1 medicine for bipolar disorder theo manschreck md mph harvard medical school james jefferson, md...
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Medicine for Bipolar Disorder
Theo Manschreck MD MPH
Harvard Medical School
James Jefferson, MD
University of Wisconsin
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Pre-Post Lecture Exam
1. 1. The most common misdiagnosis of bipolar depression is:
a) anxiety disorder
b) substance abuse
c) borderline personality disorder
d) unipolar depression
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2. Treatment of bipolar depression with antidepressants may lead to:
a) anxietyb) greater mood instabilityc) mania inductiond) psychosise) b and cf) all of the above
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3. In the treatment of moderate or severe mania, most guidelines recommend combination treatments, such as lithium or divalproex and atypical antipsychotics.
a) true
b) false
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4. Which of the following is incorrect? Lithium therapy is known to:
a) induce tremorb) cause urinary frequencyc) be associated with thirstd) increase suicide riske) induce nausea, vomiting, and diarrhea
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5. Kidney stones are associated with:a) olanzapineb) bipolar disorder complicated by
substance abusec) lithium d) divalproexe) topiramate
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* Lecture Outline• Overview: Bipolar Disorder-- Prevalence,
misdiagnosis, phasesMain Teaching Points: Challenges, many medicines, treatment goals and selection
• Treatment: Acute mania, bipolar depression, maintenance, rapid cycling
• Specific agents: Indications, efficacy, side effects, other therapeutic issues
• Pregnancy
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Bipolar Disorder Overview I • Prevalence: 1-4% (narrow vs spectrum)
• Onset in young adulthood (>60 years: medical disorders should be first consideration)
• Chronic episodic course
• Significant morbidity (disability, hospitalization, adjustment, substance problems, psychiatric disorder, medical issues)
• Significant mortality (suicide, accidents, and medical co-morbidities)
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Bipolar Disorder Overview II• Onset to proper diagnosis: 3-10 year lag (35% wait
>10 years for correct diagnosis)
• Misdiagnoses: unipolar depression (60%); anxiety disorders (26%); schizophrenia (18%); personality disorder (17%); alcohol/substance abuse (14%)
• Significant co-morbidities (e.g., 60% lifetime prevalence of alcohol and drug use disorders)
• Significant complications: cognitive, personal and occupational functioning
Regier et al, 1990; Hirschfeld et al, 2003
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Phases of Bipolar Disorder
• Acute mania
• Bipolar depression
• Maintenance
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* Challenges of Bipolar Disorder
• Complexity of the clinical presentation (heterogeneous symptom picture, co-morbid psychiatric disorders and medical disorders)
Recognition of bipolar depression
• Lack of adherence to treatment
• Necessity of a phase relevant treatment strategy
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* Many Medicines
• Antipsychotics
• Mood stabilizers
• Combinations
• ? Antidepressants
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* Treatment Goals• Acute mania Rapid onset of action, relief of symptoms, no
depression induction• Bipolar depression Relief of symptoms, no mania induction• Maintenance Prevention of relapse into depression or
mania; reduction of co-morbid anxiety
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*Selecting Medication(s)
• Phase specific considerations
• Prior response and tolerability
• Medical and psychiatric comorbidities
• Side effects
• Drug interactions
• Patient preferences
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Acute Mania
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FDA-Approved
Acute Mania
• 1970 Lithium• 1973 Chlorpromazine• 1995 Divalproex• 2005 Divalproex ER• 2000 on SGAs
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Atypical Antipsychotics for Mania• Olanzapine (Zyprexa)*• Aripiprazole (Abilify)*• Quetiapine (Seroquel)*• Risperidone (Risperdal)*• Ziprasidone (Geodon)*• Clozapine (Clozaril)
*FDA approved since 2000
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* Acute Mania: First-Line• Severe
– Li or DVPX + antipsychotic
• Less severe
– Li or DVPX or antipsychotic
APA Bipolar Guidelines, Revised 2002
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Ma
nia
Ra
tin
g S
cal
e S
core
s
Baseline 5 10 15 21
Days
PlaceboDivalproexLithium
**
**
28
26
24
22
20
18
16
n=73
n=68n=35
* Double-Blind Controlled StudyDivalproex vs Lithium vs Placebo
Reproduced with permission from Bowden CL, et al. JAMA. 1994;271:918-924.
