Transcript Mood Stabilizers in the Treatment of Bipolar Disorder: High Yield

Arunditi Xantus, MD
September 14, 2009
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Major depressive disorder
Bipolar disorder type I and II
Dysthymia
Cyclothymia
DSM-IV-TR also includes 3 mood disorder research
categories
◦ Minor depressive disorder, recurrent brief depressive
disorder, and premenstrual dysphoric disorder.
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Others
◦ Mood disorder NOS, depressive disorder NOS, SIMD.
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Symptoms present for at least 2 weeks
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Depressed mood or anhedonia plus at least
four of the following symptoms
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Significant change in weight
Sleep disturbance
Psychomotor retardation or agitation
Fatigue or loss of energy
Excessive guilt or feelings of worthlessness
Difficulty concentrating
Recurrent thoughts of death or suicide
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One week of elevated, expansive or irritable mood
(less if hospitalized)
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At least 3 of the following (4 if mood is irritable)
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Inflated self esteem or grandiosity
Decreased need for sleep
Pressured speech or more talkative
Flight of ideas or subjective sense of racing thoughts
Distractability
Increased goal directed activity or psychomotor agitation
Risk-taking behavior (sexual promiscuity, increased
spending)
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Four days of elevated, expansive, or irritable
mood.
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At least 3 of the previously mentioned
symptoms for mania (4 if mood is irritable)
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Key difference from manic episode–
◦ No marked social or occupational dysfunction
◦ Does not require hospitalization
◦ No psychotic features are present
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Criteria for both manic/hypomanic episode
and major depressive episode are present
for one week.
Symptoms cause marked social or
occupational dysfunction, require
hospitalization, or psychotic features are
present.
Subjectively patients experience rapidly
shifting mood.
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At least four mood episodes within one year.
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Mood episodes may be depressive, manic,
hypomanic, or mixed.
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Patient must be symptom free for at least two
months between episodes, or there must be a
change in mood to an opposite type of
episode.
Disorder
Manic symptom criteria
Depressive symptom criteria
Major
Depressive
Disorder
No history of mania or
hypomania
History of major depressive episode (single or
recurrent)
Dysthymic
disorder
No history of mania or
hypomania
Depressed mood, more days than not, for at least
two years (but not meeting criteria for a major
depressive episode)
Bipolar I
disorder
History of mania or mixed
episodes
Major depressive episodes typical but not required
for diagnosis
Bipolar II
disorder
At least one episode of
hypomania; no manic or
mixed episodes
History or presence of at least one or more major
depressive episodes
Cyclothymic
disorder
For at least two years, the
presence of numerous periods
of hypomanic episodes
For at least two years, numerous periods with
depressive symptoms that do not meet criteria for
a major depressive episode
Mood disorder
Lifetime prevalence
MDD
-10-25%
Dysthymia
~ 6%
Bipolar I
0.4 – 1.6%
Bipolar II
~ 0.5%
Cyclothymia
0.4 – 1.0%
for women
- 5-12% for men
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Epidemiology
◦ Life-time prevalence ~ 0.5 to 1.5 %.
◦ Male:female ratio 1:1.
◦ First episodes in males tends to be manic, 1st
episode in females tends to be depressed.
◦ Higher rates of mood disorders amongst 1st degree
relatives.
 70% concordance rate with monozygotic twins.
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Clinical features
◦ 90% of patients w/ a single manic episode will
have a recurrence
◦ Mixed episodes more likely in younger pts
◦ Episodes increase in freqency with age
◦ Common comorbid diagnoses
 Substance abuse
 Eating disorders
 ADHD
◦ 20% have rapid cycling poorer prognosis
◦ Suicide rate is 10-15%
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Traditional mood stabilizers
Antidepressants
◦ Must be used with mood stabilizer
◦ TCAs and SNRIs = higher incidence of induced mania
◦ May induce rapid cycling
Atypical antipsychotics
Benzodiazepines
ECT– for depressive or manic episodes
Psychotherapy
◦ Aim is to increase insight to consequences of manic
behavior
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Acute treatment
◦ Manic or mixed episode
 First line = lithium or valproate + antipsychotic
 For less ill patients monotherapy with lithium,
valproate or antipsychotic (olanzapine*)
 Mixed episodes = valproate over lithium
 Benzodiazepines (short term)
 Antidepressants should be d/c if possible
 If first line med fails, add another first line med
 ECT
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Acute treatment
◦ Depressive episode
 First line tx = initiation of lithium or lamotrigine
 Antidepressant monotherapy not recommended
 Breakthrough depression on first line agent?
