2003;182:141-7.
PercentResponders
(≥50%YMRSdecrease)
38%
42%
59%57%
p < 0.05
p < 0.06
Ri...
Olanzapine Placebo Olanzapine Placebo
0
10
20
30
40
50
60
70
PercentResponse
(≥50%YMRSdecrease)
49%
43%
65%
24%
Young Mani...
Response Rates
Olanzapine vs Divalproex Acute Mania Studies
Zajecka J, et al. J Clin Psychiatry 2002;63:1148-55.
PercentRe...
Young Mania Rating Scale Response Rates
Tohen M, et al. Arch Gen Psychiatry 2002;59:62-9.
PercentResponders
(≥50%YMRSdecre...
PercentageofPatients
Stabilized on OLZ+Li before randomization. Relapse criteria - YMRS or HAMD-21 >= 15.
Tohen MF, et al....
Olanzapine 12.5 mg/d (n=225)
Placebo (n=136)
0
20
40
60
80
100
Overall Relapse Relapse Into Depression Relapse Into Mania
...
OLZ 9.7 mg
(N = 351)
PBO (N = 355)
OLZ 7.4 mg
+ FLX 39.3 mg
(N = 82)
Week
0 1 2 3 4 6 8
MeanChangeinMADRSScores
-20
-15
-1...
LTG 106 mg
(N = 205)
OLZ 10.7 mg
+ FLX 38.3 mg
(N = 205)
Week
MeanChangeinMADRSScores
Brown EB, et al. J Clin Psychiatry 2...
Responders ≥ 7% Weight Gain
7-Week Randomized Double-Blind Olanzapine +7-Week Randomized Double-Blind Olanzapine +
Fluoxet...
Young Mania Rating Scale Response Rates
PercentResponders
(≥50%YMRSdecrease)
48%
31%
p < 0.0006
Quetiapine Placebo
0
10
20...
Young Mania Rating Scale Response Rates
Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606.
3-Week Double-Blind Adju...
-20
-15
-10
-5
0
Quetiapine 600 mg (N = 170)
Quetiapine 300 mg (N = 172)
Placebo (N = 169)
†
†
†
†
†
†
† †
†
†
† †
†
† † †...
ITT, LOCF
Baseline MADRS 29.6 PBO, 31.1 QTP 300, 29.9 QTP 600.
*P<0.01, †P<0.001 (quetiapine vs placebo).
8-Week Randomize...
8-Week Randomized Double-Blind Quetiapine8-Week Randomized Double-Blind Quetiapine
Monotherapy in Acute Bipolar Depression...
Bipolar Disorder I
(N=657)
Bipolar Disorder II
(N=321)
†
‡
MADRSLSMean
ChangeFromBaseline
Improvement
†
p<0.01; ‡
p<0.001 ...
Potkin SG, et al. J Clin Psychopharmacol 2005;25:301-10.Keck PE, et al. Am J Psychiatry 2003;160:741-8.
Percentresponders
...
Adjunctive PramipexoleAdjunctive Pramipexole
in Acute Bipolar Depressionin Acute Bipolar Depression
Response Rates
Percent...
Response Rates
PercentResponders
(≥50%IDSdecrease)
*p < 0.05 vs placebo
TEAS Modafinil 4.9%, Placebo 11.4%
Modafinil Place...
Sach GS, et al. J Psychopharmacol 2006.Keck PE, Jr, et al. Am J Psychiatry 2003;160:1651-8.
Percentresponders
(≥50%YMRSdec...
0
10
20
30
13%12%
6%5%
PercentofPatients
43%
25%
23%
8%
Relapse into
Mania
40
50
Relapse into
Mixed
Relapse into
Depressio...
Broad Efficacy Spectra of Atypical AntipsychoticsBroad Efficacy Spectra of Atypical Antipsychotics
1
Tohen M, et al. Am J ...
Rapid Onset of Action of Atypical AntipsychoticsRapid Onset of Action of Atypical Antipsychotics
1
Tohen M, et al. Arch Ge...
Mood StabilizerMood Stabilizer
Safety and TolerabilitySafety and Tolerability
ConcernsConcerns
DivalproexDivalproex
Gastro...
Second-GenerationSecond-Generation
Weight gainWeight gain
SedationSedation
Hyperglycemia, Diabetes*Hyperglycemia, Diabetes...
Obesity Associated with Earlier RelapseObesity Associated with Earlier Relapse
in Bipolar Disorderin Bipolar Disorder
Fagi...
Second Generation Antipsychotics and
Metabolic Abnormalities
Drug Weight Diabetes Lipids
Clozapine +++ + +
Olanzapine +++ ...
Emerging Uses of Atypical Antipsychotics
in Bipolar Disorders
Primary Therapies for Bipolar Disorder
 Olanzapine - Mania,...
ConclusionsConclusions
 Many new agents in development
– Diverse mechanistic, efficacy, and adverse effect profiles
 New...
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  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • Data points represent Mean  SE bars
    Divalproex ER was significantly superior to placebo for mean change from baseline in the MRS beginning on Day 5, which was the first on-treatment evaluation. The significant mean difference continued through Day 21.
    Rescue Medication use:
    Used 1 or more times by 79% of placebo patients and 74% of Depakote ER patients
    Lorazepam usage between the two groups was similar
    On Day 1, the average dose was statistically significantly higher in the placebo group (2.4mg) compared to the Depakote ER group (2.1mg).
    On Days 2-10, the average dose of lorazepam prescribed was similar between the treatment groups.
  • In order to help maintain serum valproate levels within the target range of 85-125 mcg/mL, an unblinded qualified person at the central lab, who was not involved with any study procedures other than blood levels, reviewed serum valproate levels. In the event that a patient had a serum valproate level &amp;lt; 85 mcg/mL or &amp;gt; 125 mcg/mL, the unblinded individual at the central laboratory telephoned the appropriate investigator and reported that the level was low or high, respectively. In order to preserve the study blind, a similar call was also made to either the same or a different investigator about a placebo patient at the same point in the study. Every investigator used clinical judgment to determine if an increase or decrease in dose was clinically warranted. Investigators understood these blinding procedures.
    Rescue medication:
    Lorazepam could be used for severe agitation or insomnia
    Screening/Washout: 2mg/dose 6mg/day, Max
    Days 1 – 7: 2mg/dose 4mg/day, Max
    Days 8 – 10: 2mg/dose 2mg/day, Max
    Adjunctive lorazepam was to be avoided for 8 hours before efficacy ratings.
    No lorazepam was to be prescribed after Day 10
  • Divalproex ER doses in this trial generally exceeded those typically used in the clinic setting.
  • Based on these results and previous acute and maintenance studies, serum valproate concentrations should generally not exceed approximately 100 mcg/mL for manic patients whose clinical improvement is adequate.
    References:
    Bowden CL, Janicak PG, Orsulak P, et al. Relation of serum valproate concentration to response in mania. Am J Psychiatry 1996;153:765-770.
    Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12 month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry 2000; 57:481-489.
  • The polarity of a patient’s index episode is strongly predictive of the polarity of relapse.
    More than 600 patients with bipolar disorder were evaluated in two 18-month maintenance studies. As part of the subanalysis of data, the polarity of the index episode of each patient in the placebo groups (n=188) was recorded and compared with the polarity of episodes that followed.
    The slide shows the pattern of relapse (by percentage) of placebo patients who were most recently manic or hypomanic or recently depressed. The curves beneath the percentages graphically illustrate the course of disease.
    Patients who entered the study after a manic or hypomanic episode were more likely to relapse into mania, and those entering after a depressive episode were more likely to relapse into depression. However, in both groups, relapse into depression was common, occurring in about 30% of recently manic or hypomanic patients and 39% of recently depressed patients. By contrast, only 16% of recently depressed patients relapsed into a mania. The ratio of relapse into depression versus mania after a depressive episode was 2.4:1. By contrast, the ratio of relapse into mania versus depression after a manic or hypomanic episode was 1.4:1.
    The figure illustrates the phrase “depression begets depression and mania begets mania.”
  • Angst, J. and M. Stabl (1992). &amp;quot;Efficacy of moclobemide in different patient groups: a meta-analysis of studies.&amp;quot; Psychopharmacology (Berl) 106 Suppl: S109-13.
    Baumhackl, U., K. Biziere, et al. (1989). &amp;quot;Efficacy and tolerability of moclobemide compared with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study.&amp;quot; Br J Psychiatry Suppl(6): 78-83.
    Calabrese, J. R., C. L. Bowden, et al. (1999). &amp;quot;Lamictal 602 Study Group. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression.&amp;quot; J Clin Psychiatry 60(2): 79-88.
    Cohn, J. B., G. Collins, et al. (1989). &amp;quot;A comparison of fluoxetine imipramine and placebo in patients with bipolar depressive disorder.&amp;quot; Int Clin Psychopharmacol 4(4): 313-22.
