Mood Stabilizers Part 2

Valproate Drug Interactions

• Antidepressants: Amitriptyline and fluoxetine may increase valproate serum concentrations.

• Diazepam: Serum concentration increased by valproate

• Clonazepam: May cause absence status (rare; reported only in patients with preexisting epilepsy).

• Phenytoin: Serum concentration decreased by valproate.

• Phenobarbital: Serum concentration increased by valproate; increased sedation.

• Other CNS depressants: Increased sedation

• Anticoagulants: Possible potentiation of effect

Valproate Laboratory Interferences

• May cause a laboratory increase of serum-free fatty acids.

• Valproate metabolites may produce a false-positive test result for urinary ketones.

• May produce falsely abnormal thyroid function test results.

Recommended Laboratory Tests During Valproate Therapy

Before Treatment:

• Standard chemistry screen with special attention to liver function tests

• CBC (complete blood count), including WBC (white blood cell) and platelet count

During Treatment:

• Liver function tests at 1 month, then every 6–24 months if no abnormalities are found.

• Complete blood count with platelet count at 1 month, then every 6–24 months if findings are normal.

Management of Abnormal Liver Function Test Results

• Mild Transaminase Elevation (less than three times normal):

  • Monitor every 1–2 weeks

  • If stable and patient is responding to valproate, monitor monthly to every 3 months

• Pronounced Transaminase Elevation (more than three times normal):

  • Dosage reduction or discontinuation of valproate

  • If transaminases normalize and patient is a valproate responder, consider increasing dose or rechallenging.

Dosage and Clinical Guidelines for Valproate Therapy

• Initial Testing:

  • Baseline hepatic panel, CBC and platelet counts, and pregnancy testing should be ordered

  • Additional testing (amylase and coagulation studies) if baseline pancreatic disease or coagulopathy is suspected

• Ongoing Monitoring:

  • Hepatic transaminase concentrations should be obtained 1 month after initiation of therapy and every 6 to 24 months after that.

  • Frequent monitoring may not predict severe organ toxicity

• Asymptomatic Transaminase Elevation:

  • Concentrations up to three times the upper limit of normal are typical and do not require any change in dosage.

• Acute Mania Treatment:

  • Oral loading strategy: initiation with 20 to 30 mg/kg a day can be used to accelerate the control of symptoms.

  • Risk excessive sedation and tremor in elderly persons.

  • Agitated behavior can be rapidly stabilized with IV infusion of valproate.

• Gradual Initiation:

  • If acute mania is absent, initiate drug treatment gradually to minimize adverse effects

  • First-day dose: 250 mg administered with a meal

  • Increase dosage to 250 mg orally three times daily for over 3 to 6 days.

• Plasma Concentrations:

  • Assess in the morning before the first daily dose is administered.

  • Therapeutic range for seizure control: 50 and 100 µg/mL.

  • Reasonable range for mental disorders: 50 to 125 µg/mL.

  • Most people attain therapeutic plasma concentrations on a dosage between 1,200 and 1,500 mg a day in divided doses

• Maintenance Dose:

  • After symptom control, the full daily dose can be taken all at once before sleep.

Valproate Preparations

Table 21-36 Valproate Preparations Available in the United States

Lamotrigine

• Developed as a result of screening folate antagonists as anticonvulsants.

• Approval:

  • Approved for the adjunctive treatment of partial seizures in the United States in 1995.

  • Approved for the maintenance treatment of bipolar I disorder in 2003.

Therapeutic indications

• Maintenance treatment for bipolar I disorder.

• Potential utility in rapid-cycling bipolar disorder.

Pharmacologic Actions

• Absorption:

  • Wholly absorbed, bioavailability of 98%.

• Half-life:

  • Steady-state plasma half-life of 25 hours, but rate of metabolism varies depending on concomitantly administered drugs.

• Dosing:

  • Escalated slowly to twice-a-day maintenance dosing.

• Food:

  • Food does not affect absorption.

