Antiepileptic drugs
Brian P. Brennan
Harrison G. Pope Jr.
Introduction
Several drugs originally developed to treat epilepsy have been found effective in certain psychiatric disorders. This chapter reviews the antiepileptic drugs most extensively studied in psychiatric disorders: valproate, carbamazepine, lamotrigine, and topiramate. We then briefly mention six other antiepileptics currently under investigation in various psychiatric disorders, but not yet extensively studied: gabapentin, oxcarbazepine, levetiracetam, tiagabine, zonisamide, and pregabalin. The antiepileptic drug phenytoin is rarely used in psychiatric disorders, and is therefore not included in this chapter. The benzodiazepines, which have antiepileptic properties, are also omitted here, as they are discussed in Chapter 6.2.2. We briefly list studies documenting the efficacy of these various agents in psychiatric disorders, but the reader is referred to the individual chapters on specific disorders for a more detailed discussion of treatment strategies.
Valproate1
Introduction
Valproate (valproic acid) is a simple branched-chain carboxylic acid, first used as an organic solvent in the late 1800s (see Fig. 6.2.6.1). Its antiepileptic properties were discovered serendipitously in 1963, and its clinical use as an antiepileptic drug began in 1964. As early as 1966, valpromide (the amide precursor of valproate) was reported to be effective in the treatment of bipolar disorder.(1) Since then, valproate has been used effectively in the treatment of numerous psychiatric and neurologic conditions, and is now widely used as a mood stabilizer in the treatment of bipolar disorder.
Valproate is currently available as five different preparations: valproate (Depakene), sodium valproate (Depakene syrup), divalproex sodium (Depakote) (which is an equal proportion of sodium valproate and valproic acid), divalproex sodium sprinkle capsules (Depakote sprinkle capsules), and valpromide (the amide precursor of valproate, which is available in Europe, but not in the United States).
Pharmacology
The mechanism of action of valproate in the treatment of epilepsy is unclear, but appears to be related to increased levels of gamma-aminobutyric acid (GABA) in the brain. It inhibits the breakdown and turnover of GABA, increases its release, and increases the density of the GABA-ββ receptor subtype.(2) Its mechanism of action in treating psychiatric disorders is unknown.
 Fig. 6.2.6.1 Molecular structures of selected antiepileptic drugs. (a) Valproate, (b) Carbamazepine, (c) Oxcarbazepine, (d) Lamotrigine, and (e) Topiramate. |
Pharmacokinetics
All preparations of valproate are completely absorbed after oral administration. The rate of absorption varies slightly with the different preparations, but these differences are probably not clinically significant. Co-administration with food can delay absorption. Valproate is approximately 90 per cent protein-bound. Only the unbound drug crosses the blood brain barrier and is pharmacologically active in the CNS. As total serum valproate concentration increases, the unbound portion of valproate is disproportionately increased, presumably due to saturation of the protein-binding sites. Therefore, at higher serum concentrations, small increases in dose may result in significant changes in efficacy and side effects. Valproate is metabolized by the liver to a glucuronide conjugate or one of several metabolites, some having antiepileptic activity. The half-life of valproate ranges from 6 to 17 h. Enzyme-inducing antiepileptic drugs, such as carbamazepine and phenytoin, shorten the half-life of valproate (see Interactions).(3)
Side effects
Valproate is often associated with minor side effects, but can rarely cause life-threatening, idiosyncratic reactions. Common side effects include gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhoea; and neurological symptoms, such as tremor, somnolence, and dizziness. Weight gain is also common. Hair loss occurs in some patients, but is often transient and reversible upon discontinuation of the drug. Rare, but potentially fatal, idiosyncratic reactions include hepatic failure, acute haemorrhagic pancreatitis, and agranulocytosis.(2,4) Known risk factors for irreversible hepatic failure include young age (especially less than 2 years old), developmental delay, a metabolic disorder, or concomitant administration of other antiepileptic drugs.(5) Because of this risk, liver function tests are recommended prior to initiation of therapy and periodically thereafter (see Dosage and Administration).
