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Chapter 37. Carbamazepine and Oxcarbazepine
CARBAMAZEPINE AND OXCARBAZEPINE: INTRODUCTION
Pharmacotherapy of bipolar disorder is a complex and rapidly evolving field. The development of new treatments
has helped to refine concepts of illness subtypes and generated important new management options. Although the
mood stabilizers—the first-line agents lithium, valproate, and lamotrigine and the alternative agents carbamazepine
(CBZ) and oxcarbazepine (OXC)—are considered the primary medications for bipolar disorder, antipsychotics,
antidepressants, anxiolytics, and a new generation of anticonvulsants are commonly combined with mood
stabilizers in clinical settings (American Psychiatric Association 2002; Ketter 2005; Suppes et al. 2005). These
diverse medications have varying pharmacodynamics, pharmacokinetics, drug–drug interactions, and adverse
effects, thus offering not only new therapeutic opportunities but also a variety of new potential pitfalls.
Therefore, clinicians are challenged with integrating complex data regarding efficacy and adverse-effect spectra
with pharmacological properties in their efforts to provide safe, effective state-of-the-art pharmacotherapy for
patients with bipolar disorder. In this chapter, we review the preclinical and clinical pharmacology of CBZ and its
analog OXC. In the past, CBZ was considered an alternative to lithium and valproate rather than a first-line
intervention in the treatment of bipolar disorder (American Psychiatric Association 2002) in view of methodological
limitations of early studies of efficacy in bipolar disorder, complexity of use because of adverse effects and
drug–drug interactions, and lack of U.S. Food and Drug Administration (FDA) indication for the treatment of bipolar
disorder. However, evidence of the efficacy of a proprietary CBZ extended-release formulation (Equetro) in two
randomized, double-blind, placebo-controlled, parallel-group studies in bipolar disorder patients with acute manic
and mixed episodes (Weisler et al. 2004, 2005) has addressed methodological concerns and led to CBZ’s receiving
an indication for the treatment of acute manic and mixed episodes in patients with bipolar disorder. Importantly, in
selected patients, CBZ and OXC may offer efficacy and tolerability that are favorable compared with first-line
therapies and thus can be important treatment options for some individuals with bipolar disorders. In particular,
CBZ’s low propensity to cause the weight gain and metabolic problems seen with some other agents may lead
clinicians to reassess its role in the management of patients with bipolar disorder (Ketter et al. 2005). Although
OXC appears easier to use than CBZ, use of OXC remains limited by the lack of compelling data regarding its
efficacy in bipolar disorder.
HISTORY AND DISCOVERY
CBZ, as one of the initial alternatives to lithium and older antipsychotics, has played an important role in the
development of therapeutic interventions for bipolar disorder (Post et al. 2007). Lithium was reported by Cade
(1949) to be effective in acute mania and saw widespread use in Europe by the 1960s, but in view of safety
concerns (risk of toxicity), it was only approved for the treatment of acute mania in the United States in 1970. CBZ
was developed in 1957 by J. R. Geigy AG in Europe, and its efficacy in epilepsy and paroxysmal pain was
appreciated by the 1960s and in bipolar disorder by the early 1970s (Takezaki and Hanaoka 1971). As with lithium,
marketing of CBZ in the United States was delayed because of safety concerns (risk of blood dyscrasias), and CBZ
was thus not approved for the treatment of epilepsy in adults until 1974, in children older than 6 years until 1978,
and without age limitation until 1987.
The first-generation antipsychotic chlorpromazine was approved for the treatment of acute mania in the United
States in 1973. The next year, lithium received a maintenance indication for the treatment of bipolar disorder. Thus,
in the 1970s, acute mania was managed primarily with lithium and first-generation antipsychotics. Lithium proved
dramatically effective in classic euphoric mania but had limitations, which included the need for initial titration and
a clinically significant response latency. In addition, lithium proved less effective in patients with mixed or
dysphoric mania, rapid cycling, greater numbers of previous episodes, mood-incongruent delusions, or concurrent
substance abuse than in those with classic bipolar disorder (Ketter and Wang 2002). The response latency and the
spectrum of efficacy limitations of lithium resulted in the common practice of concurrently administering
first-generation antipsychotics in acute mania. However, first-generation antipsychotics had adverse effects that
imposed substantial limitations, as mood disorder patients appeared to be at even greater risk than schizophrenia
patients for acute extrapyramidal side effects (Nasrallah et al. 1988) and tardive dyskinesia (Kane and Smith
1982). In addition, these agents appeared to have unimodal (antimanic but not antidepressant) activity in bipolar
disorder in that they could exacerbate the depressive component of the illness (Ahlfors et al. 1981).