• Protein Binding:

  • 55% protein-bound in the plasma.

• Excretion:

  • 94% of lamotrigine and its inactive metabolites are excreted in the urine.

• Mechanism of action

  • Blockade of voltage-sensitive sodium channels which modulates the release of glutamate and aspartate and has a slight effect on calcium channels.

  • Modestly increases plasma serotonin concentrations, possibly through inhibition of serotonin reuptake

  • Weak inhibitor of serotonin 5-HT3 receptors.

Therapeutic Indications

• Bipolar Disorder: Indicated in the treatment of bipolar disorder and may prolong the time between episodes of depression and mania. More effective in lengthening the intervals between depressive episodes than manic episodes. Useful as a treatment for rapid-cycling bipolar disorder.

• Other Indications: Reports of therapeutic benefit in the treatment of borderline personality disorder and the treatment for various pain syndromes.

Precautions and Adverse Reactions

• Absence of sedation, weight gain, and other metabolic effects are noteworthy.

• Common adverse effects include dizziness, ataxia, somnolence, headache, diplopia, blurred vision, and nausea, are typically mild.

• Anecdotal reports of cognitive impairment and joint or back pain are standard.

• Rash:

  • About 8% of patients started on lamotrigine develop a benign maculopapular rash during the first 4 months of treatment

  • The drug should be discontinued if a rash develops.

  • In some cases, they may represent early manifestations of Stevens–Johnson syndrome or toxic epidermal necrolysis

  • Estimates of the rate of severe rash vary, depending on the source of the data.

  • The appearance of any rash necessitates immediate discontinuation of drug administration.

  • Likelihood of a rash increases if the recommended starting dose and speed of dose increase exceed what is recommended.

  • Concomitant administration of valproic acid also increases risk and should be avoided if possible.

  • Children and adolescents younger than age 16 years appear to be more susceptible to rash with lamotrigine.

  • If patients miss more than 4 consecutive days of lamotrigine treatment, they need to restart therapy at the initial starting dose and titrate upward as if they had not already been on the medication.

Laboratory Testing

• There is no proven correlation between lamotrigine blood concentrations and either antiseizure effects or efficacy in bipolar disorders.

• Laboratory tests are not useful in predicting the occurrence of adverse events.

Drug Interactions

• Significant, well-characterized drug interactions involving other anticonvulsants.

• Concurrent use of valproic acid doubles serum lamotrigine concentrations.

• Lamotrigine decreases the plasma concentration of valproic acid by 25%.

• Sertraline (Zoloft) also increases plasma lamotrigine concentrations, but to a lesser extent than does valproic acid.

• Lamotrigine concentrations are decreased by 40 to 50% with concomitant administration of carbamazepine, phenytoin, or phenobarbital.

• Combinations of lamotrigine and other anticonvulsants have complex effects on the time of peak plasma concentration and the plasma half-life of lamotrigine.

Laboratory Interferences

• Lamotrigine does not interfere with any laboratory tests.

Dosage and Administration

• In the clinical trials leading to the approval of lamotrigine as a treatment for bipolar disorder, no consistent increase in efficacy was associated with doses above 200 mg/day.

• Most patients should take between 100 and 200 mg a day.

• In epilepsy, the drug is administered twice daily, but in bipolar disorder, the total dose can be taken once a day, either in the morning or night, depending on whether the patient finds the drug activating or sedating.

• Available as unscored 25-, 100-, 150-, and 200-mg tablets.

• The primary determinant of lamotrigine dosing is the minimization of the risk of rash.

• Lamotrigine should not be taken by anyone younger than 16 years of age.

• Concomitant administration of valproic acid necessitates a much slower titration (Table 21-37).

• People with renal insufficiency should aim for a lower maintenance dosage.

• The appearance of any rash necessitates immediate discontinuation of lamotrigine administration.

• Lamotrigine should usually be discontinued gradually over 2 weeks unless a rash emerges, in which case it should be discontinued over 1 to 2 days.