Toxic effects
(a) Overdose
Overdose with valproate can result in heart block, coma, and death. Haemodialysis may be useful in clearing the drug rapidly, and naloxone may reverse the CNS depressant effects.(3)
(b) Pregnancy
Valproate increases the risk of neural tube defects (such as spina bifida) to approximately 1–2 per cent of pregnancies when administered in the first trimester. Other reported congenital anomalies include craniofacial defects and cardiovascular malformations. Valproate is found in human breast milk, at approximately 1–10 per cent of serum concentrations, but its effects on the nursing child are unknown.(6)
Indications and contraindications
Controlled trials confirm that valproate is effective in the treatment of multiple seizure types, including complex partial, simple and complex absence, generalized tonic–clonic, and myoclonic seizures.(3) Several controlled studies indicate efficacy in the treatment of acute mania,(7,8,9,10,11,12,13) mixed episodes,(12,14) and in the prophylaxis of recurrent mood episodes.(13,15,16) One small controlled study has offered limited evidence for the efficacy of valproate in the treatment of bipolar depression.(17) There is growing support from controlled studies for the efficacy of valproate, combined with both typical and atypical antipsychotics, in the treatment of acute exacerbations of schizophrenia(18,19); particularly when the presentation includes agitation and hostility.(20) There are also several small controlled studies demonstrating the benefit of valproate in the treatment of mood instability and impulsivity associated with borderline personality disorder.(21,22,23) Other conditions for which valproate may sometimes be useful include pain syndromes, anxiety disorders, alcohol and sedative withdrawal syndrome, impulse control disorders, and behavioural and affective disturbances associated with intellectual disability and dementia.(2)
Valproate is contraindicated in patients with known hypersensitivity to the drug. It should be used cautiously in patients with significant hepatic disease.
Interactions
In general, valproate can be combined safely with other psychotropic medications and antiepileptic drugs. However, given that valproate is highly protein-bound and can inhibit hepatic enzymes, some drug– drug interactions have been identified.(3) Aspirin, which is highly protein-bound, elevates the free fraction of valproate, resulting in increased effects of valproate on the CNS. Valproate can displace diazepam, phenytoin, carbamazepine, and warfarin from proteinbinding sites, resulting in increased activity of these drugs. Co-administration of valproate with lamotrigine significantly increases the half-life of the latter and can increase the risk of lamotrigine-induced rashes. When administered with carbamazepine, three potential interactions may occur: (1) valproate can increase the concentration of carbamazepine’s metabolite, carbamazepine-10,11-epoxide, by inhibiting its further metabolism; (2) carbamazepine may lower the valproate level; and (3) valproate may increase the carbamazepine level.(24) Therefore, close monitoring of serum
concentrations of both drugs is important when they are combined. Amitriptyline and fluoxetine may increase serum valproate concentrations, possibly by inhibition of valproate metabolism.
concentrations of both drugs is important when they are combined. Amitriptyline and fluoxetine may increase serum valproate concentrations, possibly by inhibition of valproate metabolism.
Effects of withdrawal
As with other antiepileptic drugs, valproate should be tapered gradually over several weeks to minimize the risk of rebound seizures.
Dosage and administration
Before initiating treatment with valproate, it is advisable to obtain a baseline complete blood count (CBC), liver function tests (LFTs), and if appropriate, a pregnancy test. CBC and liver function tests should be performed monthly for the first 3 months, and, if no abnormalities are found, every 6 to 12 months thereafter. If hepatic transaminase levels increase to more than three times normal, valproate should be discontinued. If the transaminase levels eventually return to baseline and the patient responded to valproate previously, re-challenge can be considered. If hepatic transaminase levels increase, but are less than three times normal, monitoring should be increased to once every 1–2 weeks until transaminase levels stabilize, and then monthly thereafter.(2)
The initial starting dose of valproate in adults is 250 to 1000 mg per day, given in two or three divided doses (see Table 6.2.6.1 for dosage forms). The dose may be increased every 1–3 days depending on the patient’s response and tolerance. The usual therapeutic concentration is between 50–100 µg/ml (drawn 12 h after the last dose) for both psychiatric and neurological disorders. Some clinicians give the entire daily dose of valproate at bedtime. In patients with seizure disorders or acute mania, an oral loading strategy can be used.(25) In this situation, the patient receives 20 mg/kg as a bolus on the first day, resulting in rapid achievement of therapeutic levels. However, psychiatric patients who are not acutely manic usually have difficulty tolerating the oral loading strategy.
Carbamazepine
Introduction
Carbamazepine (Tegretol®) is an iminostilbene derivative with a structure similar to the tricyclic antidepressant imipramine (see Fig. 6.2.6.1). It was initially developed as a potential antidepressant in the 1950s, but was found to have antiepileptic and analgesic properties, and has been marketed for the treatment of seizures and pain syndromes since 1963. For many clinicians, it has been the preferred treatment for partial and generalized tonic–clonic seizures, as well as neuropathic pain. Its clinical use in affective disorders began in the early 1970s; since then, it has become widely used in psychiatry.