These limitations of lithium and first-generation antipsychotics led investigators to explore other treatment options
for bipolar disorder. On the basis of early reports of favorable psychotropic profiles in epilepsy patients andPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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preliminary observations in mood disorders, systematic investigations of CBZ (Ballenger and Post 1978) and
valproate commenced, and these anticonvulsants emerged as effective in acute mania, even in subtypes associated
with lithium resistance. Thus, CBZ and then valproate were increasingly used off label for bipolar disorder in the
1980s and early 1990s, respectively. The CBZ analog OXC was anecdotally reported as useful in bipolar disorder in
the 1980s (Müller and Stoll 1984) but was not marketed in the United States for the treatment of epilepsy until
Because of economic concerns such as patent protection limitations and the high cost of obtaining FDA approval, a
CBZ indication for bipolar disorder was not initially sought in the United States but was obtained from agencies in
Canada, Japan, Australia, and several European countries. The development of divalproex, a well-tolerated
proprietary valproate formulation, allowed the patent protection necessary to make seeking an FDA indication for
bipolar disorder economically feasible. The FDA’s approval of divalproex for the treatment of acute mania in 1994,
lack of major safety concerns, and relative ease of use were important factors in divalproex use overtaking that of
CBZ and even lithium by the late 1990s. In addition, divalproex’s efficacy in acute mania was considered better
established than that of CBZ, because the pivotal trials for obtaining the divalproex mania indication were
conducted with contemporary randomized, parallel, double-blind, placebo-controlled paradigms (Bowden et al.
1994; Pope et al. 1991), whereas early controlled CBZ studies in bipolar disorder used alternative (e.g., active
comparator and on–off–on) designs, as described later in this chapter (see section “Indications and Efficacy”).
Despite the limitations in the controlled maintenance data for both drugs, CBZ and divalproex were considered
mood stabilizers along with lithium.
The emergence of and evidence of the efficacy of a proprietary CBZ extended-release formulation (Equetro) in two
randomized, double-blind, placebo-controlled studies in patients with acute manic and mixed episodes (Weisler et
- 2004, 2005) led to an FDA indication in late 2004 for this CBZ formulation in the treatment of acute manic and
mixed episodes in patients with bipolar disorder.
OXC was approved for the treatment of epilepsy in the United States in 2000, in the setting of the development of
several new anticonvulsants in the 1990s. The new anticonvulsants appear to have heterogeneous psychotropic
profiles (Ketter et al. 2003), with only OXC thus far showing benefit in some controlled (albeit small) trials in acute
mania (Emrich 1990) and lamotrigine in the prophylaxis of and (to a lesser extent) acute treatment of bipolar
depression. As with CBZ, economic concerns such as patent protection limitations and the high cost of obtaining
FDA approval are substantial barriers to seeking an OXC indication for acute mania in the United States. Because of
its greater ease of use, OXC is considered by some to be an important alternative to CBZ (American Psychiatric
Association 2002). However, use of OXC remains limited by the lack of compelling data regarding its efficacy in
bipolar disorder.
STRUCTURE–ACTIVITY RELATIONS
CBZ is an iminostilbine derivative with a dibenzazepine nucleus. CBZ’s tricyclic nucleus appears to relate more to
local anesthetic and antihistaminic actions than to anticonvulsant actions. In contrast, the carbamyl (carboxamide)
group at position 5 appears related to substantial anticonvulsant effects. CBZ’s 5-carboxamide substituent, in
contrast to the 5-aryl substituent of imipramine, appears to account for CBZ’s markedly different effects compared
with those of imipramine, as described below. OXC differs structurally from CBZ only in that it has a ketone
substitution at the 10,11-position, and as noted below, the bulk of the evidence thus far suggests that this
structural similarity is paralleled by a mechanistic similarity.