 First optimize first line agent
 Next, add lamotrigine, buproprion, SSRI, venlafaxine, or
MAOI
 Treatment resisitant ECT
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Acute treatment
◦ Rapid cycling
 Identify and treat any underlying medical conditions
 hypothypothyroid, drug/alcohol use
 Taper antidepressants if possible
 Lithium or valproate (valproate!!!)
 Alternative = lamotrigine
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Maintenance treatment
◦ Valproate or lithium = best evidence
◦ Lamotrigine, carbamazepine, oxcarbamazepine =
alternatives
◦ Antipsychotic should be tapered if not indicated*
◦ Psychosocial intervention– group therapy, therapy
that addresses illness management
◦ Maintenance ECT
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Manic or mixed episodes
◦ Multiple studies show atypicals (monotherapy or
adjunct) are superior to placebo
 All approved except clozapine, asenapine, and
paliperidone
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Depressive episodes
◦ Olanzapine+ fluoxetine (OFC) superior to
olanzapine alone and placebo-- FDA approved
◦ Quetiapine superior to placebo-- FDA approved
◦ Lamotrigine also has favorable evidence
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Maintenance
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FDA approved-- olanzapine and quetiapine
monotherapy
Psychosocial
◦ Studies have proved efficacy of
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Family-focused therapy
Cognitive therapy
Longitudinal psychoeducational programs (2 years)
Techniques aimed to regulate social rhythms
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Lithium: the classic mood stabilizer
Anticonvulsants as mood stabilizers
- Valproic acid
- Carbamazepine
- Oxcarbazepine/eslicarbazepine
- Lamotrigine
- Topiramate
- Gabapentin
Atypical antipsychotics: not just for psychotic
mania
Other agents used in bipolar disorder
Indications
 FDA approved-- bipolar manic episode and
mainatenance.
 FDA approved -- children 12 years and
older.
 Augmentation in depressed patients.
 Other clinical uses: schizoaffective disorder,
severe cyclothymia, borderline personality
disorder, impulse control disorders.
Pharmacology
 May block inositol-1-phosphatase, leading
to interuption of PIP 2nd messenger system.
 Excreted by kidneys. Not metabolized in
liver!!
 Impaired renal function or decrease in fluid
or salt intake can lead to toxicity.
◦ Lower doses required in elderly 2nd decreased
GFR.
Clinical guidelines
 First line agent for bipolar disorder.
 ~30% will not respond to lithium. *
 Screening labs: BMP (BUN/creatinine), TSH, CBC,
EKG in patients >40 or with a cardiac history, and
urine pregnancy.
 Therapeutic response may take 4-6 weeks.
 Monitoring:
◦ After 5 days then weekly for the first 2 months then
biweekly for the next 2 monthsonce stable, every 3-4
months.
◦ Upward titration until serum level = 0.8-1.2.
Clinical guidelines, cont.
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Lithium should be d/c 2 days prior to ECT
combo can lead to delerium.
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Pregnancy: category D
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First trimester Ebstein’s anomaly
After first trimester, is the DOC amongst first line
agents.
Breastfeeding contra-indicated.
