Bipolar

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Bipolar I

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one or more manic or mixed episodes with or without a depressive episode

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Bipolar II

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one or more hypomanic episodes and one or more major depressive episodes (but no manic or mixed episodes)

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Cyclothymic Disorders

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at least 2 years of numerous periods of hypomanic symptoms and numerous periods of depressive symptoms (but no major depressive episode)

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Lithium Mechanism of Action:

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mechanism as a “mood stabilizer” remains unknown
Competes with cellular sites for Na+, K+, Mg2+ and Ca2+
Overactivation of IP3 pathway has been correlated with manic events.
Li+ inhibits inositol monophosphatase,preventing the recycling of inositol phosphate into PIP2

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Lithium Pharmacokinetics

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90-95% eliminated by kidneys.
Onset of action for acute mania is 5-7 days
full therapeutic effect 10-21 days.

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Lithium Adverse Effects

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Polydipsia, Polyuria (uncouples Vasopressin)
Weight Gain (uncouples TSH)
Tremor, N/V, diarrhea,Edema,ECG changes,acne, rash
Teratogen-birth defects

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Lithium Toxic Concentration
Therapeutic Concentration:

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> 1.5 mEq/L
0.6-1.2 mEq/L (maintenance therapy)
1.0-1.5 mEq/L (acute mania)

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Lithium Toxicity

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• Mild: N/V/D, Tremor, Weakness, Fatigue
• Moderate: Confusion, Lethargy, Coarse tremor, Ataxia, Dysarthria, Nystagmus
• Severe: Seizures, Stupor, Coma, Death

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Lithium Interactions:

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• Increase Li+ concentrations: thiazide diuretics, NSAIDs, ACE-Is
• Decrease Li+ concentrations: caffeine, osmotic diuretics and carbonic anhydrase
inhibitors

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Lithium Interactions:

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• Increased toxicity with antipsychotics (eg. increased EPS in combination with
FGAs, Increased risk of NMS with SGAs) and anticonvulsants despite therapeutic
concentrations of each agent.
• Potential for Serotonin Syndrome with SSRIs, SNRIs, TCAs, etc.

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Anticonvulsants:
Carbamazepine

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Tegretol, Tegretol XR, Carbatrol, Equetro, generic

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Carbamazepine Indications

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Bipolar, mania, neuropathic pain, partial seizures, tonic-clonic
seizures, trigeminal neuralgia

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Carbamazepine Mechanism of Action:

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• Carbamazepine blocks use-dependent Na+ channels, inhibiting sustained repetitive firing in the CNS. This mechanism is shared with other agents.
• Carbamazepine prolongs the time in which the channel spends in the
“inactivated state”
• Carbamazepine may also act presynaptically to decrease synaptic transmission.

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Carbamazepine

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Food delays absorption
Extensive hepatic metabolism
T1/2 may decrease due to CYP3A4
induction
Serum drug level monitoring is required!

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CYP Inducers that decrease Carbamazepine

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Phenobarbital, phenytoin (anticonvulsants, CNS depression)
Action potentials generated by opening of the “use-dependent” Na+ channels. (Now Blocked)

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Carbamazepine Adverse Effects on CNS

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Diplopia (double vision), Ataxia (wobbliness, uncoordinated muscle
movement), Dysarthria (difficulty articulating speech), Drowsiness (higher doses)

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Carbamazepine Adverse Effects

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N/V, Diarrhea,liver transaminase elevation (usually benign), leukopenia, thrombocytopenia
rash, hyponatremia (SIADH), ECG changes
• Teratogen

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Carbamazepine Serious/life-threatening Adverse Effects:

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• Stevens-Johnson syndrome (5% mortality) or Toxic Epidermal Necrolysis (TEN,25% mortality)
• Agranulocytosis, aplastic anemia
• Hepatic failure
• Pancreatitis

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Valproic Acid

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Anticonvulsants
(Depakene, Depakote, Depakote ER, generic)

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Valproic Acid Mechanism of Action:

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Same blockage of use-dependent Na+ channels as carbamazepine
decreasing degradation of GABA
may block NMDA receptors, reducing excitatory amino acid
(Glutamate, Aspartate) effects
reduces brain concentrations of
Aspartate.

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Valproic Acid Pharmacokinetics

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Food delays absorption and may
decrease toxicity
Peak effects observed after 2 hr.
highly ionized and protein bound
thus has small VD of 0.15 L/kg.
T1/2 varies from 9-18 hr.

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Divalproex sodium

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is a sodium valproate:valproic acid combination that helps reduce GI
effects.

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Valproic Acid Pharmacokinetic Interactions:

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displaces phenytoin from plasma proteins
increases levels of Phenobarbital, phenytoin, carbamazepine and
lamotrigine
Fluoxetine, erythromycin, cimetidine can increase valproate levels

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Valproic Acid Adverse Effects:

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GI: nausea, vomiting, diarrhea, dyspepsia
• CNS: sedation, tremor, ataxia
• Metabolic: weight gain
• Dermatologic: alopecia
• Hematologic: thrombocytopenia
• Teratogen: avoid in pregnancy

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Valproic Acid Serious/Life-threatening Adverse Effects:

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Liver Failure: Monitor LFTs!
• Elevated ammonia levels: monitor
• Agranulocytosis and thrombocytopenia
• Pancreatitis

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Lamotrigine

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Anticonvulsants (Lamictal}
Indications: various seizure types, bipolar (maintenance); not approved for acute mania

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Lamotrigine Mechanism of Action

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similar mechanism (reduce Na+
channel activity)
May decrease presynaptic release of Glutamate and Aspartate from
excitatory neurons

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Lamotrigine Pharmacokinetics

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can induce its own metabolism.
extensively glucuronidated by liver and excreted by kidneys
pharmacokinetic interactions are fewer than with other agents.

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Lamotrigine Adverse Effects:

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Headache, Nausea, Dizziness, Ataxia (lack of coordination), Diplopia (double vision), Drowsiness
Tremor, Rash (self-limiting, but ~7-14% incidence)

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Lamotrigine Serious/Life-Threatening Adverse Effects:

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• Black box warning for SJS or TEN (rare though)
• Hepatic failure