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Arunditi Xantus, MDSeptember 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. Others
◦ Mood disorder NOS, depressive disorder NOS, SIMD.
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Symptoms present for at least 2 weeks
Depressed mood or anhedonia plus at least four of the following symptoms◦ 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)
At least 3 of the following (4 if mood is irritable)◦ 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.
At least 3 of the previously mentioned symptoms for mania (4 if mood is irritable)
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.
Mood episodes may be depressive, manic, hypomanic, or mixed.
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.
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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
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Mood disorder Lifetime prevalence
MDD -10-25% for women- 5-12% for men
Dysthymia ~ 6%
Bipolar I 0.4 – 1.6%
Bipolar II ~ 0.5%
Cyclothymia 0.4 – 1.0%
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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 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 FDA approved-- olanzapine and quetiapine
monotherapy Psychosocial
◦ Studies have proved efficacy of 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
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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.
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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.
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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 monthsonce stable, every 3-4 months.
◦ Upward titration until serum level = 0.8-1.2.
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Clinical guidelines, cont. Lithium should be d/c 2 days prior to
ECT combo can lead to delerium. Pregnancy: category D
◦ First trimester Ebstein’s anomaly◦ After first trimester, is the DOC amongst first
line agents. ◦ Breastfeeding contra-indicated.
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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
Thyroid– hypothyroidism (monitor q 6 months)
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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
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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
Treatment– discontinue lithium, hydrate, Kayexalate or GoLYTELY (decreases GI absorption )◦ Most severe cases = hemodialysis*
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Medications that decrease lithium levels
Medications that increase lithium levels
Xanthines (theophyllines, caffeines)Sodium bicarb (antacids)AcetazolamideOsmotic diuretics (mannitol)
Diuretics (thiazides and K+ sparing)NSAIDSCOX-2 inhibitorsMetronidazoleACE inhibitorsFluoxetine
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Indications FDA approved indications:
◦ 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.
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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.
Elimination– largely renal. Half life 9-16 hours (bid dosing often required). Highly protein bound.*
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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.
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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.
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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!
Pancreatitis: rare, occurs early in treatment. Hematologic: thrombocytopenia and platelet
dysfunctions bleeding disorders.
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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.
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Other drug-drug interactions Valproate can displace warfarin from
protein binding– monitor carefully! Valproate inhibits the metabolism, leading
to higher serum levels of◦Lamotrigine◦ Ethosuxamide◦ Diazepam◦ AZT
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Drugs that increase valproate levels
Drugs that decrease valproate levels
aspirin rifampin phenobarbitol (non-P450 induction) phenytoin (non-P450 induction) carbamazepine (non-P450 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.
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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.
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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.
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Side effects Common:
◦ GI: n/v, diarrhea, constipation, loss of appetite◦ CNS: sedation, dizziness, ataxia, confusion
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.
Hepatic: Hepatitis, cholestatic jaundice.
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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
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Drug-drug interactions The following meds inhibit the metabolism
of carbamazepine increasing serum levels◦Cimetidine◦ Ketoconazole◦ Verapamil◦Erythromycin◦ Fluoxetine◦ Isoniazid◦ Loratadine
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Drug-drug interactions Carbamazepine induces metabolism of these
drugs decreasing serum levels of these drugs◦ 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
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Indications FDA approved for
◦ 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.
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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.
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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.
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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 Metabolic: Weight gain GI: N/V Pyschiatric: agitation, depression, mania,
irritability
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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.
Mechanism of action– largely unknown.◦ Chemically related to GABA, but does not act on receptor.
Metbolism:◦ Renally excreted, unchanged form.◦ Half life = 5-7 hours (tid dosing)
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Clinical guidelines Avoid in renal dysfunction. Monitoring
◦ Periodic monitoring of kidney function.◦ Exclude pregnancy.◦ Serum levels not necessary
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.
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-, non-
barbituate- sensitive receptor site. Metabolism: Renal, with minimal hepatic
metabolism. Clinical guidelines
◦ Monitor renal function.◦ Decrease dose to ½ in renal impairment. ◦ No dose adjustment in the elderly.◦ Serum levels not necessary.
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Side effects Common: fatigue, somnolence, dizziness,
anorexia, ataxia, anxiety, parasthesias. Renal: renal calculi (1.5%) Other: can cause hyperchloremic, non-anion
gap metabolic acidosis.
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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
FDA approved for bipolar depression◦ Quetiapine and olanzapine-fluoxetine
FDA approved for maintenance◦ Quetiapine and olanzapine
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Bipolar mania/ agitation
Bipolar maintenance
Bipolar depression
Lithium
Valproic acid
Carbamazepine
Atypicals*
Quetiapine
Olanzapine
Lamotrigine
Quetiapine
Olanzapine-fluoxetine 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, 2005-2009.
Kaplan and Saddocks’ board review chapter on mood disorders.
Commonly tested material derived from Psychiatry for the Boards.