Bipolar Disorder: New Treatment Options Michael A. Chan, MD Chair, Department of Psychiatry Mount Carmel.

Bipolar Disorder:New Treatment Options

Michael A. Chan, MDChair, Department of Psychiatry

Mount Carmel

Bipolar Disorder

Significant Public Health Impact 0.5 – 1.7% lifetime prevalence 6.4% lifetime prevalence “bipolar spectrum”¹ Suicide rate ~ 12% Annual U.S. cost > $45.2 B² 6th leading cause of disability worldwide³ Co-morbid substance abuse (ETOH) ~70% 90% recurrence rate (median # episodes = 9)

50% recurrence within one year of 1st episode

¹Judd LL, et al. J Affect Disord 2003 Jan;73(1-2):123-31

²Kleinman L, et al. Pharmacoeconomics 2003;21(9):601-22

³Woods SW. J Clin Psych 2000;61(suppl 13):38-41.

Bipolar DisorderOften misdiagnosed or undiagnosed:

35-60% have depression first¹ May have several depressive episodes

prior to manic episode² Many will not report mania/hypomania May progress to psychosis Lag between symptom onset and first

treatment with mood stabilizer³¹Goodwin FK, Jamison KR. Manic-Depressive Illness 1990:56-73;NY: Oxford Univ Press

²Lish JD, et al. J Affect Disord. 1994;31:281-294.

³Goldberg JF, Ernst CL. J Clin Psych. 2002 Nov;63(11):985-91.

Bipolar Disorder:Clues to DiagnosisHistory of maniaFamily history of bipolar disorderEarlier age of onset¹Multiple episodesAbrupt onset and termination of

depressive episodesWorsening with antidepressant

treatment²

¹Lish JD, et al. J Affect Disord. 1994 Aug;31(4):281-94.

²Ghaemi SN, et al. J Clin Psychiatry. 2000;61:804-808.

Bipolar Disorder:DSM-IV Criteria for Manic Episode

Abnormally and persistently elevated, expansive, or irritable mood > 1 week

3* or more activation symptoms: Distractibility, Increased risk-taking, Grandiosity, Fast/racing thoughts, Activity increased, Sleep decreased, Talkativeness (“DIG FAST”)

Marked social/occupational impairmentNot due to drugs or medical condition

*Four, if primarily irritable

Bipolar Disorder:DSM-IV Criteria for Depression

5 or more of following present > 2 weeks: depressed mood most of day, nearly every day decreased interest or pleasure in activities most of day,

nearly every day increased/decreased appetite & weight increased/decreased sleep psychomotor agitation/retardation decreased energy guilt/worthlessness poor concentration recurrent thoughts of death/suicide

“SIG: E-CAPS”

6%9%

32% 53%

Weeks asymptomatic Weeks depressedWeeks manic/hypomanic Weeks cycling/mixed

Bipolar Patients Are Symptomatic Almost Half Their Lives

N=146 12.8-year follow-up

Judd et al. Arch Gen Psychiatry 2002;59:530-537

2.3%1.3%

50.3% 46.1%

Weeks asymptomatic Weeks depressedWeeks hypomanic Weeks cycling/mixed

Bipolar II Patients Are Symptomatic Most Of Their Lives

N=86 13.4-year follow-up

Judd LL, et al. Arch Gen Psychiatry 2003;60:261-269.

*Akiskal HS, et al. J Affect Disord 2000 Sep;59 Suppl 1:S5-S30

Bipolar Disorder:Subtypes

Mixed Mania Simultaneous mania and depression May be > 40% prevalence of episodes*

Rapid Cycling > 4 episodes/year

Bipolar II Hypomania (< 4 days duration) alternating with

depression Secondary Mania

e.g., drugs, tumor, CVA, lupus, endocrine, infectious, Huntington’s, Wilson’s

Treatment:APA Practice Guidelines 2002

Acute mania/mixed mania: 1st line: lithium or valproate or antipsychotic* 1st line severe: lithium or valproate + antipsychotic*

Acute depression: 1st line: lithium or lamotrigine 1st line severe: lithium + antidepressant

Maintenance lithium or valproate: Alternatives: lamotrigine, carbamazepine, oxycarbazepine Atypical antipsychotics “may be considered”

*APA recommends atypical antipsychotics > typical antipsychotics

Treatment:Mood Stabilizers

Lithium*Depakote* (divalproex sodium)Lamictal* (lamotrigine)Tegretol (carbamazepine)Trileptal (oxcarbazepine)Neurontin (gabapentin)Topamax (topiramate)Gabitril (tiagibine)Keppra (levetiracetam)

*FDA-approved

Mood Stabilizers:Lithium

Advantages: 50+ years worldwide experience (FDA-approved 1970) effective in euphoric mania and hypomania inexpensive reduces suicide rate¹‚²

Disadvantages: slow onset ~ 14 days narrow therapeutic index non-response in > 50% (usually bipolar subtypes) frequent side effects (polyuria, tremor, GI symptoms) and

non-compliance discontinuation associated with high relapse rate³

¹Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52.

²Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73.

³Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.

Mood Stabilizers:Lithium

Predictors of response to Lithium: euphoric mania good inter-episode functioning family history of Bipolar Disorder (and of

Lithium response¹) mania/depression/euthymia sequence vs.

depression/mania/euthymia²

¹Duffy A, et al. J Clin Psych. 2002 Dec;63(12):1171-8.

²Kleindienst N, Greil W. Neuropsychobiology. 2002;42 Suppl 1:2-10.

Mood Stabilizers:Divalproex

Advantages: extensive experience (FDA-approved for epilepsy 1983; for

bipolar mania 1995) rapid onset (1-4 days) loading dose strategy¹ well-tolerated:

20 mgs/kg 77% moderate to marked response

effective in Bipolar subtypes effective for psychotic symptoms² plasma levels (50-125 mcg/ml) less cognitive impairment than lithium³

¹McElroy SL, Keck PE. Neuropsychobiol. 1993;27(3):146-9.

²McElroy SL, et al. J Clin Psych. 1996 Apr;57(4):142-6.

³Zajecka J, et al. J Clin Psych. 1996 Aug;57(8):356-9.

Mood Stabilizers:DivalproexDisadvantages:

sedation transient hair loss weight gain tremor GI upset dose-related thrombocytopenia rare hepatotoxicity, pancreatitis possible Polycystic Ovarian Syndrome plasma level monitoring

Mood Stabilizers:Lamictal

FDA-approved for maintenance treatment of Bipolar I Disorder

Black box warning for serious rash (includes Stevens-Johnson Syndrome and toxic epidermal necrolysis)

Slow titration necessary Interaction with other AEDs (especially

valproic acid and carbamazepine)

Lamictal:Efficacy in Bipolar Disorder

Placebo controlled 18-month trials of lamotrigine and lithium – pooled analysis

8-16 week open label treatment with lamotrigine or lithium before randomization: N = 191 for placebo N = 280 for lamotrigine (100-400 mgs/d) N = 167 for lithium (0.8-1.1 mEq/L)

18-month maintenance treatment phase Both lamotrigine and lithium superior to

placebo in preventing any mood episodeGoodwin GM, et al;J Clin Psych 2004 Mar;65(3):432-441

Bowden CL, et al;Arch Gen Psych 2003 Apr;60(4):392-400

Calabrese JR, et al;J Clin Psych 2003 Sep;64(9):1013-1024

Treatment:Atypical Antipsychotics

Clozaril (clozapine)Risperdal* (risperidone)Zyprexa* (olanzapine)Seroquel* (quetiapine)Geodon* (ziprasidone)Abilify* (aripiprazole)

*FDA-approved

Atypical Antipsychotics Comparable efficacy on positive symptom Better efficacy for improving cognitive and

affective (“negative”) symptoms Less risk of extrapyramidal symptoms______________________________________

“Brightening” effects related to receptor actions that differ from one agent to another

Appropriate dosing is key for optimal benefits with any atypical

D1 D2

5HT2A

5HT1A

A1

A2

H1

M

ClozapineClozapineOlanzapineOlanzapine

RisperidoneRisperidone

D1 D2

5HT2A

5HT1A

A1

A2

H1

QuetiapineQuetiapine

ZiprasidoneZiprasidoneD2

D1

5HT2A

5HT1A

A1

HaloperidolHaloperidol

Antipsychotic Receptor Binding Profiles

Receptor:Receptor:

AA1, 2 1, 2 = a= a11, a, a22 adrenergicadrenergic

DD1,21,2 = dopamine = dopamine

HH11 = histamine = histamine

5HT5HT1A, 2A1A, 2A = serotonin = serotonin

M = muscarinicM = muscarinicGoldstein 1999Goldstein 1999

Atypical AntipsychoticsHigh 5HT2:DA blockade (aripiprazole: unique

mechanism)

5HT-2a antagonism: Mesolimbic: does not reverse

antipsychotic action at D2 receptors Nigrostriatal: reverses enough D2

blockade to EPS Mesocortical: DA enough to improve

cognition

Atypical AntipsychoticsReceptor actions that improve mood

and cognition: 5HT2a antagonism (CLZ/RIS/OLZ/QTP/ZIP/ARI)

5HT2c antagonism (RIS/OLZ/ZIP)

5HT1a agonism (CLZ/QTP/ZIP/ARI)

5HT/NE reuptake blockade (ZIP)

Atypical Antipsychotics

Proper dosing:

Drug Initial launch Current

Risperidone 16 mgs 4-8 mgs

Olanzapine 10 mgs 15-20 mgs

Quetiapine 200-300 mgs 600-800 mgs

Ziprasidone 40-80 mgs 120-160 mgs

Aripiprazole 20-30 mgs 5-10 mgs

Evaluation of Mania Young Mania Rating Scale items*:

Elevated mood Increased motor activity Sexual interest Sleep Irritability Speech Language Content Disruptive/aggressive behavior Appearance Insight

*Possible Score = 0-60

Antipsychotics:Olanzapine

FDA-approved for acute mania (2000) and bipolar maintenance (2004)

First-line treatment for mania per APA 2002 Practice Guidelines (along with lithium & divalproex)

Superior to placebo¹ Equivalent to lithium² Superior efficacy (vs. placebo) as add-on to

lithium or valproate ³ Superior to divalproex4

1. Tohen M, et al. Am J Psych. 1999 May;156(5):702-9.

2. Berk M, et al. Int Clin Psychopharmacol. 1999 Nov;14(6):339-43.

3. Tohen M, et al. Arch Gen Psych. 2002 Jan;59(1):62-9.

4. Tohen M, et al. Am J Psych. 2003 Jul;160(7):1263-71.

Antipsychotics:Risperidone

FDA-approved for acute mania (2003)Superior to placebo (equivalent to haloperidol)

as add-on to mood stabilizer (lithium or divalproex)¹

Equivalent to lithium or haloperidol monotherapy²

¹Sachs, et al. Am J Psych 2002 Jul;159(7):1146-54

²Segal J, et al. Clin Neuropharm 1998 May-Jun;21(3):176-80

Antipsychotics:Quetiapine

FDA-approved for acute mania up to 12 weeks (2004)

2 monotherapy and 2 adjunct therapy studies completed*

Superior efficacy on YMRS, PANSS, CGI (including Response and Remission rates on YMRS) for 3 of 4 studies

*Data on file, AstraZeneca Pharmaceuticals LP, Wilmington, DEPresented at 16th Annual U.S. Psychiatric & Mental Health Congress. Nov 6-9, 2003. Orlando, FL

Quetiapine:Safety SummaryMonotherapy/Adjunct Therapy No clinically significant changes observed on ECG

parameters (including QTc)

No clinically significant changes in glucose levels (random test) from baseline to endpoint

No other laboratory abnormalities occurred

No clinically significant change observed in blood pressure (including orthostatic)

No difference from placebo in EPS or prolactin levels

No difference from placebo in withdrawal due to adverse events

Antipsychotics:Ziprasidone FDA-approved for mania August 2004 3-week, double-blind, randomized trial (DSM-IV

mania/mixed mania) N = 210 Ziprasidone 40-80 mgs B.I.D. vs. placebo Outcome: SADS (MRS), PANSS, CGI-I, CGI-S,

GAF Ziprasidone superior from day 2 on all primary

and most secondary efficacy measures

Keck PE, et al. Am J Psych. 2003 Apr; 160(4):741-8.

Antipsychotics:Aripiprazole FDA-approved for mania October 2004 3-week, multi-center, double-blind, randomized trial

(acute mania/mixed mania) N=262 aripiprazole 30 mgs vs. placebo Outcome: YMRS change from baseline and response

rate ( > 50%) aripiprazole superior from day 4:

YMRS (-8.2 vs. –3.4) YMRS response (40% vs. 19%) Similar discontinuation rate, weight, prolactin, QTc

Keck PE, et al. Am J Psych. 2003 Sep; 160(9):1651-8.

Atypical Antipsychotics:Metabolic Abnormalities

DRUG WEIGHT GAIN DIABETES RISK

WORSENING LIPID PROFILE

CLOZAPINE +++ + +

OLANZAPINE +++ + +

RISPERIDONE ++ D D

QUETIAPINE ++ D D

ARIPIPRAZOLE +/– – –

ZIPRASIDONE +/– – –

(+) = increase; (–) = no effect; D = discrepant results

Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes.

Diabetes Care. 2004 Feb. 27(2):596-601.

Atypical Antipsychotics:Case Reports Summary*

New Onset DM DKA/Coma Deaths

Clozapine 242 80 25

Olanzapine 225 100 23

Risperidone 131 36 5

Quetiapine° 69 21 11

Ziprasidone 1 1 0

Aripiprazole ? ? ?

*Data from MedWatch and Koller et al. Am J Med. 2001;111:716-23/ Koller et al. Pharmaotherapy. 2002;22:841-52.