• Lamotrigine orally disintegrating tablets (Lamictal ODT) are available for patients who have difficulty swallowing. Matches the dose of lamotrigine tablets.

• Chewable dispersible tablets of 2, 5, and 25 mg are also available.

Table 21-37 Lamotrigine Dosing (mg/day)

Carbamazepine and Oxcarbazepine

• Carbamazepine (Tegretol):

  • Possesses some structural similarity to the TCA imipramine (Tofranil).

  • Approved for use in the United States for the treatment of trigeminal neuralgia in 1968 and temporal lobe epilepsy (complex partial seizures) in 1974.

  • First synthesized as a potential antidepressant, but developed for use in pain and seizure disorders.

  • Recognized as a second-line mood stabilizer useful in the treatment and prevention of both phases of bipolar affective disorder.

  • A long-acting sustained release formulation (Equetro) was approved by the U.S. FDA for the treatment of acute mania in 2002.

• Oxcarbazepine (Trileptal):

  • An analog of carbamazepine, marketed as an antiseizure medication in the United States in 2000.

  • Previously used as a treatment for pediatric epilepsy in Europe since 1990.

Carbamazepine Pharmacologic Actions

• Absorption:

  • Slow and unpredictable.

  • Food enhances absorption.

  • Peak plasma concentrations are reached 2 to 8 hours after a single dose.

  • Steady-state levels are reached after 2 to 4 days on a steady dosage.

• Protein Binding:

  • 70 to 80% protein-bound.

• Half-life:

  • Ranges from 18 to 54 hours, with an average of 26 hours.

  • Decreases to an average of 12 hours with chronic administration due to induction of hepatic CYP450 enzymes (autoinduction of carbamazepine metabolism).

  • The induction of hepatic enzymes reaches its maximum level after about 3 to 5 weeks of therapy.

• Metabolism:

  • Metabolized in the liver, and the 10,11-epoxide metabolite is active as an anticonvulsant.

  • Long-term use is associated with an increased ratio of the epoxide to the parent molecule.

• Mechanism of Action:

  • Anticonvulsant effects are thought to be mediated mainly by binding to voltage-dependent sodium channels in the inactive state and prolonging their inactivation.

  • Reduces voltage- dependent calcium channel activation and, thus, synaptic transmission.

  • Additional effects include reduction of currents through N-methyl-D-aspartate (NMDA) glutamate-receptor channels, competitive antagonism of adenosine a1-receptors, and potentiation of CNS catecholamine neurotransmission.

Therapeutic Indications

• Bipolar Disorder:

  • Acute Mania:

    • The acute antimanic effects of carbamazepine are typically evident within the first several days of treatment.

    • About 50 to 70% of all persons respond within 2 to 3 weeks of initiation.

    • May be especially useful in persons who are not responsive to lithium (Eskalith), such as persons with dysphoric mania, rapid cycling, or an adverse family history of mood disorders.

    • The antimanic effects of carbamazepine can be, and often are, augmented by concomitant administration of lithium, valproic acid (Depakene), thyroid hormones, DRAs, or SDAs.

  • Prophylaxis:

    • Effective in preventing relapses, particularly among patients with bipolar II disorder and schizoaffective disorder and dysphoric mania.

  • Acute Depression:

    • A subgroup of treatment-refractory patients with acute depression responds well to carbamazepine.

    • Patients with more severe episodic and less chronic depression seem to be better responders to carbamazepine.

• Other Disorders:

  • Helps to control symptoms associated with acute alcohol withdrawal, although benzodiazepines are more effective in this population.

  • Has been suggested as a treatment for the recurrent paroxysmal component of PTSD.

  • Effective in controlling impulsive, aggressive behavior in nonpsychotic persons of all ages, including children and elderly persons.

  • Effective in controlling nonacute agitation and aggressive behavior in patients with schizophrenia and schizoaffective disorder.

Precautions and Adverse Reactions

• Carbamazepine is relatively well tolerated.