Pharmacology
Carbamazepine’s mechanism of action in the treatment of seizures and pain syndromes is controversial, but probably results from blockade of voltage-sensitive sodium channels or enhancement of gamma-aminobutyric acid (GABA) activity. Its mechanism of action in psychiatric disorders is unknown, and may be different, given that it affects numerous neurotransmitter systems.(26, 27)
Pharmacokinetics
Carbamazepine is absorbed slowly, with peak plasma levels occurring 4–5 h after administration of the tablets. Absorption is faster for the carbamazepine liquid, and slower for carbamazepine extended-release tablets. Oral bioavailability is about 80 per cent; plasma protein binding is approximately 75 per cent. The half-life of carbamazepine is variable, as it induces its own metabolism with chronic administration (autoinduction). Initially, the half-life ranges from 18–65 h, but after autoinduction is complete (usually 3–5 weeks), it is decreased to 5–25 h. Children metabolize carbamazepine more rapidly than adults, and therefore require higher doses to achieve similar levels. Carbamazepine is metabolized in the liver by the cytochrome P450 system to a wide variety of metabolites, some with antiepileptic activity. The predominant metabolite, carbamazepine-10, 11-epoxide (CBZ-E), is further metabolized by epoxide hydrolase to an inactive form. Most of carbamazepine’s metabolites are excreted as glucuronide conjugates in the urine.(28, 29)
Table 6.2.6.1 Available dosage forms of antiepileptic drugs | ||||||||||||||||||||||||||||||||||||
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Side effects
Carbamazepine is generally well tolerated, with less than 5 per cent of patients discontinuing the medication because of adverse effects. Common side effects seen during initiation of treatment include dizziness, ataxia, sedation, nausea, and diplopia. These are often mild in severity, and frequently resolve with continued treatment.
(a) Haematological side effects
Carbamazepine commonly causes a benign suppression of white blood cell count, but in rare cases may cause severe and potentially fatal blood dyscrasias, including agranulocytosis, pancytopenia, and aplastic anaemia. The incidence of these non-dose-related, idiosyncratic reactions has been estimated to range between 1 in 10 000 to 1 in 300 000.(4)
(b) Hepatic toxicity
Carbamazepine is frequently associated with benign transaminase elevations. Very rarely, a non-dose-related, idiosyncratic reaction causes hepatic failure, which can be fatal.
(c) Cardiovascular effects
Carbamazepine slows intracardiac conduction, and is relatively contraindicated in patients with heart block.
(d) Dermatologic effects
Rashes occur in 5–15 per cent of patients. These are usually benign, but rarely lead to exfoliative dermatitis, Stevens–Johnson syndrome, or toxic epidermal necrolysis. Therefore, it is usually recommended that the drug be discontinued if any rash develops.
(e) Endocrine effects
Carbamazepine can exert antidiuretic effects, which result in hyponatremia in 5–40 per cent of patients.(30) Usually, this effect is clinically insignificant.
Carbamazepine can result in decrease in free T3 and T4, but clinical hypothyroidism is extremely rare.
Toxic effects
(a) Overdose
Carbamazepine overdose can be fatal. Common symptoms include nystagmus, tremor, ophthalmoplegia, and myoclonus. Lifethreatening effects include atrioventricular block, coma, seizures, and respiratory depression.(31)
(b) Pregnancy
Indications and contraindications
Carbamazepine is indicated for the treatment of simple partial, complex partial, and generalized tonic–clonic seizures. It is ineffective against absence seizures, and may even exacerbate them. Carbamazepine is also indicated in the treatment of trigeminal neuralgia and other neuropathic pain syndromes. Several doubleblind, placebo-controlled trials confirm carbamazepine’s efficacy in treating both the manic and mixed phase of bipolar disorder.(33,34) There is limited evidence demonstrating efficacy in the treatment of either bipolar or unipolar depression. Uncontrolled reports also suggest that carbamazepine may be useful in the treatment of personality disorders, impulse control disorders, and alcohol/sedative withdrawal syndrome.
Carbamazepine is contraindicated in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or hypersensitivity to any of the tricyclic antidepressants (given its structural similarity to imipramine). Its use with monoamine oxidase inhibitors is not recommended, and carbamazepine should be used with caution in patients with cardiac disease.
Interactions
Given that carbamazepine is extensively metabolized by the liver and induces hepatic enzymes, it produces many significant drug–drug interactions (Table 6.2.6.2).(35,36,37) Many drug levels are reduced by carbamazepine and can become subtherapeutic. Therefore, it is important to monitor concomitantly administered medications, as dosage adjustments may be necessary.
Table 6.2.6.2 Carbamazepine (CBZ)-drug interactions | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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