PHARMACOLOGICAL PROFILE
CBZ and OXC have a preclinical anticonvulsant profile similar to that of phenytoin and less broad than that of
valproate or lamotrigine. Thus, CBZ and OXC, like phenytoin, valproate, and lamotrigine, are effective in the
maximal electroshock model of generalized tonic and/or clonic seizures, and like phenytoin but unlike valproate
and lamotrigine, they are not effective in the pentylenetetrazole model of absence seizures. CBZ and OXC, like
phenytoin, valproate, and lamotrigine, are effective in blocking seizures resulting from amygdala kindling (a model
of partial seizures). However, CBZ and OXC, like phenytoin and lamotrigine but unlike valproate, fail to block
kindling development (a model of epileptogenesis).
As expected from their preclinical profiles, CBZ and OXC, like phenytoin, valproate, and lamotrigine, are effective in
partial seizures with and without secondary generalization, and like phenytoin but unlike valproate and lamotrigine,
they are ineffective in absence seizures. CBZ and OXC also have analgesic effects and thus are effective in
trigeminal neuralgia.
PHARMACOKINETICS AND DISPOSITION
Carbamazepine
CBZ is available in the United States as a proprietary product (Tegretol) marketed for epilepsy by Novartis
Pharmaceuticals Corporation in suspension (100 mg/5 mL), chewable tablets (100 mg), nonchewable tablets (200
mg), and extended-release (Tegretol XR) tablets (100-, 200-, and 400-mg) (“Tegretol” 2008). An additional
proprietary extended-release formulation marketed for epilepsy as Carbatrol (by Shire US Inc.) and for bipolarPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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disorder as Equetro (by Validus Pharmaceuticals) is available in 100-, 200-, and 300-mg capsules (“Carbatrol”
2008; “Equetro” 2008). Intramuscular and depot formulations are not available. CBZ is also available in generic
formulations. Differences have been observed in the bioavailability of proprietary and generic formulations (Meyer
et al. 1992).
CBZ is extensively metabolized, with only about 3% excreted unchanged in the urine. The main metabolic pathway
of CBZ (to its active 10,11-epoxide, CBZ-E) appears to be mediated primarily by cytochrome P450 (CYP) 3A3/4
(Figure 37–1, top), with a minor contribution by CYP2C8 (Kerr et al. 1994). This epoxide pathway accounts for
about 40% of CBZ disposition and an even greater proportion in patients with induced epoxide pathway metabolism
(presumably via CYP3A3/4 induction) (Faigle and Feldmann 1995). Although a genetic polymorphism has been
observed for CYP2C8 (Wrighton and Stevens 1992), this probably does not account for the variability observed in
CBZ disposition, in view of the minor role of this isoform. The frequency distribution of CBZ kinetic parameters is
unimodal, consistent with CYP3A3/4 (which lacks genetic polymorphism) being the crucial isoform. With enzyme
induction (of the epoxide pathway, presumably via CYP3A3/4 induction), formation of CBZ-E triples, its subsequent
transformation to the inactive diol (CBZ-D) doubles, and thus the ratio of CBZ-E to CBZ increases (Eichelbaum et al.
1985). Other pathways include aromatic hydroxylation (25%), which is apparently mediated by CYP1A2 and not
induced concurrently with the epoxide pathway, and glucuronide conjugation of the carbamoyl side chain (15%) by
uridine diphosphoglucuronosyltransferase (UGT), presumably primarily by UGT2B7 (Staines et al. 2004). These
other pathways yield inactive metabolites.
FIGURE 37–1. Carbamazepine and oxcarbazepine metabolism.