*P<.05 vs placebo
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* Divalproex vs Valproic Acid• Divalproex (Depakote) is up to 5 times the cost of valproic acid
(Depakene)• Evidence-base is mostly with divalproex• Valproic acid is available in liquid form• Nausea is more frequent with valproic acid• Extended release offers single daily dose advantage• Recommend: Initiate new patients on single dose divalproex ER
(advantages despite cost)
• Wassief AA et al. AJP 2005;162:330-339
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* Atypical (Second Generation) Antipsychotics in Mania
• All such agents apparently effective• Generally no worsening of depression (unlike
conventional antipsychotics)• Antidepressant effects (i.e., as seen with
quetiapine) & some adjunctive mood stabilization effects
• Less EPS but be wary of metabolic risks, especially weight gain (except possibly for aripiprazole & ziprasidone) and abnormalities in glucose, lipids, or prolactin
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* Use of Antipsychotics II
• Fairly rapid titration (e.g., 1-3 days), e.g., ziprasidone start 40 mg bid, titrate dose.
• Often used adjunctively • May discontinue antipsychotic at
some point.
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23*P<0.01 vs placebo, last observation carried forward (LOCF) analysis. Jody et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S57.
-10
-9
-8-7
-6
-5
-4
-3
-2
-1
0
Me
an
ch
an
ge
fro
mb
ase
line
Placebo (n=122; mean baseline: 29.7)
* Example: Aripiprazole in Acute Mania:
Mean Change From Baseline in YMRS
*
** **
Day 4 Week 1 Day 10 Week 2 Week 3
Aripiprazole (n=123; mean baseline: 28.2)
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* Clozapine for Bipolar Disorder
• Open label reports of benefit for mania, maintenance, and possibly depression
• No double-blind studies
Alphs and Campbell. Psychiatric Annals 32:722-729, Dec. 2002
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Bipolar Depression
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* Bipolar Depression• First-line – lithium, quetiapine, lamotrigine,*
OFC (olanzapine/fluoxetine combination)
• Antidepressants
– Monotherapy not advised
– Bupropion, SSRIs, venlafaxine may be added to mood stabilizer but rate of response (without stimulating mania) is 16%. (Leverich GS et al, Am J Psychiatry 2006;232-9)
• ECT, psychotherapy
* Yet several studies show no advantage over placebo for LTG
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* Bipolar Depression: Olanzapine and Olanzapine-Fluoxetine Combination (OFC)
(8-week, double-blind, n=833)• Olanzapine (n=370): 9.7 mg (mean)
Dropouts 51.6%
• OFC (n=82): – Olanzapine 7.4 mg (mean)– Fluoxetine 25 mg
Dropouts 36%
• Placebo (n=355)Dropouts 51.6%
Tohen et al. AGP, 2003
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* Olanzapine/OFC for Bipolar Depression (FDA Approved)
MMRM=Mixed Modal Repeated Measures, Tohen et al. AGP, 2003
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* Quetiapine (QTP) in Bipolar Depression
• 8 weeks of monotherapy with 300 or 600 mg/day vs. placebo (Calabrese JR et al. AJP 2005;162:1351-1360)
• Remission in 53% of quetiapine patients vs. 28% on placebo
• Core symptoms of depression improved on quetiapine.
• Treatment-emergent mania in 3.2% vs 3.9%• This result has been replicated• QTP: FDA-approved for bipolar depression.
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Lithium Carbonate
C
O
Li
O
O
Li
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FDA ApprovedLithium Indications
• Acute mania
• Maintenance in bipolar disorder
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70%
Rapid Dysphoric History of (-) Family >3 cycling mania substance history episodes
abuse}
} Nonrapid Euphoric No (+) Family Few cycling mania substance history lifetime
abuse episodes
M
M
D
D
30%
* Lithium Response Rates
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* Long-Term Lithium Maintenance(n=360, average duration 6 years)
• Complete remission 29%
• 50-90% improved 36%
• Poor outcome not related to psychotic, mixed, rapid cycling, or episode sequence
Tondo et al. BJP 2001;178(suppl 41):184-190
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34Baldessarini RJ, Tondo L, Faedda GL, et al. J Clin Psychiatry. 1996(Oct);57(10):441-448
* Gradual vs. Rapid Lithium Discontinuation
Months After Stopping Lithium
Pro
po
rtio
n R
emai
nin
g
Sta
ble
(%
)
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
00 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60
Rapid (N=32)
Gradual (N=26)
Rapid (N=53)
Gradual (N=33)
Bipolar I Bipolar II
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* Antisuicidal Effect of Lithium
Clinical Response No Attempts
• Excellent (n=45) 93.3%
• Moderate (n=81) 82.7%
• Poor (n=41) 48.8%
Ahrens and Müller-Oerlinghausen. Pharmacopsychiatry 2001;34:132-136
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* Lithium• Half-life: 24 hours
• Not metabolized– Renal excretion
• Not protein bound
• Dosing– Initial
• 600-900 mg/day (divided or single dose)
– Maintenance• Serum levels: 0.6-1.2 mmol/l
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* Lithium Baseline Tests
• BUN, creatinine
• Thyroid
• CBC
• EKG (if indicated)
• Pregnancy (if indicated)
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* Lithium
• Black box warning– Toxicity
• Monitoring– Serum levels– Kidney and thyroid
function– Serum calcium (?)
