Pharmacologic Considerations in
the Treatment of Bipolar Affective
Disorder
Presented by: Ann M. Hamer, PharmD, BCPP
Date: 11/6/2014
Disclosures and Learning Objectives
• Learning Objectives
–
–
–
Be able to recognize common adverse
effects of mood stabilizers
Be able to identify common drug
interactions associated with mood
stabilizers
Be able to discuss differences between
the available mood stabilizers
Disclosures: Dr. Ann Hamer has nothing to disclose.
Pharmacologic Treatment of Bipolar
Disorder
•
•
•
•
•
Review adverse effects
Review drug interactions
Review dosing
Review monitoring parameters
Review comparative cost
Treatment Recommendations
Acute Mania
Stop antidepressants
(or inciting agents)
Use a mood stabilizer
first:
Lithium, Valproate
Carbamazepine,
Oxcarbazepine
If psychosis occurs,
use an antipsychotic:
Olanzapine,
Risperidone,
Asenapine
Aripiprazole,
Ziprasidone,
Quetiapine
Consider short term
use of a benzo
Acute Depression
Start with lithium or
lamotrigine
(alternatives include:
quetiapine,
olanzapine/fluoxetine)
“Antidepressant
monotherapy is not
recommended.”
Add lamotrigine or
bupropion if needed
ECT if severely
depressed or pregnant
CBT and Behavioral
Activation
Rapid Cycling
Identify and treat
comorbid contributors
such as
hypothyroidism or
drug/alcohol use
Taper contributing
medications
Valproate often
preferred (alternatives
include
carbamazepine,
lithium, or lamotrigine)
Combination treatment
often required
Maintenance
Continue agent that
helped in acute phase
Taper benzodiazepines
Taper antipsychotics
when mood stable
Lamotrigine and lithium
may help ward off
depression
Lithium may be better
at warding off mania
Valproate, Olanzapine,
Carbamazepine,
Oxcarbazepine also
evidence-based
Lithium
Lithium Adverse Effects
• Common: Leukocytosis (most patients), Polyuria/polydipsia (3050%), Dry mouth (20-50%), Hand tremor (45% initially, 10% after 1
year of treatment), Confusion (40%), Decreased memory (40%),
Headache (40%), Muscle weakness (30% initially, 1% after 1 year of
treatment), Electrocardiographic (ECG) changes (20-30%), Nausea,
vomiting, diarrhea (10-30% initially, 1-10% after 1-2 years of
treatment), Hyperreflexia (15%), Muscle twitch (15%), Vertigo (15%)
• Less common: Extrapyramidal symptoms, goiter (5%),
Hypothyroidism (1-4%), Acne (1%), Hair thinning (1%)
• Black Box Warning: Toxicity with higher plasma concentrations
• Pregnancy Category D
Lithium Drug Interactions
• Caution with medications known to prolong the
QT interval
• Caution with other medications that may
increase serotonin levels
• Caution with medications/conditions that affect
renal clearance (e.g. thiazides, pregnancy)
Lithium Dosing
• Immediate release: 900-2400 mg/day PO
divided q6-8hr
• Extended release: 900-1800 mg/day PO
divided q12hr
• Lower initial dosage may be used to minimize
adverse drug reactions
Lithium Monitoring
•
•
Lithium levels
•
T1/2 = 18-24 hours; ss 4-5 days; draw levels 12 hours post-dose,
usually prior to the morning dose
•
Target level = 0.6 -1.2 mEq/L; should not exceed 1.5mEq/L
•
LiCp < 1.5 mEq/L (mild toxicity and transient effects) = Fine hand tremor, GI upset
(N/V/D/anorexia), mild polyuria, polydipsia, muscle weakness
•
LiCp = 1.5 – 2.5 mEq/L (moderate toxicity) = Course hand tremor, twitching,
reoccurrence of GI upset, slurred speech, vertigo, confusion, sedation, lethargy,
hyperreflexia
•
LiCp > 2.5 mEq/L (severe toxicity) = Seizures, stupor, coma, cardiovascular collapse,
death
Other common monitoring parameters: pregnancy test at baseline; Ca, Cr,
urinalysis, TSH at baseline, then at least q6-12mo; serum drug levels 2x/wk
until stable, then q2mo until chronic steady dose, then q6-12mo; ECG at
baseline in pts >40 yo or if cardiovascular dz, then q6-12mo; consider CBC
at baseline
Valproate
Valproate Adverse Effects
• Common : Headache (31%), Asthenia (27%), Somnolence (27%),
Tremor (25%), Dizziness (25%), Diplopia (16%), Amblyopia/blurred
vision (12%), Nausea (48%), Vomiting (27%), Abdominal pain