°J Clin Psychiatry 2004;65:857-863

Literature reports through July 2003 and post-marketing surveillance date through August 2002

Comparative Side Effect Profile of Atypical Neuroleptics

Drug: EPS: Weight Gain:

Sedation: Prolactin:

Aripiprazole 0/+ 0 0 0Clozapine 0 +++++ +++++ 0

Olanzapine ++ ++++ ++ ++

Quetiapine 0 ++ +++ 0Risperidone +++ +++ + +++Ziprasidone ++ 0 + +

Benefits of Lower EPS “Negative” symptom benefitsCognitive benefitsDecreased dysphoria Improved complianceLower risk for tardive dyskinesia

Tandon R, Jibson MD. Annals Clin Psychiatry 2002;14(2):123-9.

Prolactin Elevation* Loss of libido Anorgasmia/Ejaculation difficulty Amenorrhea Gynecomastia Galactorrhea Osteoporosis

*DA blockade in tubero-infundibular tract

Treatment:Antidepressants Appropriate use and effectiveness is

controversial Antidepressant-induced mania in 20-40% with

all antidepressant classes (TCAs > others)¹‚² Increased risk of switching³:

Previous antidepressant-induced mania Bipolar family history Exposure to multiple antidepressant trials

¹Stoll AL, et al. Am J Psych 1994 Nov;151(1):1642-45

²Calabrese JR, et al. Eur Neuropsychopharm 1999 Aug;9 Suppl 4:S109-12

³Goldberg JF, et al. Bipolar Disord 2003 Dec;5(6):407-20

Treatment:Antidepressants

Conflicting evidence for efficacy against depressive relapse: Protective?:

Altshuler L, et al¹ (retrospective, 39 pts, 1 year): 35% relapse rate with antidepressant continuation 68% relapse rate with antidepressant discontinuation

Altshuler L, et al² (prospective, 84 pts, 1 year): 36% relapse rate with antidepressant continuation 70% relapse rate with antidepressant discontinuation

¹Altshuler L, et al. J Clin Psychiatry. 2001;62:612-16.

²Altshuler L, et al. Am J Psychiatry. 2003;160:1252-62.

Treatment:Antidepressants

No benefit?: Frankle WG, et al¹ (retrospective, 50 pts, 30

weeks): No difference in length of depressive episode

regardless of antidepressant status Ghaemi S, et al² (open, randomized 33 pts, 1

year): Relapse rate 50% within 20 weeks regardless of

antidepressant status

¹Frankle WG, et al. Psychol Med. 2002 Nov;32:1417-23.

²Ghaemi S, et al. San Juan, PR: American College of Neuropsychopharmacology annual meeting, 2003.

Treatment:Antidepressants

Antidepressants can be safe and effective* Review of 12 randomized, controlled trials

in Bipolar Depression (1,088 patients): Antidepressants more effective than placebo Switch rate 3.8% for antidepressants and 4.7%

for placebo Tricyclics had 10% switch rate vs. 3.2% for all

other antidepressants

*Gijsman HJ, et al. Am J Psychiatry 2004; 161:1537-1547.

Treatment:Antidepressants Recommendations for Bipolar depression*:

Augment mood stabilizer with antidepressant, unless:

“ultra-rapid” cycler (>4 episodes/week) History of antidepressant-induced cycle acceleration History of multiple episodes antidepressant-induced

mania despite mood stabilizer treatment

Continue maintenance antidepressant if stable for 2 months

*Post RM. Current Psychiatry. 2004 July. 3(7):40-49.

Treatment Electroconvulsive treatment¹‚²:

superior to pharmacotherapy bilateral ECT superior to unilateral ECT psychotic depression predicts better response effective in depressed and manic phases > 300 case reports of ECT during pregnancy

Phototherapy (bright light treatment) Benefit as monotherapy³ or augmentation4

especially if seasonal component Sleep deprivation5

improvement in 40-60% (may last weeks) some risk of hypo-mania

¹UK ECT Review Group. Lancet. 2003 Mar 8;361(9360):799-808; ²Kho KH, et al. J ECT. 2003 Sep;19(3):139-47; ³Levitt AJ, et al. J Affect Disord. 2002 Sep;71(1-3):243-8; 4Loving RT, et al. Depress Anxiety. 2002;16(1):1-3; 5Giedke H, Schwarzler F. Sleep Med Rev. 2002 Oct;6(5):361-77.

*Keck PE, et al. Psychopharm Bull 1997;33(1):87-91

TreatmentPsychotherapy issues:

acceptance of illness effect of illness on relationships effect on employment enhance compliance (>50% non-compliance:

M>F, white>non-white, combination therapy>monotherapy, substance abusers)*

identify precipitants to mood episodes manage/reduce stress

Summary Bipolar disorder:

Significant public health impact Highly recurrent Must look to find

Usually presents in depressed phase

Subtypes exist and are less lithium-responsive First-line treatment:

Mood stabilizers Atypical antipsychotics

Bipolar Disorder:New Treatment Options

Michael A. Chan, MDChair, Department of Psychiatry

Mount Carmel