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* Lithium Side Effects• Cognitive• Tremor• Gastrointestinal• Endocrine
– Thyroid– Parathyroid
• Weight gain• Skin• Renal• Toxicity
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* Serum Lithium Levels
Increased Not Changed Decreased
Thiazides Amiloride (?) Acetazolamide
NSAIDs Furosemide Mannitol
ACE inhibitors Aspirin Aminophylline
Low sodium diet Sulindac Theophylline
Dehydration Caffeine
Elderly Mania
Renal disease Pregnancy
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CH3CH2CH2
CH2CH2CH3CH3CH2CH2
NA+
CH2CH2CH3
CH
CH
C
C
O
HO O
O-
Divalproex Sodium/Valproate
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* Valproate
• Indications – Epilepsy– Acute mania (FDA: 1995)– Migraine prophylaxis – Manic and mixed episodes--divalproex ER (FDA:
2005)• Role
– Acute and prophylactic treatment of bipolar disorder
-- Good therapeutic index-- Superior to lithium for acute mixed episode
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* Valproate Baseline Tests
• CBC
• LFTs
• Amylase
• If applicable, pregnancy
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* Valproate
• Half-life: 6-16 hours• Protein binding: >90%• Daily formulation (divalproex ER) available• Dosing in mania
– Initial: 250 mg tid or oral loading (20-30 mg/kg)(ER version bioequivalent to divalproex at ER
dose 8 to 20% higher)– Maintenance: serum concentration (trough) = 50-125
g/ml (ER 85-125 g/ml)
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* Valproate• Black box warnings
– Hepatotoxicity
– Teratogenicity
– Pancreatitis
• Monitoring– Blood levels
– CBC, platelets, LFTs
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* Valproate Side Effects
• Cognitive (uncommon)
• Tremor
• Gastrointestinal
• Weight gain
• Hair loss
• Hepatotoxicity
• Pancreatitis
• Teratogenicity
• Polycystic ovaries (?)
• Bleeding tendencies
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* Valproate Interactions(An Incomplete Listing)
• Aspirin (avoid) free VPA, platelet function
• Carbamazepine
VPA, CBZ-epoxide
• Lamotrigine
lamotrigine
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Carbamazepine
N
CONH2
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* Carbamazepine
• Indications– Trigeminal neuralgia– Epilepsy
-- Acute mania (extended release)
• Role– Acute and prophylactic treatment of bipolar disorder– Adjunctive treatment with other mood stabilizers– Favored in Japan and Europe over VPA, though
lithium #1.