• Mild GI (nausea, vomiting, gastric distress, constipation, diarrhea, and anorexia) and CNS (ataxia, drowsiness) side effects are the most common.

• The severity of these adverse effects is reduced if the dosage of carbamazepine is increased slowly and kept at the minimal effective plasma concentration.

• Does not appear to cause weight gain.

• Most of the adverse effects are correlated with plasma concentrations above 9 µg/mL.

• The rarest but most serious adverse effects are blood dyscrasias, hepatitis, and severe skin reactions

• Blood Dyscrasias:

  • The drug’s hematologic effects are not dose-related.

  • Severe blood dyscrasias (aplastic anemia, agranulocytosis) occur in about 1 in 125,000 persons treated with carbamazepine.

  • Routine hematologic monitoring is recommended at 3, 6, 9, and 12 months. Frequent blood monitoring during long-term treatment may not be useful

  • Symptoms such as fever, sore throat, rash, petechiae, bruising, and easy bleeding can potentially herald a serious dyscrasia.

• Hepatitis:

  • Within the first few weeks of therapy, carbamazepine can cause hepatitis associated with increases in liver enzymes, particularly transaminases, and cholestasis associated with elevated bilirubin and alkaline phosphatase.

  • Mild transaminase elevations warrant observation only, but persistent elevations more than three times the upper limit of normal indicate the need to discontinue the drug.

  • Hepatitis can recur if the drug is reintroduced to the person and can result in death.

• Dermatologic Effects:

  • About 10 to 15% of those treated with carbamazepine develop a benign maculopapular rash within the first 3 weeks of treatment. Stopping the medication usually leads to resolution of the rash.

  • Some patients may experience life-threatening dermatologic syndromes, including exfoliative dermatitis, erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis.

  • A retrial of the drug can be undertaken if carbamazepine seems to be the only effective drug for a person who has a benign rash with carbamazepine treatment.

• Renal Effects:

  • Carbamazepine is occasionally used to treat diabetes insipidus not associated with lithium use due to direct or indirect effects at the vasopressin receptor.

  • Carbamazepine may also lead to the development of hyponatremia and water intoxication, mainly in elderly persons, or when used in high doses.

• Other Adverse Effects:

  • Carbamazepine decreases cardiac conduction and can thus exacerbate preexisting cardiac disease.

  • Carbamazepine should be used with caution in persons with glaucoma, prostatic hypertrophy, diabetes, or a history of alcohol abuse.

  • Carbamazepine occasionally activates vasopressin receptor function, which results in a condition resembling the syndrome of secretion of inappropriate antidiuretic hormone, characterized by hyponatremia and, rarely, water intoxication.

  • Carbamazepine use rarely elicits an immune hypersensitivity response consisting of fever, rash, eosinophilia, and possibly fatal myocarditis.

  • Cleft palate, fingernail hypoplasia, microcephaly, and spina bifida in infants may be associated with the maternal use of carbamazepine during pregnancy.

Table 21-38 Adverse Events Associated with Carbamazepine

Drug Interactions

• Carbamazepine decreases serum concentrations of numerous drugs as a result of the prominent induction of hepatic CYP3A4

• Carbamazepine can decrease the blood concentrations of oral contraceptives, resulting in breakthrough bleeding and uncertain prophylaxis against pregnancy.

• Carbamazepine should not be administered with MAOIs, which should be discontinued at least 2 weeks before initiating treatment with carbamazepine.

• Grapefruit juice inhibits the hepatic metabolism of carbamazepine.

• When carbamazepine and valproate are used in combination, the dosage of carbamazepine should be decreased because valproate displaces carbamazepine binding on proteins, and the dosage of valproate may need to be increased.

Table 21-39 Carbamazepine: Drug Interactions

Laboratory Interferences

• Circulating levels of thyroxine and triiodothyronine are associated with a decrease in TSH and may be associated with treatment.

• Carbamazepine is also associated with an increase in total serum cholesterol, primarily by increasing high-density lipoproteins.

• The thyroid and cholesterol effects are not clinically significant.