Side effects
 Common– GI distress, weight gain, fine
tremor, and cognitive impairment (“fuzzy
thinking”)
 Renal
◦ Polyuria with 2nd polydipsia in 20% nephrogenic
diabetes insipidus
◦ Rare: nonspecific interstitial kidney fibrosis
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Thyroid– hypothyroidism (monitor q 6
months)
Side effects
 Cardiovascular– T wave flattening (similar to
hypokalemia), arrhythmias (rare)
 Dermatologic– rash, acne, alopecia, worsens
psoriasis
 Hematologic—benign leukocytosis
 Neurologic—muscle weakness, slurred
speech, HAs
Lithium toxicity
 Usually due to decrease fluid or salt intake, or to
increased fluid loss
 Sx = n/v, diarrhea, coarse tremor, ataxia,
headache, slurred speech, confusion, brisk DTRs,
coma, death
◦ Mild-mod toxicity = 1.5-2.0
◦ Severe = >2.5
◦ Death may occur at >4.0 mEq/L
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Treatment– discontinue lithium, hydrate,
Kayexalate or GoLYTELY (decreases GI absorption )
◦ Most severe cases = hemodialysis*
Medications that
Medications that
decrease lithium levels
increase lithium levels
Xanthines (theophyllines, Diuretics (thiazides and
K+ sparing)
caffeines)
NSAIDS
Sodium bicarb (antacids)
COX-2 inhibitors
Acetazolamide
Metronidazole
Osmotic diuretics
ACE inhibitors
(mannitol)
Fluoxetine
Indications
 FDA approved indications:
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Absence seizure, simple and complex
Complex partial epileptic seizure
Manic bipolar I disorder
Migraine, prophylaxis
Seizure, multiple seizure types; adjunct
More effective for rapid- or ultra rapid-cycling and
for mixed episodes than lithium.
Other clinical uses: ICD, IED, kleptomania,
aggressive behavior in patients with developmental
disorders or organic brain lesions.
Pharmacology*
 Mechanism of action: neuronal signal transduction
through protein kinase C. May also involve GABA.
 Metabolism:
◦ Hepatic conjugation, mitochondrial beta-oxidation and
other oxidative mechanisms extensive.
◦ P450 system relatively unimportant.
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Elimination– largely renal.
Half life 9-16 hours (bid dosing often required).
Highly protein bound.*
Clinical guidelines
 First line agent for bipolar disorder, esp for rapid
cycling or mixed mood episodes.
 Avoid in patients with pre-existing hepatic or
hematologic disease.
 Screening labs: CBC, LFTs, and urine pregnancy.
 Monitoring:
◦ Serum level: after 3 days then weekly x 1-2 mo  then
biweeekly x 2 months then q 3-4 months.
◦ Serum level for adequate symptom relief = 50-125 (usually)
◦ CBC and LFTs after one month, and then quarterly x 1 yr.
Clinical guidelines
 Dosing in elderly: ½ that of younger pts.
 Therapeutic response: can take 2-4 wks.
 Pregnancy: category D
◦ Should not be used in pregnancy neural tube
defects (1-2%) and other birth defects.
◦ Hepatic failure and clotting disorders in infants
do not breastfeed.
Side effects
 Common: sedation, dizziness, n/v
 Hepatitis:
◦ Can be lethal, occurs more often in children, usually w/in
first 6 months, sx = n/v, lethargy, jaundice, and weakness.
◦ Occurs in 0.0005%; d/c immediately.
◦ 25% will have transient increase in LFTs; monitor!
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Pancreatitis: rare, occurs early in treatment.
Hematologic: thrombocytopenia and platelet
dysfunctions bleeding disorders.
Side effects, cont.
 Neurologic: tremor, ataxia, HA, insomnia,
agitation.
 Other GI: changes in appetite, wt gain,
diarrhea, constipation.
 Dermatologic: alopecia, hirsutism, changes
in facial features, maculopapular rash.
 Overdose: symptoms include somnolence,
heart block, and coma.
Other drug-drug interactions
 Valproate can displace warfarin from
protein binding– monitor carefully!