CBZ = carbamazepine; CBZ-D = carbamazepine-10,11-dihydro-dihydroxide; CBZ-E = carbamazepine-10,11-epoxide;
CYP3A3/4 = cytochrome P450 3A3/4 isoenzyme; MHD = monohydroxy derivative; OXC = oxcarbazepine.
+ = indicates enzyme induction; – = indicates enzyme inhibition.
CBZ has erratic absorption and a bioavailability of about 80%. CBZ should not be exposed to humidity, because this
can cause solidification and decrease bioavailability (Nightingale 1990). It is about 75% bound to plasma proteins
and has a moderate volume of distribution (about 1 L/kg). Before autoinduction of the epoxide pathway, the
half-life of CBZ is about 24 hours, and the clearance is about 25 mL/minute. However, after autoinduction (2–4
weeks into therapy), the half-life falls to about 8 hours, and clearance rises to about 75 mL/minute. This may
require dosage adjustment to maintain adequate blood concentrations and therapeutic effects. The active CBZ-E
metabolite has a half-life of about 6 hours and is converted to an inactive diol (CBZ-D) by epoxide hydrolase. The
extended-release CBZ formulations available in the United States given twice a day yield steady-state CBZPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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concentrations similar to those seen with the immediate-release formulation given four times a day (Garnett et al.
1998; Thakker et al. 1992).
In the treatment of acute mania, two divergent clinical needs influence the rate of dosage titration. First, there is a
pressing need for rapid control of the manic syndrome, which suggests that faster titration to higher doses could
provide more rapid attainment of sufficient serum concentrations, potentially yielding quicker onset not only of
nonspecific sedation but also of specific antimanic effects. On the other hand, there is a need to not excessively
burden patients with the increased adverse effects associated with overly rapid escalation of CBZ dosage. Such
adverse effects include neurotoxicity (sedation, diplopia, and ataxia) and gastrointestinal disturbances that not
only can complicate acute management but also may lead patients to develop negative perceptions about the
adverse effects of CBZ that later interfere with their adherence to prophylactic therapy. Thus, although a
loading-dose strategy may be tolerated and effective in the treatment of mania with valproate (Keck et al. 1993),
the potential for neurotoxic adverse effects limits such an approach with CBZ.
Nonetheless, in the inpatient therapy of mania, CBZ is commonly started at 400–800 mg/day in divided doses, with
the dosage increased as tolerated (by 200 mg/day every 1–4 days) to provide clinical efficacy. In recent controlled
studies, a beaded extended-release capsule formulation was started at 200 mg twice per day and titrated by daily
increments of 200 mg to final dosages as high as 1,600 mg/day (Weisler et al. 2004, 2005). Titration of dosage
against adverse effects is more important than blood concentrations, which usually reach between 4 and 12 g/mL
(17 and 51 M/L), and there does not appear to be a close blood concentration–efficacy relationship for CBZ in
treating either seizure or mood disorders. Usual dosages are 800–1,600 mg/day given in up to three or four divided
doses with the immediate-release formulation. Extended-release formulations permit two divided doses per day,
and most mood disorder patients may even be able to take the entire daily dose at bedtime. Although this strategy
is convenient, it may not be feasible in some individuals because of neurotoxicity at peak serum concentrations,
which occurs about 4–8 hours after ingesting CBZ. CBZ has fairly rapid onset of antimanic efficacy, in some
comparisons similar to that of neuroleptics. Thus, lack of clinical improvement after 7–10 days may be an indication
that augmentation or alternative strategies should be considered.