• Carbamazepine may interfere with the dexamethasone (Decadron) suppression test and may also cause false-positive pregnancy test results.

Dosing and Administration

• The target dose for antimanic activity is 1,200 mg a day, although this varies considerably.

• Immediate-release carbamazepine needs to be taken three or four times a day, which leads to lapses in compliance.

• Extended-release formulations are thus preferred because they can be taken once or twice a day.

• Hepatic disease require only one-third to one-half the usual dosage

• The laboratory examination should include a CBC with platelet count, liver function tests, serum electrolytes, and an electrocardiogram in persons older than 40 years of age or with preexisting cardiac disease.

Routine Laboratory Monitoring

• Serum levels for antimanic efficacy have not been established.

• The anticonvulsant blood concentration range for carbamazepine is 4 to 12 µg/mL, and this range should be reached before determining that carbamazepine is not effective in the treatment of a mood disorder.

• A clinically insignificant suppression of the WBC count commonly occurs during carbamazepine treatment. This benign decrease can be reversed by adding lithium, which enhances colony-stimulating factor.

• Potential serious hematologic effects of carbamazepine, such as pancytopenia, agranulocytosis, and aplastic anemia, occur in about 1 in 125,000 patients.

• Complete laboratory blood assessments may be performed every 2 weeks for the first 2 months of treatment and quarterly after that.

• Patients should be informed that fever, sore throat, rash, petechiae, bruising, or unusual bleeding may indicate a hematologic problem and should prompt immediate notification of a physician.

• Liver and renal function tests be conducted quarterly

Table 21-40 Carbamazepine in Bipolar Illness: A Brief User’s Guide

Table 21-41 Laboratory Monitoring of
Carbamazepine for Adult Psychiatric Disorders

Oxcarbazepine

• The usefulness of oxcarbazepine as a treatment for mania has not been established in controlled trials.

Pharmacokinetics

• Absorption is rapid and unaffected by food.

• Peak concentrations occur after about 45 minutes.

• The elimination half-life of the parent compound is 2 hours, which remains stable over long-term treatment.

• The monohydroxide has a half-life of 9 hours.

• Most of the drug’s anticonvulsant activity is presumed to result from this monohydroxy derivative.

Side Effects

• The most common side effects are sedation and nausea.

• Less frequent side effects are cognitive impairment, ataxia, diplopia, nystagmus, dizziness, and tremor.

• Does not have an increased risk of severe blood dyscrasias, so hematologic monitoring is not necessary.

• The frequency of benign rash is lower than observed with carbamazepine, and severe rashes are extremely rare.

• Oxcarbazepine is more likely to cause hyponatremia than carbamazepine.

Dosing and Administration

• Oxcarbazepine dosing for bipolar disorder has not been established.

• The dose range may vary from 150 to 2,400 mg/day, given in divided doses twice a day.

• In clinical trials for mania, the doses typically used were from 900 to 1,200 mg/day with a starting dose of 150 or 300 mg at night.

Drug Interactions

• Drugs such as phenobarbital and alcohol, which induce CYP34A, increase clearance and reduce oxcarbazepine concentrations.

• Oxcarbazepine induces CYP3A4/5 and inhibits CYP2C19, which may affect the metabolism of drugs that use that pathway.

• Women taking oral contraceptives should be told to consult with their gynecologists, because oxcarbazepine may reduce concentrations of their contraceptive and thus decrease its efficacy.

Other Anticonvulsants

• Developed for the treatment of epilepsy but were also found to have beneficial effects in psychiatric disorders.

• Also used as skeletal muscle relaxants and in neurogenic pain.

• Examples:

  • Gabapentin (Neurontin)

  • Levetiracetam (Keppra)

  • Pregabalin (Lyrica)

  • Tiagabine (Gabitril)

  • Topiramate (Topamax)

  • Zonisamide (Zonegran)

  • Phenytoin (Dilantin)

• In 2008, the FDA issued a warning that these drugs may increase the risk of suicidal ideation but some published data contradict this warning. Suicidality was higher in patients with epilepsy compared with those with psychiatric disorders. Anticonvulsants may have a protective effect on suicidal thoughts in bipolar disorder.

