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`
`The use of anticonvulsants is expanding in the treatment of bipolar and related disorders. Although
`they have characteristics in common, the anticonvulsants currently used are quite diverse and vary in
`their spectrum of activity, quality of supporting evidence, and organ toxicities. Common side effects
`of anticonvulsants that can limit tolerability but are not physiologically severe include sedation and
`other cognitive impairments, tremor, and gastrointestinal side effects. Possibly less common, but of
`more physiologic significance, are effects on body weight and metabolism and dose-related hepatic
`and hematologic effects. Severe, but rare, toxicities include skin, bone marrow, and hepatic toxicity
`due to hypersensitivity. The most important aspect of successful management of severe toxicities is
`early detection, discontinuation of the medicine, and vigorous treatment of the toxicity. Anticonvul-
`sants can also be associated with fetal toxicity, especially neural tube defects. In general, anticonvul-
`sants are well tolerated and their effectiveness greatly outweighs risk or annoyance from side effects,
`but side effects must be kept in mind when choosing and monitoring treatment.
`"7!2KJM!9RXEIJCSQX!)’’(/,)ARTOOK!(+B.(,[)(#
`
`Aeral, they are well tolerated. Like any pharmacologic treat-
`
`nticonvulsants have increased the range of options
`for effective treatment of bipolar disorder. In gen-
`
`ments, however, they can have acute or long-term toxic
`effects. These must be taken into account in determining
`the value of anticonvulsants and developing strategies for
`their use. This review will focus on major toxicities of the
`most-used anticonvulsants in treatment of bipolar disorder:
`carbamazepine, valproate, lamotrigine, gabapentin, and to-
`piramate. I will consider effects of anticonvulsants on the
`central nervous system, liver, metabolism, and immune sys-
`tem, discuss their use during and directly after pregnancy,
`and then summarize the relative toxicities of these drugs.
`In considering reports of anticonvulsant toxicities, one
`must consider the populations from which they were de-
`rived. Most long-term data are from patients with epilepsy,
`who may differ from those with bipolar disorder in suscep-
`tibility to adverse effects. Second, many of the data from
`patients with epilepsy are from children. Most patients
`with bipolar disorder who receive anticonvulsants, at least
`so far, are adults. Children are more susceptible than
`adults to many of the metabolic and immune effects of
`anticonvulsants.
`
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`%/).+3+5’!’((’%32
`
`Cognitive effects of commonly used anticonvulsants
`are generally mild. Valproate is associated with mild seda-
`tion and a reversible impairment of attention at high
`doses.1 Severe sedation is unusual even with 30-mg/kg
`loading doses.2 In a series of 21 patients between 60 and
`82 years old, only 2 experienced marked sedation.3 Stoll et
`al.4 reported that a series of patients experiencing cogni-
`tive difficulties during lithium treatment improved after
`their treatment was changed to divalproex sodium.
`Among newer anticonvulsants, lamotrigine and gaba-
`pentin appear to be associated with mild sedation and
`minimal or no cognitive performance deficits.5 Topira-
`mate, however, is more likely to be associated with defi-
`cits in word finding and other aspects of memory and con-
`centration,5 which appear dose dependent.6
`Psychomotor effects of drugs can depend on how they
`affect mood state. For example, carbamazepine is gener-
`ally considered to have mildly sedating effects,7,8 but Joffe
`et al.9 reported increased motor activity in depressed pa-
`tients who improved with carbamazepine.
`
`*’0#3+%!’((’%32
`
`Most anticonvulsants are metabolized, at least partially,
`in the liver. Therefore, they or their metabolites have the
`potential for hepatotoxic effects.
`Elevations, usually transient, in liver enzymes are com-
`mon in drugs that are metabolized in the liver.10 Severe
`liver failure is much less common, but has been reported
`
`&)
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`with carbamazepine,11,12 lamotrigine,13,14 topiramate,15 and
`valproate.16,17 Risk is increased by young age, combination
`therapies, and any coexisting condition that compromises
`liver function.14,16 However, fatalities have also been re-
`ported in healthy adults without evidence of previous he-
`patic or metabolic disease.17 Fatal liver failure is rare,
`however, having been reported with valproate in a total of
`26 adults in the world literature; 3 were receiving mono-
`therapy.17
`There are 2 principal mechanisms of drug-induced hepa-
`totoxicity. The first is direct toxicity of a drug or metabo-
`lite. This toxicity is dose related. An example is toxicity of
`the valproate metabolite 4-en-valproate, which occurs only
`when liver immaturity, disease, or excessive load of val-
`proate results in unusual concentrations of this metabolite.