    Fabre, L. F., H. K. Brodie, et al. (1983). &amp;quot;A multicenter evaluation of bupropion versus placebo in hospitalized depressed patients.&amp;quot; J Clin Psychiatry 44(5 Pt 2): 88-94.
    Fieve, R. R., S. R. Platman, et al. (1968). &amp;quot;The use of lithium in affective disorders. I. Acute endogenous depression.&amp;quot; Am J Psychiatry 125(4): 487-91.
    Himmelhoch, J. M., M. E. Thase, et al. (1991). &amp;quot;Tranylcypromine versus imipramine in anergic bipolar depression.&amp;quot; Am J Psychiatry 148(7): 910-6.
    Kessell, A. and N. F. Holt (1975). &amp;quot;A controlled study of a tetracyclic antidepressant--maprotiline (Ludiomil).&amp;quot; Med J Aust 1(25): 773-6.
    McIntyre, R. S., D. A. Mancini, et al. (2002). &amp;quot;Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.&amp;quot; Bipolar Disord 4(3): 207-13.
    Merideth, C. H. and J. P. Feighner (1983). &amp;quot;The use of bupropion in hospitalized depressed patients.&amp;quot; J Clin Psychiatry 44(5 Pt 2): 85-7.
    Nemeroff, C. B., D. L. Evans, et al. (2001). &amp;quot;Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression.&amp;quot; Am J Psychiatry 158(6): 906-12.
    Sachs, G. S., B. Lafer, et al. (1994). &amp;quot;A double-blind trial of bupropion versus desipramine for bipolar depression.&amp;quot; J Clin Psychiatry 55(9): 391-3.
    Silverstone, T. (2001). &amp;quot;Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial.&amp;quot; Acta Psychiatr Scand 104(2): 104-9.
    Thase, M. E., A. G. Mallinger, et al. (1992). &amp;quot;Treatment of imipramine-resistant recurrent depression, IV: A double-blind crossover study of tranylcypromine for anergic bipolar depression.&amp;quot; Am J Psychiatry 149(2): 195-8.
    Vieta, E., A. Martinez-Aran, et al. (2002). &amp;quot;A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers.&amp;quot; J Clin Psychiatry 63(6): 508-12.
    Worrall, E. P., J. P. Moody, et al. (1979). &amp;quot;Controlled studies of the acute antidepressant effects of lithium.&amp;quot; Br J Psychiatry 135: 255-62.
  • &amp;lt;number&amp;gt;
  • Slide 44. Reducing the Risk of Rash With Lamotrigine
    Lamotrigine (LTG) is used “off-label” for treating bipolar disorder, so specific dosage guidelines are not provided in the package insert. The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2, increase to 50 mg for weeks 3 and 4, and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week. The maintenance dosage for LTG monotherapy is 100 to 400 mg daily. Retitrate if 5 or more days elapse without drug administration.1
    If the patient is already receiving carbamazepine, then the initial, titration, and maintenance doses of LTG should be increased. Use 50 mg once daily for weeks 1 and 2, follow with 50 mg twice daily for weeks 3 and 4, and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily.2
    Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers, the recommended titration schedule for LTG in combination with VPA should be “low and slow.” In this case, LTG dosing is 25 mg every other day for weeks 1 and 2, followed by 25 mg daily for weeks 3 and 4, then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward. The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses.2
    The safest approach to LTG dosing in general is to “start low, go slow.” High initial doses and rapid dose escalation significantly increase the risk of rash. A serious rash is most likely to occur in the first 2 to 8 weeks of therapy, but isolated cases have been reported after prolonged treatment (approximately 6 months). Therefore, the patient should be monitored for the duration of LTG therapy.1
    The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 2.8-fold higher in patients with any history of drug allergy and 3.8-fold higher in patients with a history of allergy to an antiepileptic drug.
  • Slide 55. Stanford Dermatology Precautions to Decrease Drug-Induced Rash
    Many rashes reported during initial treatment with an anticonvulsant are not drug-related. Investigators at Stanford University designed a protocol to allow physicians to focus on drug-related rash.
    Protocol recommendations:
    Avoid starting a new drug within 2 weeks of experiencing a rash, infection, or vaccination
    Avoid changing common household products (eg, soaps, deodorants, or detergents) within 3 months of starting a new drug
    Following these precautions may allow patients to reduce the number of rashes unrelated to treatment. Anecdotal evidence suggests this may lower the overall rash rate from ~10% to &amp;lt;5%.
    In a retrospective chart review, rash incidence was assessed in 66 bipolar disorder patients following these precautions during the first 3 months on lamotrigine (LTG).
    Results:
    No patient had serious rash
    1 patient discontinued LTG due to benign rash
    1 patient with recurrent mouth sores whose mother had pemphigus discontinued due to allergy concerns
    5 patients had benign rash (2 had not adhered to dosing recommendations or dermatology precautions)
    Of the remaining patients, 3 had benign rash, with 2 considered LTG-related
    3 adherent patients developed treatment-emergent rash
    Systematic studies are needed to confirm these preliminary findings.
  • ABSTRACT
    Objective: To examine the effects of mood stabilizers for bipolar I disorder on body weight.
    Methods: 638 patients randomized to 18 months of double-blind monotherapy with lamotrigine (n=280; 50-400mg/day fixed and flexible dose), lithium (n=167; 0.8-1.1mEq) or placebo (n=191) were grouped by pretreatment body mass index (BMI): not obese = BMI &amp;lt; 30, obese = BMI &amp;gt; 30. Mean observed change in body weight was examined through 52 weeks of treatment. Random effects mixed model with subject as a random effect and treatment, baseline weight, BMI category, visit, BMI category by visit interaction, treatment by visit interaction, and treatment by visit by BMI interaction as fixed effects was performed.
    Results: After 52 weeks of treatment, mean change in body weight was significantly lower in the lamotrigine treatment group compared with placebo (p&amp;lt;0.02) and compared with lithium (p&amp;lt;0.0001). These differences were evident in both BMI categories, but were most evident in the obese category of patients: placebo + 1.46 kg, lithium +3.3 kg, and lamotrigine -2.96 kg.
    Conclusions: Changes in body weight were correlated with choice of mood stabilizer and body mass index. Patients categorized as obese were at greatest risk for weight gain with lithium.
  • &amp;lt;number&amp;gt;
    Identical to previous slide, but with additional of PBO and LTG 12 &amp; 18 month relapse rates in lower left inset.
    On the combined primary outcome measure:
    Lamotrigine was significantly superior to placebo on time to intervention for any mood episode
    Lithium was also superior to placebo.
    There was no significant difference between lamotrigine and lithium.
    P-values on the slide are unadjusted for study. When these combined analyses were adjusted for study (stratified) p-values were:
    LTG vs. PBO p=0.002
    Li vs. PBO p&amp;lt;0.001
    Li vs. LTG p=0.644
    Source: SCAB2003 &amp; SCAB2006
  • &amp;lt;number&amp;gt;
    Identical to previous slide, but with additional of PBO and LTG 12 &amp; 18 month relapse rates in lower left inset.
    This analysis examines time to intervention for depressive episodes only. Manic and hypomanic events and other dropouts were censored in the analysis. On this measure:
    Lamotrigine was superior to placebo in prolonging time to intervention for a depressive event
    Lithium did not separate statistically from placebo, only reaching a statistical trend despite the large sample size (larger than any other previous lithium sample)
    There was no significant difference between lamotrigine and lithium.
    P-values on the slide are unadjusted for study. When these combined analyses were adjusted for study (stratified) p-values were:
    LTG vs. PBO p=0.004
    Li vs. PBO p=0.076
    Li vs. LTG p=0.281
    Source: SCAB2003 &amp; SCAB2006
  • &amp;lt;number&amp;gt;
    This analysis examines time to intervention for manic or hypomanic episodes only. Depressive events and other dropouts were censored in the analysis. On this measure:
    Lithium was superior to placebo in prolonging time to intervention for a manic event.
    Lamotrigine was also superior to placebo in prolonging time to intervention for a manic event.
    Lithium was superior to lamotrigine in prolonging time to intervention for a manic event.
    P-values on the slide are unadjusted for study. When these combined analyses were adjusted for study (stratified) p-values were:
    LTG vs. PBO p=0.149
    Li vs. PBO p&amp;lt;0.001
    Li vs. LTG p=0.024
    This alternative analysis provides additional evidence that the efficacy of lamotrigine against mania is less robust than its effect against depression.
    Source: SCAB2003 &amp; SCAB2006
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
    OBJECTIVE: Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania.
    METHOD: Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study.
    RESULTS: Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder.
    CONCLUSIONS: The results of this study support clozapine&amp;apos;s independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
    Sachs
    Drug [Li] [VPA]
    PBO 0.8 77
    RSP 0.7 65
    HAL 0.7 76
    Yatham - no main effect for psychosis - YMRS changes -
    Pts with Psychosis on RSP (-15.1) and PBO (-12.2)
    Pts without Psychosis on RSP (-13.8) and PBO (-9.2)
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  • Slide 34.Double-Blind Olanzapine vs Lithium Maintenance Monotherapy
    The efficacy of olanzapine (OLZ) and lithium (Li) in the prevention of relapse into a bipolar episode was compared in a randomized, double-blind study of bipolar I disorder (N=431).