Gabapentin

• First introduced as an antiepileptic drug and was found to have sedative effects

• Used in anxiety disorders (social phobia and panic disorder), but not as the primary intervention in mania or treatment-resistant mood disorders.

Pharmacologic Actions

• Gabapentin circulates in the blood primarily unbound and is not appreciably metabolized in humans.

• It is eliminated unchanged by renal excretion and can be removed by hemodialysis.

• Food only moderately affects the rate and extent of absorption.

• Clearance is decreased in elderly persons, requiring dosage adjustments.

• Appears to increase cerebral GABA and may inhibit glutamate synthesis as well.

• Increases human whole blood serotonin concentrations and modulates calcium channels to reduce monoamine release.

• It has antiseizure as well as antispastic activity and antinociceptive effects in pain.

Therapeutic Indications

• Neurology: Used for the treatment of both general and partial seizures. Useful in reducing the pain of postherpetic neuralgia and other pain syndromes.

• Psychiatry: Used as a hypnotic agent because of its sedating effects. Has anxiolytic properties and benefits patients with social anxiety and panic disorder. May decrease the craving for alcohol in some patients and improve mood. Some bipolar patients have benefited when gabapentin is used adjunctively with mood stabilizers.

Precautions and Adverse Reactions

• Adverse effects are mild, with the most common being daytime somnolence, ataxia, and fatigue, which are usually dose-related.

• Overdose (over 45 g) has been associated with diplopia, slurred screech, lethargy, and diarrhea, but all patients recovered.

• Classified as pregnancy category C in the former FDA classification system and is excreted in breast milk

Drug Interactions

• Gabapentin bioavailability may decrease as much as 20% when administered with antacids.

• Chronic use does not interfere with lithium administration.

Laboratory Interferences

• Gabapentin does not interfere with any laboratory tests, although spontaneous reports of false-positive drug toxicology screenings have been reported.

Dosages and Clinical Guidelines

• A general approach is to start with 300 mg on day 1, increase to 600 mg on day 2, 900 mg on day 3, and subsequently increase up to 1,800 mg/day in divided doses as needed to relieve symptoms.

• Final total daily doses tend to be between 1,200 and 2,400 mg/day, but occasionally results may be achieved with dosages as low as 200 to 300 mg/day, especially in elderly persons.

• Sedation is usually the limiting factor in determining the dosage.

• Although abrupt discontinuation of gabapentin does not cause withdrawal effects, the use of all anticonvulsant drugs should be gradually tapered.

Topiramate

• Developed as an anticonvulsant and was found useful in a variety of psychiatric and neurologic conditions, including migraine prevention, treatment of obesity, bulimia, binge eating, and alcohol dependence.

Pharmacologic Actions

• Topiramate has GABAergic effects and increases cerebral GABA in humans.

• It has 80% oral bioavailability and is not significantly altered by food.

• It is 15% protein-bound, and about 70% of the drug is eliminated by renal excretion. Clearance decreases by about 50% in renal insufficiency.

• It has a half-life of around 24 hours.

Therapeutic Indications

• Used mainly as an antiepileptic medication and has been found superior to placebo as monotherapy in patients with seizure disorders.

• It is also used in the prevention of migraine, smoking cessation, pain syndromes (e.g., low back pain), PTSD, and essential tremor.

• The drug has been associated with weight loss

Precautions and Adverse Reactions

• The most common adverse effects include paresthesias, weight loss, somnolence, anorexia, dizziness, and memory problems.

• No deaths have been reported during an overdose.

• The drug affects acid–base balance (low serum bicarbonate), which can be associated with cardiac arrhythmias and the formation of renal calculi in about 1.5 percent of cases.

• Patients taking the drug should be encouraged to drink plenty of fluids.

• It is not known if the drug passes through the placenta or is present in breast milk.