`The second mechanism of toxicity is hypersensitivity.18
`This differs from direct toxicity in that hypersensitivity is
`dose independent, more rare, and associated with fever and
`eosinophilia and has a shortened latency for development
`if the drug is readministered. Autoantibodies are occasion-
`ally present. I will discuss hypersensitivity to anticonvul-
`sants in more detail in the section on the immune system.
`Early symptoms of liver toxicity include apathy, mal-
`aise, decreased appetite, nausea, vomiting, and fever. Apa-
`thy combined with other signs of more severe febrile ill-
`ness should alert the clinician to act promptly; patients and
`their significant others should be alerted to the importance
`of this combination. Prompt detection of toxicity and dis-
`continuation of treatment are vital for a favorable outcome.
`Better recognition and early discontinuation of treatment
`may account for recent increases in recovery rates from
`drug-induced hepatotoxicity.16
`
`-’3#$/,+%!’((’%32
`
`Weight gain is the bane of many otherwise valuable
`psychotropic drugs.19 Patients may select a less effective
`treatment if they believe it is less likely to cause weight
`gain.20 By anticipating problems and combining regulation
`of activity and diet, however, weight gain can potentially
`be controlled.19
`Valproate is the anticonvulsant most often associated
`with weight gain, although others also can have this effect.
`One study found that, over a 12-month period, 71% of pa-
`tients taking valproate and 43% of those taking carba-
`mazepine gained weight.21 Weight gain with valproic acid
`occurs most often in patients with low or normal body
`mass index.21 Chronic gabapentin can also be associated
`with weight gain.22,23
`Weight gain during valproate treatment may be, at least
`partially, independent of change in caloric intake and may
`be related to impaired b-oxidation of fatty acids.24 Impaired
`fatty acid intoxication may result from reduced carnitine
`concentrations.24 Reduction in carnitine levels during val-
`proate treatment is increased if valproate is combined with
`
`4?G<6<C<8B!5>7!3<78!09986CB!?9!.>C<6?>ED=B5>CB
`
`induce microsomal oxidation; accordingly,
`drugs that
`plasma free carnitine correlates with the valproate level/
`dose ratio.25 Valproate or a metabolite may compete with
`carnitine transport.26 This may compound already deficient
`carnitine in some patients with epilepsy27 and may there-
`fore be less evident in bipolar disorder. Patients with a
`hereditary defect in carnitine transport may be especially
`susceptible.28 Healthy adults may be less susceptible to car-
`nitine-related effects because of an adaptive increase over
`time in renal carnitine reabsorption.29
`For the above reasons, carnitine supplementation has
`been found useful in cases of severe valproate toxicity30–32
`and in patients, especially children, at high risk.27 Due to
`the cost of carnitine replacement, and its lack of benefit in
`low-risk populations, routine carnitine supplementation is
`not recommended.27
`
`’.&/%1+.’!’((’%32
`
`Isojarvi et al.33 reported obesity, hyperandrogenism, and
`polycystic ovaries in more than half of a cohort of Finnish
`women taking valproate for partial complex epilepsy. As
`noted above, they attributed this effect to weight gain and
`increased insulin levels and suggested management by
`switching to an anticonvulsant that caused less weight
`gain.34 Subsequent studies have cast doubt on the general-
`izability of any association between polycystic ovaries and
`valproate. Murialdo et al.35 reported no differences among
`valproate, phenobarbital, and carbamazepine in polycystic
`ovaries or hirsutism in a group of women with epilepsy. In
`bipolar women receiving lithium or valproate, Rasgon et
`al.36 found no evidence of polycystic ovaries, although men-
`strual irregularities were common in both treatment groups.
