Exam 3 - Pharmacology of Mood Stabilizers (Sant)

Learning Objectives:

• Describe bipolar disorder and its presentation

• Understand the progression of bipolar disorder and various types of bipolar disorder

• Know about various classes of drugs used in treatment, prophylaxis and management of bipolar disorder

• Understand the mechanism, pharmacokinetics, adverse effects of important drugs used in treatment of bipolar disorder

What are mood disorders?

• Range of mental illnesses characterized by alterations in mood and emotional state.

  • Affect daily functioning

• Unipolar depression (Major depressive disorder)

• Bipolar disorder: Mania & depression

What are symptoms of mania?

• Distractibility

• Impulsive – risk taking

• Grandiosity

• Flight of ideas

• Excessive talkativeness

• Hyperactivity

• Decreased need forsleep

What are symptoms of depression?

• Sadness / hopelessness

• Irritability or frustration, angry

• Loss of interest or pleasure

• Sleep disturbances: insomnia or too much

• Suicidal thoughts / attempts

What is the proposed pathophysiology of bipolar depression?

Neurotransmitter imbalance

• Mania → excess of norepinephrine & dopamine

• Depression → deficiency of serotonin, norepinephrine & dopamine

What is the presentation of bipolar disorder?

• Mood episodes – mania, hypomania, depressive, mixed

• Bipolar I disorder: mania or mixed episodes with or without major depressive episodes

  • At least 3 symptoms of mania for 1 week, or hospitalization

• Bipolar II disorder: major depressive episodes with hypomanic episodes (no mania)

  • At least 3 symptoms for 4 days

  • Mixed episodes

What is the treatment goals/pathway for bipolar disorder?

1) Control agitation, reduce risk of harm (self & others), return of normal functioning

• Induction of sedation & sleep

• Mood stabilizers: lithium, divalproex sodium

• Adjunctive treatment: antipsychotics or benzodiazepines (clonazepam, lorazepam)

2) Bipolar depression – relieve depression without inducing manic episode

• Antidepressant + mood stabilizer / antipsychotic

3) Maintenance treatment – prevent / minimize future episodes, maximize functioning ability, improve quality of life

• Lithium, divalproex sodium, carbamazepine, lamotrigine

Wh

What is our first line agents for treatment of bipolar diroder?

LITHIUM

• First line treatment – acute manic, mixed episodes & maintenance

• Useful for patients not responding to other treatments

• Useful in patients with history of suicidal behavior

• Reduces emergence of depressive phase

• Adjunctive treatment with other drugsfor refractory cases

What is Lithium’s proposed mechanism of action?

NOT a substrate of Na+ pump

• Suppresses inositol signaling by depletion of intracellular inositol

• Disrupts 2nd messengers in inositol signaling pathway

  • Inositol triphosphate (IP3 ) and diacylglycerol (DAG)

  • Both involved in adrenergic and muscarinic transmission

• Can inhibit adenylyl cyclase (sensitive to NE)

• May uncouple receptors from their G proteins – side effects include polyuria and hypothyroidism

What are Lithium’s PK?

• Rapid oral absorption

• Excreted unchanged in urine

• Half life: 24h

• Slow onset of action: 5-7 days for acute mania, 2-3 weeks for depression

• Plasma levels: Significant interpersonal variability

  • Toxicity related to plasma levels

Does lithium have a narrow or wide therapeutic index?

Narrow therapeutic window – serum concentration monitoring

What are adverse effects of Lithium?

• GI disturbances - nausea, vomiting, diarrhea

• Tremor

• Polyuria, polydipsia

• Hypothyroidism – blocks release of thyroid hormone (T3 and thyroxine)

• Weight gain, edema (sodium retention)

• Teratogenic

• Drug-drug interactions – active monitoring

What should we counsel on to patient’s starting lithium therapy?

• Maintain adequate water intake: dehydration ↑ serum concentration

• Keep sodium intake consistent → low sodium ↑ lithium

• Large amounts of caffeine can ↓ lithium concentration by diuresis

What are CONTRAINDICATIONS to lithium therapy?q

• Renal failure

• Pregnancy (1st trimester)

What is lithium’s use in therapy?