In a recent report of open extension therapy after controlled acute mania studies, beaded extended-release capsule
CBZ was started at 200 mg twice per day and titrated by increments of 200 mg every 3 days (versus every day in
the acute studies) to final dosages as high as 1,600 mg/day (Ketter et al. 2004). This approach decreased the
incidence of central nervous system (dizziness, somnolence, ataxia), digestive (nausea, vomiting), and
dermatological (pruritus) adverse effects by about 50%. Euthymic or depressed patients tend to tolerate
aggressive initiation less well than do manic patients. Thus, in less acute situations such as the initiation of
prophylaxis or adjunctive use, CBZ is often started at 100–200 mg/day and increased (as necessary and tolerated)
by 200 mg/day every 4–7 days. Even this gradual initiation may result in adverse effects. Thus, starting with 50 mg
(half of a chewable 100-mg tablet) at bedtime and increasing the dosage by 50 mg every 4 days may provide better
tolerability. Moreover, doses of CBZ initially associated with adverse effects during the first 2 weeks of therapy may
be readily used after 1 month of therapy, once autoinduction of CBZ metabolism has decreased serum CBZ
concentrations (Cereghino 1975) and accommodation and tolerance to adverse effects such as sedation have
occurred. Target dosages are commonly between 600 and 1,200 mg/day, yielding serum levels from 4 to 12 g/mL,
with the higher portion of the range used acutely, and lower doses used in prophylaxis or adjunctive therapy. In a
CBZ versus lithium maintenance study, serum trough CBZ concentrations were maintained at 4–12 g/mL, with a
mean of 6.4 g/mL (Greil et al. 1997). In another CBZ versus lithium maintenance study, serum trough CBZ
concentrations were maintained at 4 to 12 g/mL, with a mean of 7.7 g/mL (Denicoff et al. 1997).
Because CBZ dosage and serum and cerebrospinal fluid concentrations fail to correlate with psychotropic efficacy
(Post 1989; Post et al. 1983a, 1984a), it is common practice to gradually increase CBZ dosage as tolerated,
monitoring both adverse effects and clinical efficacy, until therapeutic efficacy is adequate, adverse effects
supervene, or serum concentrations exceed 12 g/mL. The 4- to 12- g/mL serum CBZ concentration range from use
in epilepsy may be considered as a broad target, and CBZ serum concentrations may be used as checks for
pharmacokinetic problems. The active CBZ-E metabolite can yield therapeutic and adverse effects similar to those
of CBZ but is not detected in conventional CBZ assays. Thus, the unwary clinician may misinterpret the significance
of therapeutic or adverse effects associated with low or moderate serum CBZ concentrations.
Cerebrospinal fluid CBZ-E (but not CBZ) concentrations may correlate with degree of clinical improvement in
patients with mood disorders (Post et al. 1983a, 1984a, 1984c). Clinical improvement in depressed patients may
tend to correlate with serum CBZ-E (but not CBZ) concentration and serum CBZ-E to CBZ ratio. This ratio may
suggest a possible relationship between clinical response and the degree of enzyme induction.
In responders, a dose–response relationship may be evident, so that slowly increasing CBZ doses to maximize
response in the absence of significant adverse effects is a clinically useful strategy. However, if there is no hint of
therapeutic response at moderate doses, it is unlikely that pushing to very high doses will be beneficial.
OxcarbazepinePrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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OXC is available in the United States as a proprietary product (Trileptal) manufactured by Novartis Pharmaceuticals
Corporation in a 300-mg/5-mL suspension and in 150-, 300-, and 600-mg tablets (“Trileptal” 2008).
Extended-release, intramuscular, and depot formulations are not available.
OXC is 96% absorbed, and the modest effect of food on OXC kinetics does not appear to be of therapeutic
consequence (Degen et al. 1994). OXC is 60% bound to plasma proteins. Like CBZ, OXC has complex metabolism
(see Figure 37–1, bottom). Thus, OXC is rapidly reduced to an active monohydroxy derivative (MHD) by cytosol
arylketone reductase. The MHD is 40% bound to plasma proteins, has a moderate volume of distribution (about 0.8
L/kg), and has a half-life of about 9 hours. OXC is eliminated primarily in the form of MHD (70%) and MHD
glucuronide conjugates (20%), with small portions (10%) in the form of OXC glucuronide conjugates and CBZ-D.
OXC does not cause autoinduction and yields substantially less heteroinduction than does CBZ. Thus, as described
below, drug–drug interactions are less problematic with OXC than with CBZ (Baruzzi et al. 1994).