    Patients who achieved remission with 6 to 12 weeks of open-label OLZ/Li combination therapy were randomized to 52 weeks of monotherapy with either drug
    Significantly more OLZ patients (46.5%) than Li patients (32.7%) completed the trial (P=.004)
    Results: Relapse rate was generally lower for OLZ versus Li, as indicated by the change in symptom ratings/psychiatric rehospitalization (P=.017), syndromic criteria (P=.50) or symptom ratings (P=.055). Specifically:
    Rate of relapse into an affective episode was lower for patients receiving OLZ vs Li (30% vs 38.8%, respectively; P=.055), based on a Young Mania Rating Scale total score 15 or 21-item Hamilton Depression Rating Scale score 15
    Rate of relapse into mania was significantly lower for OLZ compared with Li (14.3% vs 28%, respectively; P&amp;lt;.001)
    Rate of relapse into depression was similar for both drugs (16.1% vs 15.4%, respectively); the difference was not significant
    Weight gain in both the open-label and double-blind phases of the study was significantly greater for OLZ patients (P=.001)
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    Seroquel 99 Study Teleconference
    [email_address]
    Three-week, multicenter, double-blind, randomized, parallel-group, placebo-controlled trial
    Adjunctive / combination – similar to Janssen - DVPX:Li10:7
    All comers add-on (some but not all already on Li, DVPX, about 1/4 being actively
    Inpatients - 90 QUE, 56 completers - 100 PBO, 49 competers
    100 -&amp;gt; 200 -&amp;gt; 300 -&amp;gt; 400 -&amp;gt; 200 to 600 -&amp;gt; 200 to 800
    91% received ≥ 400 mg; 59% received ≥ 600 mg; Mean final dose 500 mg
    Results
    QUE &amp;gt; PBO YMRS decreases starting at day 21 (LOCF) (p &amp;lt; 0.03)
    Response rates QUE 53%, PBO 32% (p &amp;lt; 0.005)
    QUE and PBO had similar modest (3 point) MADRS decreases
    QUE and PBO had similar PANSS decreases (baseline ratings weren’t very high)
    QUE and PBO had similar GAS improvement (trend favored QUE)
    Baseline BMI QUE 29.6; PBO 29.6
    Mean weight change slightly higher with QUE (males +1.9 kg, females +1.3 kg) than PBO (males +0.8 kg, females -0.2 kg)
    Greater increase in weight with BMI 18.5-24.9 (+2.6) than in higher BMI (+0.1)
    Similar proportion gained more than 7% weight with QUE (3.9%) and PBO (1.2%)
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  • Goldberg - 6 wks
    15/22 BPI, 7/22 BPII - all outpatients
    Pts on Li, DVPX, CBZ, LTG, TPM/GBP
    .125 BID increased .125 BID q3-5 days
    AE’s
    Nausea, sedation
    1/12 PRAM -&amp;gt; Psychotic mania
    Zarate - 6 wks
    12/21 outpts, 9/21 inpts - all BPII
    Pts on Li, DVPX
    .125 TID increased .125 TID q5-7 days
    AE’s
    Insomnia, nausea/vomiting, tremor, agitation/anxiety, somnolence
    1/10 PRAM, 2/11 PBO -&amp;gt; Hypomania
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    At the conclusion of this presentation, the participant should be able to understand the efficacy of aripiprazole for the maintenance treatment of bipolar I disorder.
    Objective: To compare aripiprazole with placebo in the maintenance of stability of patients with bipolar I disorder in a 26-week, double-blind relapse prevention study.
    Methods: Patients who had recently experienced a manic or mixed episode, entered a stabilization phase receiving open-label aripiprazole 15ミ30 mg/day (starting dose = 30 mg/day), for 6ミ18 weeks. After meeting stabilization criteria (Y-MRS&amp;lt;f1&amp;gt;」&amp;lt;/f1&amp;gt;10 and MADRS&amp;lt;f1&amp;gt;」&amp;lt;/f1&amp;gt;13 for four consecutive visits or six weeks), 161 patients were randomized to aripiprazole or placebo for the 26-week maintenance phase. The primary endpoint was time to relapse of manic, mixed, or depressive symptoms, defined as discontinuation due to lack of efficacy (hospitalization for manic or depressive symptoms, or requiring a dosing change in psychotropic medications other than study drug).
    Results: Time to relapse of symptoms was significantly prolonged with aripiprazole compared to placebo (p=0.020). Total number of relapses (manic, mixed, or depressive symptoms) were significantly fewer in patients treated with aripiprazole than placebo (25% vs. 43%, p=0.013). The only adverse events (&amp;lt;f1&amp;gt;ウ&amp;lt;/f1&amp;gt;10% incidence) more common than placebo were anxiety and nervousness.
    Conclusion: Aripiprazole prolongs time to relapse of symptoms in stabilized patients with bipolar I disorder who previously experienced a manic or mixed episode.
    Funding Source(s): Bristol-Myers Squibb Company and Otsuka Pharmaceutical Co., Ltd
    1. Ertugrul A, Meltzer HY. Antipsychotic drugs in bipolar disorder. Int J Neuropsychopharmacol. 2003; 6(3):277ミ84.
    2. Keck PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G on behalf of the Aripiprazole Study Group. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003; 160:1651ミ1658.
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  • Upgrading Your Brain Made Easy

    1. 1. UpgradingUpgrading Your BrainYour Brain MadeMade EasyEasy
    2. 2. New Treatment Options for Patients with Bipolar Disorders Terence A. Ketter, M.D.
    3. 3. Disclosure InformationDisclosure Information Research Support / Consultant / SpeakerResearch Support / Consultant / Speaker Abbott Laboratories, Inc. AstraZeneca Pharmaceuticals LP Bristol-Myers Squibb Company Cephalon Inc. Corcept Therapeutics Elan Pharmaceuticals, Inc. Eli Lilly and Company Forest Laboratories, Inc. GlaxoSmithKline Janssen Pharmaceutica Products, LP Jazz Pharmaceuticals, Inc. Merck & Co., Inc. Novartis Pharmaceuticals Corporation Pfizer Inc. Shire Pharmaceuticals Group plc. Solvay Pharmaceuticals, Inc. UCB Pharmaceuticals Wyeth Pharmaceuticals
    4. 4. OverviewOverview  Mood Stabilizers – A - Lithium, divalproex, carbamazepine – B - Lamotrigine  New Anticonvulsants – Oxcarbazepine – Gabapentin, topiramate, tiagabine – Levetiracetam, zonisamide  New Antipsychotics – Clozapine – Risperidone, olanzapine, quetiapine – Ziprasidone, aripiprazole
    5. 5. Agents Approved for Bipolar I Disorder in the U.S.Agents Approved for Bipolar I Disorder in the U.S. Acute Mania Year Drug 1970 Lithium 1973 Chlorpromazine 1994 Divalproex 2000 Olanzapine* 2003 Risperidone* 2004 Quetiapine* 2004 Ziprasidone 2004 Aripiprazole 2004 Carbamazepine Maintenance Year Drug 1974 Lithium 2003 Lamotrigine 2004 Olanzapine 2005 Aripiprazole Acute Depression Year Drug 2003 Olanzapine-   fluoxetine   combination 2006 Quetiapine *Adjunctive as well as monotherapy Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:2.
    6. 6. Overview of 20 Acute Mania StudiesOverview of 20 Acute Mania Studies Response Rates 5 Combination Therapy Studies 15 Monotherapy Studies Percentresponders (≥50%maniaratingdecrease) P<0.0001 0 5 10 15 20 25 30 35 40 45 50 55 P<0.000150% Li/DVPX/CBZ/Atypical Monotherapy N = 2338 Atypical + Li/DVPX Combination 62% N = 521 Li/DVPX Monotherapy 42% N = 413 29% Placebo N = 1265 60 65 Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:12.
    7. 7. Summary of 15 Acute Mania Monotherapy StudiesSummary of 15 Acute Mania Monotherapy Studies Response Rates Atypical AntipsychoticsMood Stabilizers 0 10 20 30 40 50 60 Carbamazepine 707 mg/d N = 223 Risperidone 4.9 mg/d N = 273 Quetiapine 575 mg/d N = 208 Ziprasidone 121 mg/d N = 268 Aripiprazole 28 mg/d N = 260 Placebo N = 1265 Olanzapine 16 mg/d N = 304 Divalproex 1694 mg/d N = 255 Lithium 1950 mg/d N = 134 Percentresponders (≥50%maniaratingdecrease) Placebo Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:13.