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* Carbamazepine
• Half-life– Initial: 25-65 hours– Induced: 12-17 hours
• Protein binding: 76%• Metabolism
– CYP3A4 – Hepatic autoinduction– 10, 11-epoxide
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* Carbamazepine Baseline Tests
• CBC with platelets
• LFTs
• If applicable, pregnancy
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* Carbamazepine
• Immediate and extended release
• Dosing
– Initial: 200-400 mg/day (divided)
– Maintenance: serum conc = 4-12 g/ml
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* Carbamazepine
• Black box warnings
– Aplastic anemia (1/100,000)
– Agranulocytosis (1/100,000)
• Monitoring
– Blood levels
– CBC, platelets, LFTs
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* Carbamazepine Side Effects
• Sedation
• Dizziness
• Ataxia
• Double/blurred vision
• GI distress
• Hematopoietic suppression
• Hepatotoxicity (rare)
• Dermatologic
• Teratogenicity
• Hyponatremia
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* Carbamazepine Interactions
• CBZ decreases levels of:– Clonazepam, clozapine, olanzapine, haloperidol,
alprazolam, bupropion, oral contraceptives
• CBZ levels increased by:– Cimetidine, macrolides, fluoxetine, valproate,
isoniazid, verapamil, ketoconazole
An Incomplete Listing
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CI
CI
H2N N NH2
NN
Lamotrigine
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* Side Effects of Lamotrigine
Dose Related Not Dose Related
DizzinessDiplopiaAtaxia Blurred visionNausea and vomitingInsomnia
HeadacheDermatologic 10% benign rash 3/1,000 adults—severe rash Do not rapidly escalate dose Warn patients about rash Malformations: 2.7%
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*
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* Rash with Lamotrigine Use• Black box warning
• Overall rash prevalence: 10%– 0.3% severe in adults– 1% severe in children (not for those <15yoa)
• Predictors of rash: starting dose, titration, concurrent divalproex, use in children, history of prior rash
• Stevens-Johnson syndrome with lamotrigine– 1993: 5/4,450– 1999: 3/17,648
Messenheimer et al. Drug Safety. 1998;18:281-96; Physicians’ Desk Reference. 55th ed. 2001
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* Lamotrigine Dosing
• Monotherapy– Weeks 1 and 2: 12.5-25 mg/day
– Weeks 3 and 4: 25-50 mg/day
• With valproate: dose by 50%
• Maintenance: 50-400 mg/day
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* Lamotrigine and RashMood Disorder Clinical Trials
• Rash (all types)LTG (92/979) 9.4%Placebo (77/935) 8.2%Other (21/307) 7.0%
• Serious rashLTG (1/979) 0.1%Placebo (1/935) 0.1%
• No cases of SJS, TEN
Calabrese et al., ACNP, 2001
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Incidence of Rash in Controlled Bipolar Disorder Studies
Non-serious Serious Rash Rash1
Lamotrigine (n=827) 8.8%
0.0%
Lithium (n=280) 4.3%
0.0%
Placebo (n=685) 7.7%
0.1%
11Requiring hospitalisation and drug discontinuationRequiring hospitalisation and drug discontinuation
Bowden et al., 2003 Bowden et al., 2003
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* Lamotrigine (LTG) Interactions
• Valproate doubles LTG levels• LTG valproate levels 25%• CBZ LTG levels 40%• Oral contraceptives LTG levels 49% (n=7)• Sertraline LTG levels 2-fold (n=2)• LTG clozapine levels 3-fold (n=1)• Pregnancy LTG clearance >50%
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* Oxcarbazepine
• 10-keto analogue of CBZ
• Prodrug MHD (10-hydroxycarbazepine)
• Half-life OXC 2 hoursMHD 9 hours
• Protein binding 40%
• Initial 150 mg bid/target 800-1800 mg/day
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* Oxcarbazepine for Acute Mania
• Better than placebo (n=6)Emrich et al., 1983
• Equal to haloperidol (n=38)Emrich, 1990
• Equal to lithium (n=52)Emrich, 1990
• No better than placebo in children and adolescents (n=116)
– Wagner et al, 2006
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* Oxcarbazepine Side Effects• AE dropouts 23%
- monotherapy 9%- pediatrics 11%
• Common – nausea, vomiting, dizziness, somnolence, ataxia
• Uncommon – hyponatremia (< 125 mEq/L 2.5%)
• Rare: Stevens-Johnson syndrome and toxic epidermal necrolysis
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* Oxcarbazepine and Hyponatremia
• Sodium < 125 mmol/l in 2.5%• Symptomatic hyponatremia –
uncommon• CBZ OXC: Sodium levels may • Monitor at risk patients• Treat - or stop drug, restrict fluids
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* Oxcarbazepine Interactions
• No autoinduction
• Inhibits 2C19(e.g., phenytoin)
• Induces 3A4(e.g., ethinylestradiol
• Fewer interactions than CBZ
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CH2OSO2NH2
O
OO
O
CH3
CH3H3C
H3C
O
Topiramate
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Topiramate (Topamax)
• Half life 21 hours
• Minimal metabolism (< 30%)
• Inhibits CYP2C19
estrogen in oral contraceptives
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* Topiramate for Bipolar Disorders• No double-blind controlled efficacy studies in
bipolar
• Dose range: 25-400 mg/day
• Open-label results:moderate/marked improvement 52%minimal/no improvement 36%worse 11%
• Adverse events dropouts (6/58) 10%
Marcott D: J Affect Dis 1998;50:245-251
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* Topiramate
• AE dropouts (epilepsy trials): 28%
• More common: somnolence, cognitive impairment, dizziness, ataxia, psychomotor slowing, paresthesias, weight loss
• Kidney stones: 1.5%
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* Topiramate and Kidney Stones
• Occurred in 1.5% (32/2086)
• 2 to 4 times risk
• Men > women
• Reported in kids
• One bipolar II woman
• Carbonic anhydrase inhibition
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* Adding Topiramate vs. Bupropion SRfor Bipolar Depression
• 8 weeks, single blind, n=36, added to Li+ or VPA
• Topiramate 176 mg/day, bupropion 250 mg/day
• >50% drop in HDRS: 56% with topiramate, 59% with bupropion
• No mood switches
• Six dropouts due to side effects in topiramate group, four in bupropion group.