In epilepsy patients, OXC is commonly started at 600 mg/day and increased weekly by 600 mg/day, with final
dosages commonly ranging between 900 and 2,400 mg/day in two divided doses, yielding serum concentrations of
approximately 13–35 g/mL (50–140 M/L) (Johannessen et al. 2003; “Trileptal” 2008). In bipolar disorder
patients, OXC, like CBZ, is titrated to clinical desired effect as tolerated, with the serum concentration range used in
epilepsy considered as a broad target and with OXC serum concentrations used as checks for pharmacokinetic
problems. For patients taking CBZ, equipotent doses of OXC range from 1.2 to 1.5 times the CBZ dose. In an early
small, double-blind, on–off–on acute mania trial, the mean OXC dose was 1,886 mg/day (range 1,800–2,100)
(Emrich et al. 1983). In small active-comparator multicenter studies in acute mania, mean OXC dosages were 2,400
mg/day and 1,400 mg/day in comparison with haloperidol and lithium, respectively (Emrich 1990). In a recent
pediatric acute mania study, OXC was increased every 2 days by 300 mg/day to a maximum of 900–2,400 mg/day,
with mean dosages of 1,200 mg/day and 2,040 mg/day in children and adolescents, respectively, but therapeutic
effects did not exceed that of placebo (Wagner et al. 2006).
MECHANISMS OF ACTION
CBZ and OXC have not only structural but also mechanistic similarities. However, these agents have such a diversity
of biochemical effects that linking these mechanisms to their varying clinical actions presents a considerable
challenge.
Carbamazepine
As noted above, although CBZ has a tricyclic structure like imipramine’s, the two agents have markedly different
neurochemical, hepatic, and clinical effects. Thus, CBZ, unlike imipramine, lacks major effects on monoamine
reuptake or high affinity for histaminergic or cholinergic receptors and, unlike many antidepressants, fails to
downregulate -adrenergic receptors. Also, CBZ, unlike antipsychotics, does not block dopamine receptors.
However, CBZ has a wide range of other cellular and intracellular effects, as described below.
One way to consider CBZ’s diverse actions is from the perspective of commonalities with and dissociations from the
actions of the other mood stabilizers, lithium and valproate. CBZ shares a few mechanistic commonalities with both
of these mood stabilizers in that all three agents increase limbic -aminobutyric acid type B (GABAB) receptors,
decrease GABA and dopamine turnover, inhibit inositol transport, and weakly inhibit calcium influx by an
N-methyl-D-aspartate (NMDA)–mediated effect in preclinical studies. Chronic (but not acute) lithium, CBZ, and
valproate increase hippocampal (but not frontal, thalamic, or striatal) GABAB (but not GABAA) receptors in rats
(Motohashi 1992; Motohashi et al. 1989) and decrease GABA turnover in rodents (Bernasconi 1982; Bernasconi and
Martin 1979; Bernasconi et al. 1984), suggesting that hippocampal GABAB receptor mechanisms and decreased
GABA turnover could be important in medications that stabilize mood.
However, CBZ shares some actions with valproate but not lithium, and shares other actions with lithium but not
valproate. Thus, CBZ, like valproate but unlike lithium, decreases glutamate and aspartate release by blocking
sodium channels, decreases somatostatin-like immunoreactivity, and increases potassium efflux and serum
L-tryptophan. CBZ, like lithium but unlike valproate, decreases serum levothyroxine, cyclic adenosine
monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) and increases serotonin and substance P
neurotransmission. CBZ differs from both lithium and valproate in that it has effects at peripheral-type
benzodiazepine receptors, blocks adenosine A1 receptors, increases G protein–stimulating alpha subunits (Gs ) and
inositol monophosphatase (IMPase), and decreases G protein–inhibitory alpha subunits (Gi ).