    8. 8. 22 36 25 29 24 25 19 29 11 35 4 35 8 25 0% 10% 20% 30% 40% 50% 60% Q T P 600mg Q TP 300mg LTG 200mg OFC LTG 50mg Li Pax Li IM I Olz Active-Placebo Response Rate Difference ResponseRate (≥50%decreaseindepressionrating) Summary of 4 Acute Bipolar Depression StudiesSummary of 4 Acute Bipolar Depression Studies Response Rates Placebo Response Rate Sachs GS. In Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005. 22 36
    9. 9. Response Rates Pope HG, et al. Arch Gen Psychiatry 1991;48:62-8. Bowden CL, et al. JAMA 1994;271:918-24. PercentResponders (≥50%YMRS/SADS-CMRSdecrease) 25% 49% 11% *p < 0.05 **p ≤ 0.01 vs placebo 53% 48% Divalproex Placebo Divalproex Lithium Placebo 0 10 20 30 40 50 60 2000 mg/d 93 ug/mL N = 69 1950 mg/d 1.2 mEq/L N = 36 N = 74 2400 mg/d N = 17 N = 19 *** ** 3-Week Double-Blind Divalproex vs Placebo Monotherapy in Acute Mania Excluded mixed patients.Later studies found loading 20-30 mg/kg was well tolerated.
    10. 10. Acute Antimanic Effect Size Increases with Serum Valproate Concentration in Controlled Studies Allen MH et al., Am J Psychiatry 2006;163;272-5. N = 374
    11. 11. Response Rates PercentResponders (≥50%SADS-CMRSdecrease) *p < 0.05 vs placebo Divalproex Placebo 0 10 20 30 40 50 60 34% 48% 3057 mg/d 96 ug/mL N = 187 N = 177 * 3-Week Double-Blind Divalproex ER vs Placebo Monotherapy in Acute Mania Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006. day ug/mL 5 97 21 96 DVPX started at 25 mg/kg/d (rounded up to nearest 500 mg), increased 500 mg on day 3.
    12. 12. Baseline MRS 26.6 for both Placebo and Divalproex ER Placebo (n = 177) Divalproex ER 3065 mg/d, 95.9 ug/mL (n = 187) -14 -12 -10 -8 -6 -4 -2 Day 1 Day 5 Day 10 Day 15 Day 21 * * *** ** Change in Mania Ratings ChangeinSADS-CMRS *p < 0.05, **p < 0.01, ***p < 0.001 vs placebo 3-Week Double-Blind Divalproex ER vs Placebo Monotherapy in Acute Mania Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
    13. 13. Divalproex ER Dosing RegimenDivalproex ER Dosing Regimen  Initiated at 25mg/kg/day, rounded up to nearest 500mg  Additional 500mg/day beginning on Day 3  Dosage adjustments on Days 7, 12 and 17 – At investigator’s discretion based on clinical effect, adverse events, and serum valproate levels – Investigator titrated to target of 85-125 mcg/mL  Limited rescue lorazepam allowed during first 10 days Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
    14. 14. Divalproex ERDivalproex ER Mean Doses & LevelsMean Doses & Levels  Target serum valproate level 85 – 125 ug/mL Time Dose (mg/d) (mg/kg/d) Level (ug/mL) Day 5 2,874 33.2 96.5 Final 3,065 35.4 95.9 Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
    15. 15. Adverse Effect DiscontinuationsAdverse Effect Discontinuations and Serum Valproate Levelsand Serum Valproate Levels Group Valproate level (ug/mL) No adverse effect discontinuation 93.9 Adverse effect discontinuation 114.1 GI adverse effect discontinuation 123.2 Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
    16. 16. VPA + Antipsychotic Superior to Antipsychotic Monotherapy * 20 mg/kg/day Muller-Oerlinghausen et al., J Clin Psychopharmacol 20; 195-203, 2000 Placebo + Antipsychotic Valproate* + Antipsychotic Clinical Global Impression Very much improved Much improved 40% 67% 32% 31% 18% 36% P < 0.002 day ug/mL 3 60 7 76 18 80 21 80
    17. 17. Response Rates Percentresponders (≥50%YMRSdecrease) 22% 42% P<0.01 Extended-Release Carbamazepine Placebo Extended-Release Carbamazepine Placebo 0 5 10 15 20 25 30 35 40 45 50 61% 29% 55 P<0.0001 756 mg/d 8.9 ug/mL N = 94 643 mg/d N = 120 Weisler RH, et al. J Clin Psychiatry 2005;66:323- 30. Weisler RH, et al. J Clin Psychiatry 2004;65:478-84. N = 98 N = 115 3-Week Double-Blind ERC-Carbamazepine vs Placebo Monotherapy in Acute Mania 60 Titration necessary, watch for drug interactions.
    18. 18. Design N Finding N Finding Monotherapy vs PBO 443 CBZ > PBO 1-2 - - Monotherapy vs NL/Li 173 CBZ = NL/Li 3-6 90 OXC = NL/Li 18 Adjunct vs PBO 231 CBZ ≥ PBO 7-12 - - Adjunct vs NL/Li 216 CBZ ≥ NL/Li 13-17 20 OXC = NL 19 Total N 1063 110 Controlled Carbamazepine andControlled Carbamazepine and Oxcarbazepine Acute Mania StudiesOxcarbazepine Acute Mania Studies CBZ - 1 Weisler, et al. 2004; 2 Weisler, et al. 2005; 3 Okuma, et al. 1979; 4 Grossi, et al. 1984; 5 Lerer, et al. 1987; 6 Small, et al. 1991; 7 Klein, et al. 1984; 8 Müller & Stoll 1984; 9 Gonclaves & Stoll 1985; 10 Desai, et al. 1987; 11 Möller, et al. 1989; 12 Okuma, et al. 1989; 13 Stoll, et al. 1986; 14 Brown, et al. 1989; 15 Lenzi, et al. 1986; 16 Luznat, et al. 1988; 17 Okuma, et al. 1990. OXC - 18 Emrich, et al. 1990; 19 Müller & Stoll 1984. Carbamazepine Oxcarbazepine
    19. 19. 7-Week Double-Blind Oxcarbazepine vs Placebo Monotherapy in Acute Pediatric Mania Wagner KD, et al. Am J Psychiatry 2006:163:1179-86. Response Rates Percentresponders (≥50%YMRSdecrease) 26% 42% P = NS Oxcarbazepine Placebo Oxcarbazepine Placebo 0 5 10 15 20 25 30 35 40 45 50 41% 17% 55 1515 mg/d N = 59 1200 mg/d N = 37N = 56 N = 36 60 Oxcarbazepine Placebo 43% 40% 2040 mg/d N = 22 N = 20 All (7-18 yrs) Children (7-12 yrs) Adolescents (13-18 yrs) P < 0.04 P = NS
    20. 20. Weight Gain During Maintenance TreatmentWeight Gain During Maintenance Treatment Divalproex Lithium Placebo 0 5 10 15 20 25 PercentageofPatientswithWeightGain Bowden CL, et al. Arch Gen Psychiatry 2000;57:481-9.Bowden CL, et al. Arch Gen Psychiatry 2000;57:481-9. ** p = 0.004 vs PBO** p = 0.004 vs PBO ****
    21. 21. Bipolar Disorder Symptoms areBipolar Disorder Symptoms are Chronic and Predominantly DepressiveChronic and Predominantly Depressive 53% 32% 9% 6% Asymptomatic Depressed Manic/hypomanic Cycling / mixed % of Weeks 146 bipolar I patients146 bipolar I patients followed 12.8 yearsfollowed 12.8 years 86 bipolar II patients86 bipolar II patients followed 13.4 yearsfollowed 13.4 years 46% 50% 1% 2% Judd et al. Arch Gen Psychiatry. 2002;59:530-7. Judd et al. Arch Gen Psychiatry. 2003;60:261-9.
    22. 22. Polarity of Index Episode Predicts Polarity ofPolarity of Index Episode Predicts Polarity of Relapse: Relapses on PlaceboRelapse: Relapses on Placebo Index Episode Relapse Into Depression Relapse Into Mania Recently Depressed 39% 16% 2.4:1 Recently Manic or Hypomanic 30% 41% 1.4:1 Bowden et al. Arch Gen Psychiatry. 2003;60:392-400; Calabrese et al. J Clin Psychiatry. 2003;64:1013- 1024; Calabrese et al. J Clin Psychiatry. 2002;63(suppl 10):18-22.
    23. 23. Controlled Trials in Acute Bipolar DepressionControlled Trials in Acute Bipolar Depression Better than Placebo Imipramine1-2 Bupropion3-4 Fluoxetine5 Lamotrigine6 Olanzapine+Fluoxetine > Olanzapine7 Pramipexole8-9 Quetiapine10 Modafinil22 Similar to Placebo * Imipramine11 * Paroxetine11 Better than Imipramine Tranylcypromine12-13 Fluoxetine5 Similar to Tricyclic Maprotiline = Imipramine14 Moclobemide = Imipramine15-16 Moclobemide = Tricyclic17 s Bupropion = Desipramine18 s Paroxetine = Imipramine11 * > PBO if [Li] < 0.8 mEq/L s Less switch Similar to One Another s Paroxetine = Venlafaxine19 Bupropion = Topiramate20 Paroxetine+(Li/VPA) = Li+VPA21 1 Fieve, 1968; 2 Worrall 1979; 3 Fabre 1983; 4 Merideth 1983; 5 Cohn 1989; 6 Calabrese 1999; 7 Tohen 2003; 8 Goldberg 2004; 9 Zarate 2004; 10 Calabrese 2004; 11 Nemeroff 2001; 12 Himmelhoch 1991; 13 Thase 1992; 14 Kessell 1975; 15 Baumhackl 1989; 16 Silverstone 2001; 17 Angst 1992; 18 Sachs 1994; 19 Vieta 2002; 20 McIntyre 2002; 21 Young 2000; 22 Frye 2006.