• Weight loss: 5.8 kg on topiramate, 1.2 on bup. (Mcintyre RS et al. Bipolar Disorders 2002;4:207-213)
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CH2CO2H
CH2NH2
Gabapentin
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Gabapentin• Half-life: 5-7 hours
• Bioavailability decreases with dose
• Not protein bound
• Not metabolized
• No important drug interactions (except felbamate)
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Gabapentin Side Effects
• AE dropouts (epilepsy trials): 7%
• Most common—somnolence, fatigue, ataxia, dizziness
• Uncommon—weight gain, edema, incontinence, hypomania
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* Gabapentin: Limitations in Bipolar Disorders
• Not effective as monotherapy in treatment-resistant rapid cycling
• Not effective as primary add-on antimanic agent
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*Omega-3 Fatty Acids for Unstable Bipolar Disorder (n=30)
• 4 month, double-blind, placebo-controlled study
• Recurrence: Omega-3 7%Placebo 47%
• Mechanism: Altered post-synaptictransduction
• Note: 3 other blind studies, 2 negative and 1 positive
Stoll A et al., Arch Gen Psych 56: 407-412, 1999
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Other Promising Mania Treatments
Protein Kinase C Inhibitor-Tamoxifen
Omega-3 Fatty Acids
Stoll A et al, Arch Gen Psych 56: 407-412, 1999Zarate et al, Bipolar Disorder 9: 561-570, 2007
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* Rapid-Cycling Bipolar Disorder
• At least 4 episodes/year• Initial onset or later onset• More common in women• Thyroid abnormality seen• Role of antidepressants• May not persist
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* Rapid Cycling
• Stop antidepressants
• Use lithium or valproate
• Alternative – lamotrigine
• Combinations
– add antipsychotic
– add mood stabilizer
APA Bipolar Guidelines, Revised 2002
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Bipolar Maintenance
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* Bipolar Maintenance
• Best evidence: Lithium, olanzapine, or aripiprazole
• Alternatives: LTG, CBZ, OXC, DVX
• Combinations may be necessary
– Antipsychotic
– Antidepressant
– Psychosocial
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FDA Pregnancy Categories
A: Controlled Studies – No Risk
B: No Evidence of Risk in Women
C: Risk Cannot be Ruled Out
D: Positive Evidence of Risk
X: Contraindicated in Pregnancy
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* Mood Stabilizers and Pregnancy
FDA Risk Category
• Lithium D
• Valproate D
• Carbamazepine D
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New Anticonvulsants and Pregnancy FDA Risk Categories
• Gabapentin C
• Lamotrigine C
• Tiagabine C
• Topiramate C
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Pre-Post Lecture Exam
– 1. The most common misdiagnosis of bipolar depression is:
a) anxiety disorder
b) substance abuse
c) borderline personality disorder
d) unipolar depression
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2. Treatment of bipolar depression with antidepressants may lead to:
a) anxietyb) greater mood instabilityc) mania inductiond) psychosise) b and cf) all of the above
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3. In the treatment of moderate or severe mania, most guidelines recommend combination treatments, such as lithium or divalproex and atypical antipsychotics.
a) true
b) false
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4. Which of the following is incorrect? Lithium therapy is known to:
a) induce tremorb) cause urinary frequencyc) be associated with thirstd) increase suicide riske) induce nausea, vomiting, and diarrhea
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5. Kidney stones are associated with:a) olanzapineb) bipolar disorder complicated by
substance abusec) lithium d) divalproexe) topiramate
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Answers to Quiz
• 1) d
• 2) f
• 3) a
• 4) d
• 5) e