Lecture 70 - Pharmacotherapy of Bipolar Disorder

Question 1

Clinical factors - disease course

Answer 1

Depression is the mood pole that is experienced most often in bipolar disorder – can lead to misdiagnoses

Question 2

Clinical factors - comorbidities

Answer 2

Alcohol and substance use common (50 – 60%)
Anxiety disorders are common comorbidities and can significantly impact remission of mood episodes if left untreated or inadequately treated

Question 3

Bipolar Disorder Classification - Bipolar I Disorder

Answer 3

≥ 1 manic episodes

Question 4

Bipolar Disorder Classification - Bipolar II Disorder

Answer 4

hypomanic episodes

Question 5

Pharmacotherapy Overview

Answer 5

• Mood stabilizers are the foundation of acute and maintenance treatment
• 1st line: usually lithium or valproic acid
• Atypical antipsychotics can also be used 1st line, as monotherapy or in combination with lithium or valproic acid
• Many patients will take polytherapy with mood stabilizers

Question 6

Lithium – Use and Dosing

Answer 6

Associated with decrease in suicidality
Lithium is a narrow therapeutic index (NTI) medication
Dosage forms: Some difference in lithium content, but use 1:1 conversion

Question 7

Lithium – Monitoring and Adverse Events: narrow therapeutic index

Answer 7

• Acute treatment: 0.9 – 1.2 mEq/L
  *Maintenance: 0.6–0.9mEq/L
• Toxicity (mild to severe): 1.5 - > 3.0 mEq/L
• Draw trough serum concentration 72 hours after dose initiation, 12 hours after last dose

Question 8

Lithium – Monitoring and Adverse Events: toxicities

Answer 8

• GI, ataxia, coarse hand tremor, altered mental status, seizure, lethargy, confusion, agitation

Question 9

Lithium – Monitoring and Adverse Events: side effects

Answer 9

• Fine hand tremor, hypothyroidism, polyuria, polydipsia, acne, dry mouth, weight gain, ECG changes

Question 10

Lithium – Monitoring and Adverse Events: teratogenic

Answer 10

• Cardiac structural abnormality (Ebstein’s anomaly)
• Avoid in 1st trimester – use with caution in 2nd and 3rd trimester

Question 11

Lithium: Laboratory Monitoring

Answer 11

• SCr, BUN (almost entirely
  renally excreted)
• Urine specific gravity
• Na, K, Ca
• ECG (especially if age > 40 or cardiac risk factors)
• Thyroid Function – TSH, T4
• Parathyroid hormone
• CBC with differential
• Weight
• Pregnancy Test

Question 12

Lithium: Drug Interactions

Answer 12

• Decreased Li renal clearance (↑ Li levels) – ACEi, ARBs, thiazide diuretics, NSAIDs, dehydration
• Increased Li renal clearance (↓ Li levels) – caffeine, osmotic diuretics, +/- loop diuretics
• Increased Li excretion (↓ Li levels) – sodium bicarbonate, high Na intake
• Toxicity related to Na depletion – thiazide diuretics

Question 13

Valproate

Answer 13

Available in several dosage forms risk for med errors:
*Extended release (ER) dosage form is ~ 10-15% less bioavailable than delayed release (DR) dosage form
*1:1 conversion, expect lower serum concentration with the ER dosage form – usually not clinically significant
*Valproic acid syrup (IR) and capsule sprinkle form – higher risk for GI ulcerations (usually esophageal)
*Serum levels 80 – 125 mcg/ml associated with most efficacy in mania, obtain level at least 96 hours (4 days) after first dose or dose increase

Question 14

Valproic Acid – Adverse Effects

Answer 14

Unsafe in any trimester of pregnancy – obtain baseline pregnancy test
Polycystic ovarian syndrome occurs in up to 50% of women
GI – anorexia, N/V/D, dyspepsia, ulceration
Thrombocytopenia, platelet dysfunction
Teratogenic – neural tube defects, enduring negative effects on IQ of offspring
Hyperammonemia
Increased appetite – weight gain (~6-8 kg)

Question 15

Valproate: Laboratory Monitoring

Answer 15

Baseline – Pregnancy test, LFTs, CBC w/differential
Routine - serum concentration
Serum ammonia–if suspect
hyperammonemia; routine ammonia monitoring is not necessary

Question 16

Valproate: Drug Interactions

Answer 16

Significant concern with combination use with lamotrigine – increased lamotrigine serum concentrations ↑ risk of Stevens-Johnson syndrome

Question 17

Carbamazepine

Answer 17

thrombocytopenia/ hematologic effects

Question 18

Oxcarbazepine

Answer 18

CYP450 3A4 inducer
hyponatremia

Question 19

Lamotrigine

Answer 19

1st line treatment for DEPRESSIVE symptoms in bipolar disorder
NOT useful for acute treatment or for manic episodes

Question 20

Topiramate

Answer 20

• May cause weight loss
• Heat intolerance/ hypohidrosis
• Metabolic acidosis and kidney stones
• Possible teratogen – cardiac structural defects

Question 21

Antipsychotics in Bipolar Disorder - Pearls

Answer 21

Atypical antipsychotics may be used as monotherapy or can be used combination with other mood stabilizers (usually valproate or lithium)
All monitoring parameters for metabolic syndrome and movement side effects apply when used for bipolar disorder

Question 22

Treatment Considerations

Answer 22

Mood stabilizer treatment is long-term and considered to be maintenance treatment to reduce time to subsequent mood episodes
Suicide attempt risk is high in both poles of bipolar disorder – monitor closely, use lithium cautiously

Question 23

Treatment in Pregnancy

Answer 23

Lithium, valproic acid, carbamazepine and topiramate are known or possible teratogens

Question 24

Antidepressants in Bipolar Disorder

Answer 24

Use of antidepressants is linked with a switch to mania: Need to have maintenance mood stabilizer therapy in combination with antidepressant therapy
Anxiety disorders are a common comorbidity in bipolar disorder: Will use serotonergic antidepressants to treat anxiety
Prefer to use mood stabilizers that target the depressive pole: Lamotrigine, lithium, lurasidone, quetiapine