 Valproate inhibits the metabolism, leading
to higher serum levels of
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Lamotrigine
Ethosuxamide
Diazepam
AZT
Drugs that
increase
valproate
levels
 aspirin
Drugs that decrease
valproate levels
rifampin
 phenobarbitol (nonP450 induction)
 phenytoin (non-P450
induction)
 carbamazepine (nonP450 induction)
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FDA approved indications:
◦ Bipolar I disorder, acute manic and mixed
episodes
◦ Epilepsy, partial, generalized, and mixed types
◦ Glossopharyngeal neuralgia
◦ Trigeminal neuralgia
Other uses: cyclothymia, schizoaffective
disorder, aggression, impulsivity,
personality disorders, adjunct in
depression.
May be used alone or in combination with
lithium.
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Mechanism of action: largely unknown.
◦ Bind to voltage-dependent sodium channels in
inactive state prolonged inactivation 2nd
inactivation of Ca++ channels decreased
synaptic transmission.
Metabolism: via P450 cytochrome 3A4.
Induces its own metabolism.
Excretion: renal, including active
metabolites.
Half-life: 25-65 hrs  after 2 weeks, 12-17
hrs.
Clinical guidelines:
 Avoid in patients with liver, cardiac, hematologic
abnormalities, as well as renal dysfunction.
 Monitoring
◦ Initial: BMP (BUN/Cr), LFTs, EKG in >40 or with cardiac
abnl, u preg.
◦ Serum levels: at Day 5 then weekly x 1-2 mo then
biwekly x 2 mo then q 3-4 months (serum level 8-12)
◦ Check LFTs, renal function, CBC, and electrolytes after one
month, than q 3 months.
Clinical guidelines:
 Lithium nonresponders: can add
carbamazepine, and if effective slowly d/c
lithium.
 Pregnancy: category D
◦ Assoc w/ spina bifida and minor craniofacial
abnls.
◦ Although excreted in breastmilk, considered safe
in breastfeeding by AAP.
Side effects
 Common:
◦ GI: n/v, diarrhea, constipation, loss of appetite
◦ CNS: sedation, dizziness, ataxia, confusion
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Hematologic:
◦ Can cause a life-threatening thrombocytopenia,
agranulocytosis, and aplastic anemia in 0.0005%.
◦ Signs of bleeding abnl +/- infx?  CBC immediately!
◦ D/c if WBC < 3,000, ANC <1500, or platelets <100,000.
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Hepatic: Hepatitis, cholestatic jaundice.
Side effects
 Dermatologic: rash and uticaria (common),
photosensitivity (rare), SJS ( very rare)
 Cardiac: AV conduction defects,
arrhythmias, CHF
 Endocrine: SIADH with resulting
hyponatremia
 Toxicity: Confusion, stupor, motor
restlessness, dilated pupils, tremor,
athetoid movements, n/v
Drug-drug interactions
 The following meds inhibit the metabolism
of carbamazepine increasing serum levels
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Cimetidine
Ketoconazole
Verapamil
Erythromycin
Fluoxetine
Isoniazid
Loratadine
Drug-drug interactions
 Carbamazepine induces metabolism of these
drugs decreasing serum levels of these drugs
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Clozapine
Haloperidol
Benzodiazepines
Oral contraceptives
Methadone
Valproate
Depakote
Warfarin
Many others!
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Lamotrigine and valproate can increase
levels of the active metabolite may have
toxicity even with normal serum levels.
Carbamazepine decreases valproate levels.
Use diuretics with caution (hyponatremia.)
Due to molecular similarity with TCAs, allow
2 week washout period before initiating
MAOIs.
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Similar in efficacy to carbamazepine.
FDA approved for partial seizure, monotherapy and
adjunct.
Use in bipolar disorder = non-FDA approved
indication.
Metabolism: induces 3A4/5, inhibits 2C19
Differences from carbamazepine:
◦ Fewer drug interactions
◦ Fewer incidences of SJS, hematologic issues, and
hepatotoxicity
◦ Not associated with neutropenia
◦ Patients switched from carbamazepine require 1.5x the
dose
Indications
 FDA approved for
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Bipolar I disorder, maintenance
Lennox-Gastaut syndrome; adjunct
Partial seizure, adjunct or monotherapy
Tonic-clonic seizure, primary generalized, adjunct
Non-FDA include bipolar disorder depressed
phase.