    24. 24. Course and Subtype Depressive Burden Switch Risk Antidepressant Risk:Benefit Ratio Rapid Cycling Bipolar I Higher Higher Less Favorable Non-Rapid Cycling Bipolar I Lower Higher Less Favorable Rapid Cycling Bipolar II Higher Higher Intermediate Non-Rapid Cycling Bipolar II Higher Lower More Favorable Are Antidepressants a Good IdeaAre Antidepressants a Good Idea in Bipolar Depression?in Bipolar Depression? Ketter TA, et al. Bipolar Disord 2005;23(Suppl 2):23.
    25. 25. Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward. Davis LL, et al. J Affective Disord 2005;85:259-66. MeanHAM-DChange FromBaseline(LOCF) Week 0 1 2 3 4 5 6 7 8 -12 -10 -8 -6 -4 -2 0 Placebo (N = 12) Divalproex 82 ug/mL (N = 13) P = 0.0002 8-Week Randomized Double-Blind Divalproex8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
    26. 26. Oligomenorrhea and HyperandrogenismOligomenorrhea and Hyperandrogenismaa with Valproatewith Valproate **p <0.002 Joffe H, et al. Biol Psychiatry 2006;59(11):1078-86. Valproate PercentagewithOligomenorrhea andHyperandrogenism 0 2 4 6 8 10 12 No Valproateb 10.5% (9/86) 1.4% (2/144) ** 230 Women Age 18-45 a Hirsutism, acne, male-pattern alopecia, elevated androgens b Other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium
    27. 27. “Unfortunately, there’s no cure - there’s not even a race for a cure.”
    28. 28. AEDs Marketed in the U.S.AEDs Marketed in the U.S. Year Drug 1981 Clorazepate 1993 Felbamate 1993 Gabapentin 1994 Lamotrigine 1996 Fosphenytoin 1997 Topiramate 1997 Tiagabine 2000 Oxcarbazepine 2000 Levetiracetam 2000 Zonisamide 2005 Pregabalin Year Drug 1912 Phenobarbital 1935 Mephobarbital 1938 Phenytoin 1946 Trimethadione 1947 Mephenytoin 1951 Phenacemide 1953 Phensuximide 1954 Primidone 1957 Methsuximide 1957 Ethotoin 1960 Ethosuximide 1968 Diazepam 1974 Carbamazepine 1975 Clonazepam 1978 Valproate
    29. 29. Placebo Controlled Gabapentin Trials Diagnosis N Dose Finding Bipolar Disorder - Ineffective as Primary Treatment Mania (add-on) 1 117 600-3600 GBP <= PBO Rx Resistant RCBP 2 31 4000 GBP = PBO Comorbid Disorders - Effective for Comorbidities (Non-bipolar pts) Social Phobia 3 69 900-3600 GBP > PBO Panic Disorder 4 103 600-3600 GBP > PBO Post-herpetic Neuralgia 5 229 1200-3600 GBP > PBO Neuropathic Pain 6 305 900-2400 GBP > PBO Chronic Daily Headache 7 95 2400 GBP > PBO1 Pande AC, et al. Bipolar Disord 2000;2:249-55;2 Frye MA, et al. J Clin Psychopharmacol 2000;20:607-14; 3 Pande AC, et al. J Clin Psychopharmacol 1999;19:341-8; 4 Pande AC, et al. J Clin Psychopharmacol 2000;20:467-71; 5 Rowbotham M, et al. JAMA 1999;280:1837-42; Serpell MG. Pain 2002;99:557-66; Spira PJ, Beran RG. Neurology 2003;61:1753-9.
    30. 30. "Read the instructions very, very, very, very carefully."
    31. 31. Gradual Lamotrigine Titration Crucial toGradual Lamotrigine Titration Crucial to Reduce Risk of RashReduce Risk of Rash 1 Guberman et al. Epilepsia. 1999; 2 Physicians’ Desk Reference. 2003.  Double lamotrigine dose with carbamazepine  Halve lamotrigine dose with valproate Lamotrigine Titration in Adults1,2 Week Daily Dose 1 25 mg 2 25 mg 3 50 mg 4 50 mg Week 5 Add 50-100 mg/wk onward as clinically indicated Maintenance 100-400 mg
    32. 32. “If you remember, I did mention possible side-effects.”
    33. 33. Ketter TA, et al. J Clin Psychiatry 2005;66:642-5. Slower Titration and Dermatology PrecautionsSlower Titration and Dermatology Precautions to Decrease Drug-Induced Rashto Decrease Drug-Induced Rash • Slower titration – 25 mg/d x 2 wks, 50 mg/d x 2 wks, then increase 25 mg weekly – 80% longer to 200 mg/d (9 vs 5 wks) • Dermatology Precautions – Do not start drug within 2 weeks of • Rash, viral infection, vaccination – During first 3 months of therapy, avoid • New medicines, foods • New cosmetics, conditioners, deodorants, detergents, fabric softeners • Sunburn, poison ivy/oak • Observational evidence of potential benefit (N=100) – No serious rash; Rash discontinuation in 3% (3/100) – Rash rates • All patients 5% (5/100) • Dermatology/dosing adherent patients 3.1% (3/97)
    34. 34. Ginsberg L, et al. 156th Annual Meeting of American Psychiatric Association; San Francisco, Calif; May 17-22, 2003. Weight Loss with Lamotrigine inWeight Loss with Lamotrigine in Obese Bipolar Disorder PatientsObese Bipolar Disorder Patients -10 -8 -6 -4 -2 0 2 4 6 8 10 0 10 20 30 40 50 Week WeightChange(lb) Placebo (n=48) Lamotrigine (n=51) Lithium (n=43) * * p < 0.02 vs PBO, p < 0.0001 vs Li
    35. 35. Calabrese et al. J Clin Psychiatry. 1999;60:79-88.Calabrese et al. J Clin Psychiatry. 1999;60:79-88. Last Observation Carried Forward Observed Cases MADRSMADRS ChangeFromBaselineChangeFromBaseline PBO 5% LTG 50 3% LTG 200 8% 7-Week Randomized Double-Blind Lamotrigine7-Week Randomized Double-Blind Lamotrigine Monotherapy in Acute Bipolar I DepressionMonotherapy in Acute Bipolar I Depression LTG 50 mg/d (n = 64)LTG 50 mg/d (n = 64) LTG 200 mg/d (n = 63)LTG 200 mg/d (n = 63) Placebo (n = 65)Placebo (n = 65) WeekWeek 0 -5 -10 -15 -20 0 1 2 3 4 5 6 7 ±± ±± ** ** **** WeekWeek 0 -5 -10 -15 -20 0 1 2 3 4 5 6 7 †† ** ** ** ** ** ** ** ** LTG 50 mg/dLTG 50 mg/d LTG 200 mg/dLTG 200 mg/d PlaceboPlacebo Switch RatesSwitch Rates ±± P<0.1;P<0.1; †† * P<0.05.* P<0.05.
    36. 36. 16-Week Randomized Open Adjunctive Therapy of16-Week Randomized Open Adjunctive Therapy of Treatment Resistant Bipolar DepressionTreatment Resistant Bipolar Depression aa Nierenberg AA, et al. Am J Psychiatry 2006;163;210-6. 138 mg/d 9429 mg/d 1.5 mg/d 23.8% [5.8-41.8] 17.4% [2.4-32.4] 4.6% [0-14.6] a 54% BPI, 46% BPII.