• 1) Primary use: mood stabilizer in the treatment of bipolar disorder

  • Effective in reducing the frequency and severity of mood episodes, including mania, hypomania, and depression

  • Onset of action: 5-7 days for acute mania, 2-3 weeks for depression

• 2) Adjunctive treatment in combination with other medications for refractory cases

• 3) Prophylaxis

  • Prevent future episodes in bipolar disorder

  • Helps prevent suicide & self-harm

What is depakote?

• Depakote ® = 1:1 mole mixture of valproic acid and Sodium valproate

• Anticonvulsant

What is the MOA of Depakote?

Mechanism of action

• Inhibits Na+ channels inhibiting release of excitatory neurotransmitters (glutamate)

• Enhances inhibitory action of gamma-amino butyric acid (GABA)

What are AE’s/counseling points of Depakote?

• Adverse effects

  • Gastric disturbances – nausea, vomiting

  • Depacote – fewer gastric side effects – delayed release formulation

  • Tremor, weight gain, alopecia, thrombocytopenia

  • Teratogenic!!!

• Patient counseling

  • Take with food to minimize GI effects

  • Take Selenium and zinc to treat hair loss

What is Depakote’s role in bipolar disorder?

Initial management of acute mania – equivalent efficacy to lithium

• Preferred agent for mixed episodes of bipolar disorder

• Advantages

  • Faster onset of action

  • Wider safety margin

  • Less side effects

What is Carbamazepine’s (Tegretol) role in bipolar disorder?

• Effective in manic, mixed episodes

• Maintenance treatment of bipolar disorder

What is the MOA of Carbamazepine?

Mechanism of action:

• Na+ & K+ channel inhibitor

• Enhance inhibitory action of GABA (gamma-amino butyric acid)

Carbamazepine is an inducer of..?

Cytochrome P450 (CYP3A4) inducer → dose adjustments needed for substrates e.g. oral contraceptives

Does carbamazepine have a narrow or wide therapeutic index?

Narrow therapeutic window

• Blood level monitoring

• Therapeutic levels: 4 -12 mcg/mL

What AE’s does Carbamazepine have?

Adverse effects

• Sedation, dizziness, weight gain

• May cause Stevens-Johnson syndrome or toxic epidermal necrolysis

• Agranulocytosis

What is Lamotrigine’s role in bipolar disorder?

• Anticonvulsant medication

• Approved for maintenance treatment of bipolar I disorder

• Alternative to lithium for bipolar depressive episodes

• Not effective to treat manic episodes

Which side effects are associated with Lamotrigine?

Side effects

• Rashes (potentially life-threatening)

  • Discontinue at first sign of rash

• Headache, dizziness, GI distress

What is the role of atypical antipsychotics (AAPs) in bipolar disorder?

Growing use in bipolar disorder treatment

• Monotherapy

• Adjunct with lithium or divalproex

Used in treating acute phase of manic episode

Which atypical antipsychotics are apporved for acute manic or mixed episodes?

• Olanzapine (Zyprexa ®)

• Aripiprazole (Abilify®)

• Quetiapine (Seroquel ® or Seroquel XR®)

• Ziprasidone (Geodon®)

• Asenapine (Saphris®)

What are side effects of aytpical antipsychotics?

Side effects: Weight gain, dyslipidemia, glucose intolerance

What is the role of antidepressants in bipolar disorder?

Treatment of depressive episode in bipolar disorder

• Used in combination with mood stabilizer

• Can precipitate manic episode if used alone!!!

Which antidepressants can be used in combination with a mood stabilizer?

• SSRIs (Selective serotonin reuptake inhibitors)

  • Less likely to cause conversion to mania compared to tricyclic antidepressants (TCA)

  • Flouxetine (Prozac®)

  • Paroxetine (paxil®)

  • Sertraline (Zoloft®)

• Citalopram (Celexa®) and escitalopram (Lexapro®)

• Bupropion (Wellbutrin®), a dopamine / norepinephrine reuptake inhibitor