Lamotrigine appears to be more effective than
other mood stabilizers in unipolar depression;
studies underway.
Pharmacology
 Mechanism of action: may affect Na+
channels which modulate glutamate and
aspartate.
 Metabolism
◦ Hepatic, via glucuronidation.
◦ Renally excreted nonactive metabolite.
◦ Half life 25 hrs.
Clinical guidelines
 Renal and hepatic function should be
monitored, as well as urine pregnancy.
 Pregnancy category C: no controlled human
studies.
◦ Avoid during 1st trimester.
◦ Avoid with breastfeeding.
Side effects
 Common: diziness, sedation, HA, diploplia, ataxia,
decresed coordination
 Dermatologic
◦ Rash (10%), most likely in first 6 weeks. D/c over 1-2 days.
◦ Steven Johnson’s syndrome
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Metabolic: Weight gain
GI: N/V
Pyschiatric: agitation, depression, mania, irritability
Drug interactions:
 Carbamazepine decreases levels of
lamotrigine; lamotrigine increases levels of
carbamazepine.
 Valproate increases levels of lamotrigine by
up to 2x.
 No interaction with lithium.
 Can be used with MAOIs.
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Indications
◦ FDA-labeled indications– partial seizure, adjunct;
postherpetic neuralgia.
◦ Non-FDA labeled uses include bipolar disorder, peripheral
neuralgia, fibromyalgia, migraine prophylaxis, neuropathic
pain, social phobia, RLS and others.
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Mechanism of action– largely unknown.
◦ Chemically related to GABA, but does not act on receptor.
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Metbolism:
◦ Renally excreted, unchanged form.
◦ Half life = 5-7 hours (tid dosing)
Clinical guidelines
 Avoid in renal dysfunction.
 Monitoring
◦ Periodic monitoring of kidney function.
◦ Exclude pregnancy.
◦ Serum levels not necessary
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Pregnancy category C– avoid in first
trimester. Discourage breastfeeding.
No interaction with other anticonvulsants.
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FDA approved uses are limited to seizure
disorders.
Studies do not support the effectiveness of
topirimate in bipolar disorder.
◦ May consider as adjuvunctive in obese pts.
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May have some effectiveness in impulse
control disorder, migraines, PTSD, and
bulimia.
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Mechanism of action unknown.
◦ Potentiates GABA at non-benzo-, nonbarbituate- sensitive receptor site.
Metabolism: Renal, with minimal hepatic
metabolism.
Clinical guidelines
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Monitor renal function.
Decrease dose to ½ in renal impairment.
No dose adjustment in the elderly.
Serum levels not necessary.
Side effects
 Common: fatigue, somnolence, dizziness,
anorexia, ataxia, anxiety, parasthesias.
 Renal: renal calculi (1.5%)
 Other: can cause hyperchloremic, non-anion
gap metabolic acidosis.
Drug-drug interactions
 Carbamazepine decreases levels of
topiramate.
 Acetazolamide can increase risk of kidney
stones and should be avoided.
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FDA approved for mania
◦ All except clozapine and paliperidone
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FDA approved for bipolar depression
◦ Quetiapine and olanzapine-fluoxetine
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FDA approved for maintenance
◦ Quetiapine and olanzapine
Bipolar mania/
agitation
Lithium
Valproic acid
Carbamazepine
Atypicals*
Bipolar
maintenance
Quetiapine
Olanzapine
Lamotrigine
Bipolar
depression
Quetiapine
Olanzapinefluoxetine
combination
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Tiagabine
Pregabalin
Benzodiazepines
Calcium channel blockers (L-type)
Omega-3 fatty acids
Inositol
L-methylfolate (6-(S)-5-methyl-tetrahydrofolate,
or MTHF)
Thyroid hormone
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Questions derived from past PRITEs, 20052009.
Kaplan and Saddocks’ board review chapter
on mood disorders.
Commonly tested material derived from
Psychiatry for the Boards.