    37. 37. Goodwin et al. J Clin Psychiatry 2004;65:432-41. Lamotrigine and LithiumLamotrigine and Lithium Effective in Bipolar I ProphylaxisEffective in Bipolar I Prophylaxis Time to Intervention for Any Episode (pooled recently manic/dep pts)Time to Intervention for Any Episode (pooled recently manic/dep pts) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 10 20 30 40 50 60 70 Week SurvivalEstimate Placebo (n=188) Lamotrigine 245 mg/d (n=223) Lithium 0.7 mEq/L (n=164) LTG v. PBO, p < 0.001 Li v. PBO, p < 0.001 LTG v. Li, p = 0.629 LTG Li PBO 0 10 20 30 40 50 22% 42% 37% 18 Months
    38. 38. Some patients considered intervention-free for depression could have had intervention for mania. Goodwin et al. J Clin Psychiatry 2004;65:432-41. Lamotrigine Effective inLamotrigine Effective in Bipolar I Depression ProphylaxisBipolar I Depression ProphylaxisTime to Intervention for Depression (pooled recently manic/dep pts)Time to Intervention for Depression (pooled recently manic/dep pts) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 10 20 30 40 50 60 70 Week SurvivalEstimate LTG v. PBO, p = 0.009 Li v. PBO, p = 0.120 LTG v. Li, p = 0.325 LTG Li PBO 0 10 20 30 40 50 60 41% 53% 57% 18 Months Placebo (n=188) Lamotrigine 245 mg/d (n=223) Lithium 0.7 mEq/L (n=164)
    39. 39. Some patients considered intervention-free for mania could have had intervention for depression. Goodwin et al. J Clin Psychiatry 2004;65:432-41. Lamotrigine and Lithium Effective inLamotrigine and Lithium Effective in Bipolar I Mania ProphylaxisBipolar I Mania ProphylaxisTime to Intervention for Mania (pooled recently manic/dep pts)Time to Intervention for Mania (pooled recently manic/dep pts) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 10 20 30 40 50 60 70 Week SurvivalEstimate LTG v. PBO, p = 0.034 Li v. PBO, p < 0.001 LTG v. Li, p = 0.030 Placebo (n=188) Lamotrigine 245 mg/d (n=223) Lithium 0.7 mEq/L (n=164) LTG Li PBO 0 20 40 60 80 53% 80% 65% 18 Months
    40. 40. 6-Week Lamotrigine Versus Gabapentin Versus Placebo in Treatment Resistant Mood Disorders Lamotrigine Gabapentin Placebo 0 10 20 30 40 50 60 PercentClinicalGlobal ImpressionResponse 52% (16/31) 26% (8/31) 23% (7/31) * * p < 0.05 versus GBP and PBO. Frye MA, et al. J Clin Psychopharmacol 2000;20:607-14. 275 mg/d 4000 mg/d Crossover trial with 74% Rapid-Cycling BP, 6% Non- Rapid-Cycling BP, 20% UP
    41. 41. Lamotrigine Effective in Rapid Cycling BPII 41% 46% 18% * * p < 0.05. Calabrese JR, et al. J Clin Psychiatry 2000;61:841-50. 0 10 20 30 40 50 All BPI BPII PBO LTG 31% 39% 26% *
    42. 42. Lamotrigine Ineffective in Acute Mania 44% 42% 46% * * p < 0.05 vs PBO.Similar percentages of patients had MRS increases with LTG, LI, and PBO. Bowden C, et al. 39th Ann ACNP Meeting. San Juan, Puerto Rico, Dec 10-14, 2000. PercentResponders (≥50%MRSdecrease) Lamotrigine Placebo Lithium Lamotrigine Placebo Lithium 0 10 20 30 40 50 60 70 55% 62% 47% Response RatesLow Dose (3 weeks) Add-on (6 weeks) 50 mg/d N = 85 N = 95 0.8-1.3 mEq/L N = 36 200 mg/d N = 74 N = 77 0.8-1.3 mEq/L N = 77
    43. 43. Lamotrigine Stabilizes Mood From Below Baseline?Lamotrigine Stabilizes Mood From Below Baseline? Ketter TA, Calabrese JR. J Clin Psychiatry 2002; 63(2):146-151.  A - work “From Above baseline” to help – Manic, hypomanic, mixed episodes – Subsyndromal manic, hypomanic, mixed symptoms  B - work “From Below baseline” to help – Major depressive episode – Subsyndromal depressive symptoms Types of Mood Stabilizers
    44. 44. ”Being on a diet does not give you the right to go berserk in a donut shop."
    45. 45. Placebo Controlled Topiramate Trials Diagnosis N Dose Finding Bipolar Disorder - Ineffective as Monotherapy in Adult Mania Mania (Adult - 4 studies)1 1,301 200-600 TPM = PBO Mania (Adolescent)2 56 278 TPM ≥ PBO Comorbid Disorders - Effective for Comorbidities (Non-bipolar pts) Obesity3 376 64-384 TPM > PBO Obese+Binge Eat4 61 212 TPM > PBO Bulimia5 69 100 TPM > PBO Etoh Dependence6 150 200 TPM > PBO Migraine7 468 50-200 TPM > PBO 1 Kushner S, et al. Bipolar Disord 2006;8:15-27; 2 DelBello M, et al. J Am Acad Child Adolesc Psychiatry 2005;44:539-47; 3 Bray GA, et al. Obes Res 2003; 11:722-33; 4 McElroy SL, et al. Am J Psychiatry 2003;160:255-61; 5 Hoopes SP, et al. J Clin Psychiatry 2003;64:1335- 41; 6 Johnson BA, et al. Lancet 2003;361:1677-85; 7 Brandes JL, et al. JAMA 2004;291:965-73.
    46. 46. Weight Loss with Zonisamide in Obesity Gadde KM, et al. JAMA. 2003;289:1820-5. Obese (No psychiatric disorder) Obese Euthymic Medicated Bipolar * Week            0 1 2 3 4 6 10 14 18 22 26 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Mean Duration 9.0 ± 6.7 wks Weight (lbs) Baseline 221.2 ± 27.0 LOCF 211.3 ± 19.4 Change -9.9 ± 13.7 Rate of Change -1.3 ± 2.0 lb/wk WeightChange(lbs) * * * * ± ± p < 0.10, * p < 0.05 vs Baseline Yang YS, et al. 156th APA Ann Mtg; San Francisco; May 17-22, 2003. p < 0.001
    47. 47. Primary Therapies for Bipolar Disorders  Divalproex - Mania, ± maintenance, ± rapid cycling  Carbamazepine - Mania, ± maintenance, ± rapid cycling  Lamotrigine - Maintenance, ± depression, ± rapid cycling  Oxcarbazepine - ± Mania? Adjuncts for Comorbid Conditions  Benzodiazepines - Anxiety, insomnia, agitation  Gabapentin - Anxiety, insomnia, pain  Topiramate - Obesity, eating disorders, migraine, alcoholism  Zonisamide - ± Obesity, ± eating disorders Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:6. Emerging Diverse Roles of Anticonvulsants in Patients with Bipolar Disorders
    48. 48. New Anticonvulsants Not (Yet) Proven Effective in Mania  Oxcarbazepine - B, underpowered active-comparator monotherapy studies1  Gabapentin - F, negative placebo-controlled add-on study2  Lamotrigine - F, negative placebo- & lithium-controlled add-on studies3  Topiramate - F, negative placebo- & lithium-controlled adult monotherapy studies4  Tiagabine - D, negative open add-on study5  Levetiracetam - D, no controlled study  Zonisamide - D, no controlled study 1 Emrich HM. Int Clin Psychopharmacol 1990;5(Suppl 1):83-8; 2 Pande AC, et al. Bipolar Disord 2000;2:249-55; 3 Bowden C, et al. 39th Ann ACNP Mtg. San Juan, Puerto Rico, Dec 2000; 4 Powers P, et al. 157th APA Ann Mtg, New York, May 2004; 5 Grunze H, et al. J Clin Psychiatry 1999;60:759-62. Adapted from: Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:37.
    49. 49. “I’m going to prescribe something that works like aspirin, but costs much, much more.”
    50. 50. Suppes T, et al. Am J Psychiatry 1999;156:1164-9. 12-Month Randomized Adjunctive Clozapine in12-Month Randomized Adjunctive Clozapine in Bipolar & Schizoaffective Dsiorder PatientsBipolar & Schizoaffective Dsiorder Patients 26 bipolar, 12 schizoaffective disorder, bipolar type patients 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Clozapine 355 mg/d (n=19) Treatment as usual (n=19) Months Percentofpatientswith 30%improvement p <.05 Mean clozapine doses - in bipolar 234 mg/d, in schizoaffective 623 mg/d.
    51. 51. Smulevich AB, et al. Eur Neuropsychopharmacol 2005;15:75-84.Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65. Young Mania Rating Scale Response Rates 3-Week Double-Blind Risperidone vs Placebo Monotherapy in Acute Maniaa Risperidone Placebo 0 10 20 30 40 50 60 PercentResponse (≥50%YMRSdecrease) 43% 24% ** 4.1 mg/d N = 127 Risperidone 48% 4.2 mg/d N = 153N = 119 Placebo 33% N = 138 47% 8.0 mg/d N = 144 Haloperidol a Excluded mixed episodes; **p < 0.01 vs placebo. ** ** Watch for extrapyramidal symptoms at higher doses.
    52. 52. Yatham LN, et al. Br J Psychiatry 2003;182:141-7. PercentResponders (≥50%YMRSdecrease) 38% 42% 59%57% p < 0.05 p < 0.06 Risperidone + Li/VPA Placebo + Li/VPA Haloperidol + Li/VPA Risperidone + Li/VPA Placebo + Li/VPA 0 10 20 30 40 50 60 58% Sachs G, et al. Am J Psychiatry 2002;159:1146-54. 3.8 mg/d 4.0 mg/d 6.2 mg/d N = 52 N = 51 N = 55* N = 62*N = 53 *Excluded 14 RSP+CBZ, 12 PBO+CBZ pts. Young Mania Rating Scale Response Rates 3-Week Double-Blind Adjunctive Risperidone vs Placebo (Monotherapy) in Acute Mania Carbamazepine decreased plasma risperidone concentrations by 40 percent.