`Other endocrine effects of anticonvulsants result from
`pharmacokinetic interactions. Drugs that induce hepatic
`microsomal oxidative enzymes reduce concentrations of
`endogenous compounds, such as dihydroepiandrosterone
`sulfate, and synthetic estrogens.37
`
`+--4.’!2623’-
`
`Diagnosis and management of severe skin rash is con-
`sidered separately by Hebert and Ralston38 elsewhere in
`this supplement. I will discuss more general aspects of hy-
`persensitivity to anticonvulsants.
`Anticonvulsant hypersensitivity syndrome occurs in
`about 0.1% of patients treated with certain anticonvulsants,
`especially aromatic anticonvulsants (phenytoin, phenobar-
`bital, primidone, and carbamazepine), felbamate, and lamo-
`trigine.39 Other drugs with the potential for a similar syn-
`drome include sulfonamides, minocycline,
`terbinafine,
`azathioprine, and allopurinol.40 A case-control study found
`the relative risk for Stevens-Johnson syndrome or toxic
`epidermal necrolysis during the first 8 weeks of anticonvul-
`sant treatment (compared with patients admitted to the same
`
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`/0194!$#!/?40A;4<A!=5!(7>=90?!*7@=?34?!*B?7<6!0<3
`’5A4?!-?46<0<2F
`
`Time During Pregnancy
`Early
`Late
`Relative Risk
`Relatively safe Conventional
`Most
`with rational
`neuroleptics,
`treatments
`and careful
`electro-
`(but see text)
`monitoring
`convulsive
`therapy
`Carbamazepine,
`valproate,
`lithium
`Inadequate data Atypical antipsychotics, lamotrigine, gabapentin,
`topiramate
`
`Avoid unless
`necessary
`
`...
`
`Breastfeeding
`Neuroleptics
`(low dose),
`antidepressants,
`carbamazepine,
`valproate
`Lithium
`
`.=5>!/$!3F5>>
`
`facility for acute illness or elective procedures) to be 57 for
`phenobarbital, 91 for phenytoin, 120 for carbamazepine, 25
`for lamotrigine, and 24 for valproic acid (data for valproic
`acid based on 4 cases, all of whom were taking other drugs
`on this list).41 Onset is usually delayed by a few days—2
`months after the beginning of treatment. Initially, the indi-
`vidual may experience a rash with fever, pharyngitis, and
`malaise. The initial rash may appear benign. This can be
`followed by involvement of one or more organ systems, in-
`cluding skin, liver, bone marrow, blood vessels, kidney, and
`gastrointestinal tract.42,43
`Severe hypersensitivity reactions must be differentiated
`from more benign adverse effects. Benign rash occurs in
`5% to 20% of individuals given aromatic anticonvulsants
`or lamotrigine, for example, whereas Stevens-Johnson syn-
`drome or toxic epidermal necrolysis may occur in only 1
`case out of 3000. Hematologic reactions with carbamaze-
`pine are similar. About 12% of children and 7% of adults
`given carbamazepine experience gradual onset of leukope-
`nia during the first 3 months of treatment; this is generally
`reversible with reduction (or even continuation) of carba-
`mazepine. Patients with white blood cell counts lower
`than 3.0 · 109/L or neutrophil counts below 1.0 · 109/L
`should have dose reduction or discontinuation of carba-
`mazepine and increased monitoring. Routine monitoring is
`inadequate, however, to detect the rapid development of
`bone marrow suppression due to hypersensitivity. Patients
`and physicians must be trained to watch for early clinical
`signs of anemia, agranulocytosis, or thrombocytopenia.44
`In general, the mechanism of anticonvulsant hypersen-
`sitivity is thought to involve the formation of reactive drug
`metabolites that irreversibly modify cellular proteins. The
`modified proteins are believed to elicit an autoimmune re-
`sponse.45 Inducers of oxidative metabolism may therefore
`increase the risk of hypersensitivity. Aromatic anticonvul-
`sants may cross-react (cross-reactivity as high as 70% to
`80%39), whereas lamotrigine or felbamate may produce
`hypersensitivity via distinct modified proteins.45
`Severe hypersensitivity to anticonvulsants is unusual
`but develops quickly and unpredictably. Because system-
`atic laboratory monitoring is inadequate, education of the
`patient and other involved individuals is vital for early de-
`tection and management of these reactions.
`
`’((’%32!/(!#.3+%/.54,2#.32!&41+.)