(23%), Diarrhea (13%), Anorexia (12%), Flu syndrome (12%),
Infection (12%)
• Less Common: Dyspepsia (8%), Ataxia (8%), Nystagmus (8%),
Fever (6%), Emotional lability (6%), Thinking abnormal (6%),
Alopecia (6%), Weight loss (6%), Constipation (5%), Amnesia
(5%), Bronchitis (5%), Rhinitis (5%)
• Black Box Warnings: Hepatotoxicity, teratogenicity, pancreatitis
• Pregnancy Category: D
Valproate Drug Interactions
• CYP 450: CYP2C9 inhibitor, weak; 3A3/4
inhibitor, weak
• UGT2B7 inhibitor
• antiplatelet effects
• CNS depression
• hyperammonemia
• hyponatremia
Valproate Dosing
• Depakote initial dose: 750 mg/day PO in divided
doses
• Depakote ER initial dose: 25 mg/kg PO once
daily. Increase as rapidly as possible to achieve
the lowest therapeutic dose that provides
desired clinical effect or plasma concentration
• Doses should not exceed 60 mg/kg/day
Valproate Monitoring
•
Valproate Levels
• Target plasma levels = 50 - 125 or 150 mcg/mL
• Draw level prior to giving a dose
• SS within 1-4 days; draw level after 3rd or 4th day
• Other common monitoring parameters: LFTs at
baseline, then frequently, especially during 1st 6mo or if
suspected hereditary mitochondrial dz; Plt, coagulation
tests at baseline, then periodically, also before planned
surgery; serum drug levels; ammonia; s/sx depression,
behavior changes, suicidality
Lamotrigine
Lamotrigine Adverse Effects
• Common : Dizziness (38%), Diplopia (26-30%), Headache (29%),
Ataxia (22%), Blurred vision (16-20%), Rhinitis (11-15%),
Somnolence (14%)
• Less Common: Insomnia (6-10%), Fatigue (8%), Chest pain (5%),
Peripheral edema (2-5%), Suicidal ideation (2-5%), Dermatitis (25%), Dry skin (2-5%), Increased libido (2-5%), Rectal hemorrhage
(2-5%), Weakness (2-5%), Agitation (1-5%), Dysarthria (1-5%),
Edema (1-5%), Fever (1-5%), Migraine (1-5%), Abnormal thoughts
(1-5%), Urinary frequency (1-5%), Tremor (4%)
• Black Box Warnings: Serious rash (Stevens-Johnson syndrome)
• Pregnancy Category: C
Lamotrigine Drug Interactions
• Not a CYP inhibitor or inducer, but metabolism
is affected by inhibitors and inducers.
•
Caution when used in combination with
valproate/valproic acid
• UGT1A4 substrate
Lamotrigine Dosing
•
Monotherapy or without enzyme inducers or valproic
acid
•
Initial: 25 mg PO qDay for 2 weeks, then 50 mg PO qDay for 2
weeks; 100 mg PO qDay for 1 week; Double dose qWeek to
maintenance at 200 mg/day PO
• With AED regimen without valproic acid
•
Initial: 50 mg PO qDay for 2 weeks, then 100 mg/day PO
divided q12hr for 2 weeks; Increase by 100 mg qWeek to 400
mg/day PO divided q12hr
• With valproic acid
• Initial: 25 mg PO qOD for 2 weeks, then 25 mg PO qDay for 2
weeks; Double dose qWeek to maintenance at 100 mg/day PO
Lamotrigine Monitoring
• No specific plasma concentration monitoring
• Other common monitoring parameters: Cr at
baseline; ophthal. exams if prolonged tx; s/sx
depression, suicidality, clinical worsening if
bipolar disorder, and/or unusual behavior
changes
Carbamazepine
Carbamazepine Adverse Effects
• Common : Ataxia (15%), Dizziness (44%), Drowsiness (32%),
Nausea (29%), Vomiting (18%)
• Less Common: Dry mouth (8%)
• Rare: MI, Stevens-Johnson syndrome, Hepatic failure, Punctate
cortical lens opacities, Syndrome of inappropriate antidiuretic
hormone secretion (SIADH)
• Black Box Warnings: Serious and sometimes fatal dermatologic
reactions; aplastic anemia, agranulocytosis
• Pregnancy Category: D
Carbamazepine Drug Interactions
• CYP 450
•
CYP2C8 substrate, CYP3A4 substrate; CYP1A2/2A6 inducer, minor; CYP2B6
inducer, minor;CYP2C8 inducer, minor; CYP2C9 inducer, minor; CYP3A4
inducer, major; UGT1A4 inducer;P-gp (MDR1) inducer;
• CNS depression
• GI absorption enhanced by GLP-2 receptor agonist
• hyperammonemia
• hyponatremia
• increases thyroid hormone clearance
• serotonergic effects, weak
Carbamazepine Dosing
• Initial: 200 mg PO q12hr
• Increase by increments of 200 mg/day; not to exceed
1600 mg/day
Carbamazepine Monitoring
•