    53. 53. Olanzapine Placebo Olanzapine Placebo 0 10 20 30 40 50 60 70 PercentResponse (≥50%YMRSdecrease) 49% 43% 65% 24% Young Mania Rating Scale Response Rates p < 0.05 p < 0.01 Tohen M, et al. Am J Psychiatry 1999;156:702-9. Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9. 15 mg/d N = 69 16 mg/d N = 55N = 70 N = 60 3- and 4-Week Double-Blind Olanzapine vs Placebo Monotherapy in Acute Mania Often started clinically at 20 mg/day.
    54. 54. Response Rates Olanzapine vs Divalproex Acute Mania Studies Zajecka J, et al. J Clin Psychiatry 2002;63:1148-55. PercentResponders (≥50%Young/SADS-CMRSdecrease) p = 0.06 Olanzapine Divalproex Olanzapine Divalproex 0 10 20 30 40 50 60 70 54% 53% 62% 42% p = 0.31 Tohen M, et al. Am J Psychiatry 2002;159:1011-7. 17 mg/d N = 125 15 mg/d N = 55 1401 mg/d 84 ug/mL N = 126 1956 mg/d 85 ug/mL N = 60 day ug/mL 3 78 6 97 10 101 day ug/mL 5 77 7 82 Olanzapine slightly more effective, divalproex slightly better tolerated.
    55. 55. Young Mania Rating Scale Response Rates Tohen M, et al. Arch Gen Psychiatry 2002;59:62-9. PercentResponders (≥50%YMRSdecrease) Olanzapine + Li 0.76 mEq/L / VPA 64 ug/mL Placebo + Li 0.82 mEq/L /VPA 75 ug/mL 6-Week Double-Blind Adjunctive Olanzapine vs Placebo (Monotherapy) in Acute Mania 68% 45% *p < 0.05, ***p = 0.001 vs placebo. 0 10 20 30 40 50 60 70 10.4 mg/d N = 220 N = 114 **** *** Low therapeutic mood stabilizer plasma concentrations in combination therapy.
    56. 56. PercentageofPatients Stabilized on OLZ+Li before randomization. Relapse criteria - YMRS or HAMD-21 >= 15. Tohen MF, et al. Am J Psychiatry 2005;162:1281-90. 0 10 20 30 40 50 14.3% 28.0% p=.055 p=.895 p<.001 Overall Relapse Relapse Into Depression Relapse Into Mania 15.4%16.1% 38.8% 30.0% Olanzapine 11.9 mg/d (n=217) Lithium 1103 mg/d (0.77 mEq/L) (n=214) Double-Blind Olanzapine vs LithiumDouble-Blind Olanzapine vs Lithium Maintenance MonotherapyMaintenance Monotherapy Equivalent Depression Prevention Olanzapine Compared to Lithium After Manic/Mixed Episodes Equivalent Episode Prevention Superior Mania Prevention
    57. 57. Olanzapine 12.5 mg/d (n=225) Placebo (n=136) 0 20 40 60 80 100 Overall Relapse Relapse Into Depression Relapse Into Mania PercentageofPatients p<.001 p=.015 p<.001 16.4% 41.2% 47.8% 34.7% 80.1% 46.7% Stabilized on OLZ before randomization. Relapse criteria - hospitalized or YMRS or HAMD-21 >= 15. Tohen MF, et al. Am J Psychiatry 2006;163:247-56. Double-Blind Olanzapine Monotherapy vsDouble-Blind Olanzapine Monotherapy vs Placebo MaintenancePlacebo Maintenance Olanzapine Compared to Placebo After Manic/Mixed Episodes Superior Depression Prevention Superior Episode Prevention Superior Mania Prevention
    58. 58. OLZ 9.7 mg (N = 351) PBO (N = 355) OLZ 7.4 mg + FLX 39.3 mg (N = 82) Week 0 1 2 3 4 6 8 MeanChangeinMADRSScores -20 -15 -10 -5 0 * * * * * * † † † Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88. Baseline MADRS 31.3 PBO, 32.6 OLZ, 30.8 OLZ+FLX. * P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN. 8-Week Randomized Double-Blind Olanzapine ±8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I DepressionFluoxetine in Acute Bipolar I Depression PBO 7% OLZ 6% OFC 6% Switch Rates
    59. 59. LTG 106 mg (N = 205) OLZ 10.7 mg + FLX 38.3 mg (N = 205) Week MeanChangeinMADRSScores Brown EB, et al. J Clin Psychiatry 2006;66:1025-33. Baseline MADRS 30.9 OFC, 31.4 LTG. *P < 0.05, ***P < 0.001 OFC vs LTG. Trade-off: 3 lbs/MADRS point. 7-Week Randomized Double-Blind Olanzapine +7-Week Randomized Double-Blind Olanzapine + Fluoxetine vs Lamotrigine in Acute Bipolar I DepressionFluoxetine vs Lamotrigine in Acute Bipolar I Depression LTG 5% OFC 4% Switch Rates0 1 2 3 4 6 8 -20 -15 -10 -5 0 QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. -25 5 * * * * * LTG -0.3*** OFC +3.1 Weight Change (kg)
    60. 60. Responders ≥ 7% Weight Gain 7-Week Randomized Double-Blind Olanzapine +7-Week Randomized Double-Blind Olanzapine + Fluoxetine vs Lamotrigine in Acute Bipolar I DepressionFluoxetine vs Lamotrigine in Acute Bipolar I Depression OFC LTG OFC LTG 0 10 20 30 40 50 60 69% 60% PercentageofPatients 23% 0% ± *** 70 Brown EB, et al. J Clin Psychiatry 2006;66:1025-33. ± P < 0.08, *** P < 0.001 OFC vs LTG. Trade-off: 9% response vs 23% weight gain.
    61. 61. Young Mania Rating Scale Response Rates PercentResponders (≥50%YMRSdecrease) 48% 31% p < 0.0006 Quetiapine Placebo 0 10 20 30 40 50 60 576 mg/dr N = 208 12-Week Double-Blind Quetiapine vs Placebo Monotherapy in Acute Mania (Pooled Data)a Vieta E, et al. Curr Med Res Opin. 2005;21:923-34. N = 195 a Excluded mixed episodes, rapid cycling; b Mean final dose in respondersImportant to use adequate dosage - started at 100 mg/day and increased by 100 mg/day.
    62. 62. Young Mania Rating Scale Response Rates Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606. 3-Week Double-Blind Adjunctive Quetiapine vs Placebo (Monotherapy) in Acute Mania (Pooled Data)a PercentResponders (≥50%YMRSdecrease) Quetiapine + Li 0.76 mEq/L / VPA 70 ug/mL Placebo + Li 0.73 mEq/L / VPA 74 ug/mL 56% 41% 0 10 20 30 40 50 60 492 mg/db N = 185 N = 185 ** a Excluded mixed episodes, rapid cycling; b Mean final dose in responders; **p = 0.01 vs placebo. Low therapeutic mood stabilizer plasma concentrations in combination therapy.
    63. 63. -20 -15 -10 -5 0 Quetiapine 600 mg (N = 170) Quetiapine 300 mg (N = 172) Placebo (N = 169) † † † † † † † † † † † † † † † † 0 1 2 43 65 7 8 Study Week ITT, LOCF ChangeFromBaseline (LSMeans) Baseline MADRS 30.3 PBO, 30.4 QTP 300, 30.6 QTP 600. †P<0.001 (quetiapine vs placebo) 8-Week Randomized Double-Blind Quetiapine8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60. PBO 4% QTP 300 4% QTP 600 2% Switch Rates
    64. 64. ITT, LOCF Baseline MADRS 29.6 PBO, 31.1 QTP 300, 29.9 QTP 600. *P<0.01, †P<0.001 (quetiapine vs placebo). 8-Week Randomized Double-Blind Quetiapine8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9. Montgomery-Asberg DepressionRatingScale Implrovement PBO 7% QTP 300 2% QTP 600 4% Switch Rates
    65. 65. 8-Week Randomized Double-Blind Quetiapine8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9. BOLDER I BOLDER II PercentageofPatientsResponding (≥50%MADRSDecrease) PBO QTP 300 QTP 600 PBO 0 10 20 30 40 50 60 58% 58% 36% 40% 37% 24% * ** *** QTP 300 QTP 600 *** Response Rates Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60. *p < 0.05, **p< 0.01, *** p < 0.001 vs placebo.
