Arunditi Xantus, MDSeptember 14, 2009

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.

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

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)

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

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.

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.

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% for women- 5-12% for men

Dysthymia ~ 6%

Bipolar I 0.4 – 1.6%

Bipolar II ~ 0.5%

Cyclothymia 0.4 – 1.0%

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.

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%

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

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

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

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

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

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

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

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 monthsonce stable, every 3-4 months.

◦ Upward titration until serum level = 0.8-1.2.

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.

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)

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

Treatment– discontinue lithium, hydrate, Kayexalate or GoLYTELY (decreases GI absorption )◦ Most severe cases = hemodialysis*

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

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.

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.*

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!

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◦Lamotrigine◦ Ethosuxamide◦ Diazepam◦ AZT

Drugs that increase valproate levels

Drugs that decrease valproate levels

aspirin rifampin phenobarbitol (non-P450 induction) phenytoin (non-P450 induction) carbamazepine (non-P450 induction)

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.

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

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.

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◦Cimetidine◦ Ketoconazole◦ Verapamil◦Erythromycin◦ Fluoxetine◦ Isoniazid◦ Loratadine

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!

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.

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

◦ 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 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.

 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)

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.

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.

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.

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.

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

Bipolar mania/ agitation

Bipolar maintenance

Bipolar depression

Lithium

Valproic acid

Carbamazepine

Atypicals*

Quetiapine

Olanzapine

Lamotrigine

Quetiapine

Olanzapine-fluoxetine combination

Tiagabine Pregabalin Benzodiazepines Calcium channel blockers (L-type) Omega-3 fatty acids Inositol L-methylfolate (6-(S)-5-methyl-tetrahydrofolate,

or MTHF) Thyroid hormone

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.