Target plasma concentration is 8-12 mcg/mL
• Toxic Levels: >12 mcg/mL
• Timing: before morning dose
• Time to Steady State: >1mo
•
Other common monitoring parameters: BUN/Cr, CBC
w/ diff, LFTs, urinalysis, ophthal. exams at baseline,
then periodically; serum drug levels; s/sx depression,
behavior changes, suicidality
Oxcarbazepine
Oxcarbazepine Adverse Effects
•
Common : Dizziness (30-50%), Diplopia (30-50%), Headache (26-30%),
Nausea/vomiting (26-30%), Nystagmus (26-30%), Somnolence (26-30%),
Ataxia (10-30%), Abnormal gait (16-20%), Tremor (16-20%), Abdominal pain
(11-15%), Fatigue (11-15%), Vertigo (11-15%), Vision abnormalities (11-15%)
•
Less Common: Dyspepsia (5-6%), Rash (4%), Insomnia (2-4%), Abnormal
thinking (<4%), Hyponatremia (1-3%), Muscle weakness (1-2%), Hypotension
(<2%), Speech disorder (1%), Asthenia
•
Post-marketing reports: Angioedema, Anaphylaxis, Bone marrow depression,
agranulocytosis, aplastic anemia, pancytopenia, neutropenia, Pancreatitis
and/or lipase and/or amylase increased, Folic acid deficiency, hypothyroidism,
Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis,
Multiorgan hypersensitivity disorders characterized by features such as rash,
fever, lymphadenopathy, abnormal liver function tests, eosinophilia, and
arthralgia
•
Pregnancy Category: C
Oxcarbazepine Drug Interactions
•
•
•
•
•
CYP2C19 inhibitor, moderate
CYP3A4 inducer, minor
CNS depression
Hyponatremia
Serotonergic effects, weak
Oxcarbazepine Dosing
• 300 mg/day PO initially; may titrate to 1800-2400 mg/day
maximum
Oxcarbazepine Monitoring
•
No specific target plasma concentration
recommendations
•
Other common monitoring parameters: Cr at baseline;
Na; s/sx depression, behavior changes, suicidality
Mood Stabilizer Costs
Drug
Average Cost*
Lithium
$9 W
Lithobid (lithium er)
$18
Depakote (divalproex)
$20
Depakote ER (divalproex er)
$105
Lamotrigine
$9
Lamictal XR (lamotrigine er)
$186
Carbamazepine
$6 W
Equetro (carbamazepine)
$72
oxcarbazepine
$27
*GoodRx.com price comparison; W=Walmart $4/$10 generic
STEP-BD
NIMH-funded Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD) is a
long-term outpatient study designed to find out
which treatments, or combinations of treatments,
are most effective for treating episodes of
depression and mania and for preventing
recurrent episodes in people with bipolar
disorder.
STEP-BD
•
N= 4360 total (Bipolar I, II, NOS, cyclothymia); assigned to “STEP-BDcertified psychiatrist”
•
Major findings:
•
After up to two years of best practices treatment, 58.4% of patients
met criteria for full recovery. 48.5% had a recurrence (72% with a
depressive episode; 28% with a manic, hypomanic, or mixed
episode). Residual sx was assoc with an ↑chance of recurrence.
•
Adjunctive psychosocial treatments but not adjunctive
antidepressants yielded outcomes superior to those achieved with
mood stabilizers alone in bipolar depression.
www.nimi.nih.gov; CNS Neuroscience & Therapeutics 2012; 18(3): 253-9; Am J Psychiatry 2008; 165:370-377
STEP-BD
•
Major findings:
•
Lamotrigine appears to be more effective than risperidone in treatmentrefractory patients with bipolar depression . Study assigned pts to one of
three adjunctive treatments: lamotrigine (up to 250 mg QD), inositol (up to
25 g QD), or risperidone (up to 6 mg QD) for up to 16 weeks. The recovery
rates were: lamotrigine, 23.8%; inositol, 17.4%; risperidone, 4.6% (findings
not ss).
•
Valproate is associated with PCOS. Study evaluated 230 women (ages
18- 44) for the development of PCOS sx (menstrual irregularities,
hirsutism, acne, hair loss, ↑testosterone). They found PCOS symptoms in
9 of 86 women on valproate (10.5%) compared to only 2 of 144 women on
a nonvalproate anticonvulsant or lithium (1.4%).
•
Prevention of rapid cycling recurrences may require early intervention and
restricted use of antidepressants.
www.nimi.nih.gov; CNS Neuroscience & Therapeutics 2012; 18(3): 253-9; Am J Psychiatry 2008; 165:370-377
The End!
Next Week:
Looking forward
to Dr. Betlinski’s
return