    66. 66. Bipolar Disorder I (N=657) Bipolar Disorder II (N=321) † ‡ MADRSLSMean ChangeFromBaseline Improvement † p<0.01; ‡ p<0.001 vs. placebo (N at baseline); ITT = intent to treat; AstraZeneca (data on file); Thase ME (2006), Presented at the 159th Annual Meeting of the APA. Toronto, Canada; May 20-25; Calabrese JE et al. (2005), Am J Psychiatry 162(7):1351-1360 BOLDER I and II: MADRS Total ScoreBOLDER I and II: MADRS Total Score Bipolar I vs. II DisorderBipolar I vs. II Disorder ‡ † Quetiapine 300 Quetiapine 600 Placebo-20 -16 -12 -8 -4 0
    67. 67. Potkin SG, et al. J Clin Psychopharmacol 2005;25:301-10.Keck PE, et al. Am J Psychiatry 2003;160:741-8. Percentresponders (≥50%SADS-CMRSdecrease) 35% 50% P<0.01 Ziprasidone Placebo Ziprasidone Placebo 0 5 10 15 20 25 30 35 40 45 50 46% 29% 60 P<0.05 136 mg/d N = 131 127 mg/d N = 137N = 66 N = 65 3-Week Double-Blind Ziprasidone vs Placebo Monotherapy in Acute Mania SADS-C* Mania Rating Scale Response Rates *Schedule for Affective Disorders and Schizophrenia-ChangeImportant to use adequate dosage - day one 80 mg/day, day two 160 mg/day - with food.
    68. 68. Adjunctive PramipexoleAdjunctive Pramipexole in Acute Bipolar Depressionin Acute Bipolar Depression Response Rates Percentresponders (≥50%HDRS/MADRSdecrease) 20% (2/10) 67% (8/12) P<0.04 Pramipexole Placebo Pramipexole Placebo 0 5 10 15 20 25 30 35 40 45 50 60% (6/10) 9% (1/11) 60 P<0.02 1.7 mg/d 1.7 mg/d Zarate CA, et al. Biol Psychiatry 2004; 56:54-60. Goldberg JF, et al. Am J Psychiatry 2004; 161:564-6 70
    69. 69. Response Rates PercentResponders (≥50%IDSdecrease) *p < 0.05 vs placebo TEAS Modafinil 4.9%, Placebo 11.4% Modafinil Placebo 0 10 20 30 40 50 60 22% 44% 177 mg/d N = 41 N = 44 * Frye M, et al. APA, Toronto, 2006. 6-week Randomized Double-Blind Adjunctive6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar DepressionModafinil in Acute Bipolar Depression
    70. 70. Sach GS, et al. J Psychopharmacol 2006.Keck PE, Jr, et al. Am J Psychiatry 2003;160:1651-8. Percentresponders (≥50%YMRSdecrease) 19% 40% P<0.01 Aripiprazole Placebo Aripiprazole Placebo 0 5 10 15 20 25 30 35 40 45 50 53% 32% 60 P<0.01 28 mg/d N = 123 28 mg/d N = 135N = 120 N = 129 3-Week Double-Blind Aripiprazole vs Placebo Monotherapy in Acute Mania Young Mania Rating Scale Response Rates Starting with 15 mg/day briefly prior to increasing to 30 mg/day can decrease nausea.
    71. 71. 0 10 20 30 13%12% 6%5% PercentofPatients 43% 25% 23% 8% Relapse into Mania 40 50 Relapse into Mixed Relapse into Depression Overall Relapse Aripiprazole 24.3 mg/d (n=77) Placebo (n=83) p=.013 p=.009 Equivalent Depression Prevention Superior Episode Prevention Equivalent Mixed Prevention Superior Mania Prevention Stabilized on ARI before randomization. Keck PE, et al. J Clin Psychiatry 2006;67:626-37. 26-Week Double-Blind Aripiprazole vs Placebo26-Week Double-Blind Aripiprazole vs Placebo Continuation/Maintenance MonotherapyContinuation/Maintenance Monotherapy Aripiprazole Compared to Placebo After Manic/Mixed Episodes
    72. 72. Broad Efficacy Spectra of Atypical AntipsychoticsBroad Efficacy Spectra of Atypical Antipsychotics 1 Tohen M, et al. Am J Psychiatry 1999;156:702-9; 2 Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9; 3 Sachs G et al. Am J Psychiatry. 2002;159:1146-1154; 4 Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65; 5 Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606; 6 Potkin SG, et al. 157th APA Ann Mtg, New York, May 1-6, 2004; 7 Jody D, et al. 157th APA Ann Mtg. New York, NY, May 1-6, 2004. p = pooled data. Agent Mixed Psychotic Rapid Cycling Olanzapine1,2 + + + Risperidone3,4 + + ? Quetiapine5,p ? + ? Ziprasidone6,p + + ? Aripiprazole7,p + + +
    73. 73. Rapid Onset of Action of Atypical AntipsychoticsRapid Onset of Action of Atypical Antipsychotics 1 Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9; 2 Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65; 3 Calabrese JR, et al. In Review; 4 Keck P, et al. Am J Psychiatry. 2003;160:741-8; 5 Segal S, et al. 156th APA Ann Mtg. San Francisco, CA, May 17-22, 2003; 6 Keck PE, et al. Am J Psychiatry. 2003;160:1651-8; 7 Sachs GS, et al. 157th APA Ann Mtg. New York, NY, May 1-6, 2004. p = pooled data. Separated From Placebo by Week 1 Olanzapine 1 Risperidone2 Quetiapine3,p Ziprasidone4,5 Aripiprazole6,7
    74. 74. Mood StabilizerMood Stabilizer Safety and TolerabilitySafety and Tolerability ConcernsConcerns DivalproexDivalproex GastrointestinalGastrointestinal Weight gainWeight gain TremorTremor HepaticHepatic CoagulationCoagulation Hair LossHair Loss PancreatitisPancreatitis TeratogenTeratogen PCOSPCOS CarbamazepineCarbamazepine GastrointestinalGastrointestinal RashRash NeurotoxicityNeurotoxicity HepaticHepatic ThyroidThyroid HematologicHematologic CardiacCardiac TeratogenTeratogen HyponatremiaHyponatremia = boxed warning in prescribing information Lithium Gastrointestinal Weight gain Neurotoxicity Renal Thyroid Hair Loss Cardiac Teratogen Acne, Psoriasis Adapted from: Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:11-55.
    75. 75. Second-GenerationSecond-Generation Weight gainWeight gain SedationSedation Hyperglycemia, Diabetes*Hyperglycemia, Diabetes* CardiacCardiac ± Akathisia± Akathisia ± Hyperprolactinemia± Hyperprolactinemia ± Cerebrovascular*± Cerebrovascular* ± Tardive dyskinesia*± Tardive dyskinesia* ± Neuroleptic malignant*± Neuroleptic malignant* Cardiac/pneumonia in elderly*Cardiac/pneumonia in elderly* AntipsychoticAntipsychotic Safety and TolerabilitySafety and Tolerability ConcernsConcerns Warnings - *In prescribing information; ? Under consideration; boxed First-Generation Depression Akathisia Acute dystonia Tardive dyskinesia* Weight gain Sedation Cardiac Hyperprolactinemia ± Neuroleptic malignant*± Neuroleptic malignant* ± Cardiac/pneumonia in elderly± Cardiac/pneumonia in elderly? Adapted from: Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:11-55.
    76. 76. Obesity Associated with Earlier RelapseObesity Associated with Earlier Relapse in Bipolar Disorderin Bipolar Disorder Fagiolini A et al. Am J Psychiatry. 2003;160:112-7. Any RelapseAny Relapse Depressive RelapseDepressive Relapse p < 0.02p < 0.02 p < 0.007p < 0.007
    77. 77. Second Generation Antipsychotics and Metabolic Abnormalities Drug Weight Diabetes Lipids Clozapine +++ + + Olanzapine +++ + + Risperidone ++ D D Quetiapine ++ D D Aripiprazole* ± - - Ziprasidone* ± - - Am Diabetes Assoc, Am Psychiatric Assoc, Am Assoc Clin Endocrinologists, N Am Assoc for Study of Obesity: Diabetes Care 2004;27:596:601. + = increase effect; - = no effect; D = discrepant. * Newer drugs with limited long-term data.
    78. 78. Emerging Uses of Atypical Antipsychotics in Bipolar Disorders Primary Therapies for Bipolar Disorder  Olanzapine - Mania, maintenance, depression (combined w fluoxetine)  Risperidone - Mania  Quetiapine - Mania, depression  Ziprasidone - Mania  Aripiprazole - Mania, maintenance Adjuncts for Bipolar Disorder  Olanzapine - Mania  Risperidone - Mania  Quetiapine - Mania  Clozapine - Treatment resistant Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:6.
    79. 79. ConclusionsConclusions  Many new agents in development – Diverse mechanistic, efficacy, and adverse effect profiles  New Anticonvulsants – Not as a class effective in acute mania – Variable efficacy in bipolar disorders and comorbid conditions  Newer Antipsychotics – As a class effective in acute mania – Emerging efficacy in acute depression and maintenance
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