`01’).#.%6!#.&!3*’!0/230#134-!0’1+/&
`
`Table 1 provides an overview of the relative risk associ-
`ated with the different treatments for bipolar disorder, in-
`cluding anticonvulsants, during and after pregnancy.
`
`&<K<BEFC<DI7B!’==<9IH
`Anticonvulsants have been associated with fetal abnor-
`malities. Neural tube defects have been reported in 1% to
`2% of infants who were exposed to anticonvulsants during
`
`the first trimester.46 Other malformations, including facial
`dysmorphias, skeletal abnormalities, and cardiac defects,
`are also reported, constituting what is called the fetal anti-
`convulsant syndrome.46–49 Risk of malformations may be
`related in part to oxidative metabolites of aromatic anti-
`convulsants.47 Incidence of malformations is increased by
`concomitant caffeine use; by combination treatments, es-
`pecially if at least one drug is an inducer of microsomal
`oxidative enzymes; and by clonazepam if it is combined
`with other agents.50
`A recent study of 983 births found a 3.1% incidence of
`anomalies in infants who were not exposed to any drugs in
`utero. Anticonvulsants were associated with increased
`malformation rates: 14.3% with primidone, 11.1% with
`valproate, 9.1% with phenytoin, and 5.7% with carba-
`mazepine.48 Incidence of birth defects in infants exposed
`to valproate was related to dose and level, showing an in-
`crease only when the dose was over 1 g/day and the ma-
`ternal blood level was at least 70 mg/mL.48
`Limited information is available about long-term out-
`come in children who were exposed to anticonvulsants.
`A group of adults who had been exposed to phenytoin or
`carbamazepine had normal word fluency and lateraliza-
`tion but showed impairments in spatial integrative abil-
`ity.51 Children exposed to carbamazepine were found to be
`smaller than expected.52 A group of children who experi-
`enced fetal anticonvulsant syndromes had an increased in-
`cidence of problems, including learning disabilities, de-
`velopmental delays, and joint laxity.53
`Alternatives to anticonvulsants are also not without
`problems. In addition to the poorly quantified risk of
`Ebstein’s anomaly, lithium is associated with problems
`later in and after pregnancy including polyhydramnios,
`premature labor, neonatal lithium toxicity, and neonatal
`hypothyroidism.54
`
`0EHIF7GIJC!0<G@E;
`Women with bipolar disorder are at increased risk for
`recurrence during the postpartum period, so effective treat-
`ment is necessary. This raises the question of the presence,
`and safety, of anticonvulsant medicines in breast milk.
`
`&+
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`tors, and, for severe episodes, electroconvulsive therapy.
`Later, usual treatment can be reimplemented if desired,
`with the caveats described in this section.
`
`24--#16
`
`Anticonvulsants are playing an expanding role in the
`treatment of bipolar disorder. These medications are effec-
`tive for many patients and are well tolerated by most. Like
`any active treatment, however, they have toxicities that
`can be substantial. Like the therapeutic effects, toxic ef-
`fects of anticonvulsants are heterogeneous. Tables 2 and 3
`summarize the severity of major side effects and toxicities
`among anticonvulsants. Strategies for optimal use of anti-
`convulsants are still evolving. Their specific roles will re-
`quire a balance between toxicity, subjective tolerability,
`and effectiveness.
`
`Drug names: azathioprine (Imuran), carbamazepine (Tegretol and oth-
`ers), clonazepam (Klonopin and others), divalproex sodium (Depakote),
`felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal),
`minocycline (Minocin and others), phenobarbital (Donnatal and others),
`phenytoin (Dilantin and others), primidone (Mysoline),
`terbinafine
`(Lamisil), topiramate (Topamax), valproic acid (Depakene).
`
`Disclosure of off-label usage: The author of this article has determined
`that, to the best of his knowledge, carbamazepine, clonazepam, gaba-
`pentin, lamotrigine, and topiramate are not approved by the U.S. Food
`and Drug Administration for treatment of bipolar disorder.
`
`1’(’1’.%’2
`
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`’%
`
`1!/=<>!2BH6;<5CAH!’%%&-)’!"BD@@=!&(#
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`tivity reaction to carbamazepine including dyserythropoietic anemia. Ann
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`hematologic reactions and monitoring recommendations. DICP 1990;24:
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