In contrast, CBZ may lack certain intracellular actions shared by valproate and lithium, such as increasing
expression of the cytoprotective protein bcl-2 and transcription factor AP-1 binding and decreasing glycogen
synthase kinase-3 beta (GSK-3 ), protein kinase C (PKC), and myristoylated alanine-rich C kinase substrate
(MARCKS). CBZ appears to lack additional intracellular signaling actions seen with lithium but not valproate, such
as decreasing G protein coupling to phosphatidylinositol (PI) and adenylate cyclase, phospholipase C, and inositol
and increasing intracellular calcium, as well as increasing basal and decreasing stimulated cAMP. CBZ also lacks
other actions seen with lithium but not valproate, such as having effects on neuropeptide Y or glucocorticoid type II
receptors or decreasing calcium influx or 2-adrenergic neurotransmission. CBZ appears to lack some actions seenPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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with valproate but not lithium, such as increasing microtubule-associated protein (MAP) kinase, decreasing GABA
catabolism, and increasing GABA release.
In one three-way mechanistic dissociation, lithium decreased, CBZ increased, and valproate did not change IMPase
(Vadnal and Parthasarathy 1995). CBZ’s mixture of mechanistic commonalities with and dissociations from lithium
and valproate is consistent with the view that CBZ’s clinical effects in bipolar disorder may overlap with but are not
identical to those of lithium and valproate.
Another potentially useful way of considering CBZ’s diverse mechanisms is from the perspective of onset of action
(Post 1988). Thus, CBZ cellular actions with acute onset that might parallel the time course of clinical
anticonvulsant effects include decreasing sodium influx and glutamate release, increasing potassium conductance,
and acting on peripheral benzodiazepine and 2-adrenergic receptors. Acute GABAB receptor actions like those of
baclofen may relate to the rapid onset of clinical analgesic effects. Acute or subchronic actions such as increasing
striatal cholinergic neurotransmission; decreasing adenylate cyclase activity stimulated by dopamine,
norepinephrine and serotonin; and decreasing turnover of dopamine, norepinephrine, and GABA may be pertinent to
clinical antimanic effects. Finally, actions requiring chronic administration may be most closely related to clinical
antidepressant effects. These include increasing serum and urinary free cortisol, free tryptophan, substance P
sensitivity, and adenosine A1 receptors and decreasing cerebrospinal somatostatin-like immunoreactivity.
Oxcarbazepine
Less is known about OXC mechanisms than about CBZ mechanisms. The bulk of the evidence thus far suggests that
OXC’s structural similarity to CBZ is paralleled by mechanistic similarity (Ambrosio et al. 2002). For example, OXC,
like CBZ, appears to decrease sodium (Benes et al. 1999; Wamil et al. 1994) and calcium (Stefani et al. 1995) influx,
glutamate release (Ambrosio et al. 2001), and serum thyroxine (T4) concentrations (Isojarvi et al. 2001b); increase
potassium conductance (McLean et al. 1994) and dopaminergic neurotransmission (Joca et al. 2000); and block
adenosine A1 receptors (Deckert et al. 1993). However, there may be some mechanistic dissociations, particularly
given OXC’s and CBZ’s marked differences in degree of hepatic enzyme induction. For example, OXC appears to be a
less potent modulator of voltage-gated calcium channels compared with CBZ (Schmutz et al. 1994; Stefani et al.
1997). The general OXC–CBZ mechanistic overlap is consistent with the hypothesis that OXC and CBZ have similar
effects in bipolar disorder, which is consistent with preliminary clinical observations but remains to be established
in large controlled clinical studies.
INDICATIONS AND EFFICACY
Seizure Disorders and Trigeminal Neuralgia
In the United States, CBZ is approved by the FDA as monotherapy for the treatment of trigeminal neuralgia and
complex partial, generalized tonic–clonic, and mixed seizure disorders (“Carbatrol” 2008; “Tegretol” 2008). OXC is
approved for the treatment of partial seizures as monotherapy in adults and as adjunctive therapy in adults and
children older than 4 years (“Trileptal” 2008). CBZ and OXC appear to have overlapping anticonvulsant effects, with
similar efficacy in patients with newly diagnosed epilepsy (Dam et al. 1989). However, there may be dissociations.
For example, switching to OXC may be effective in patients with inadequate responses or intolerable adverse
effects with CBZ (Beydoun et al. 2000; Van Parys and Meinardi 1994), and adding OXC may yield efficacy in patients
with inadequate responses to CBZ (Barcs et al. 2000; Glauser et al. 2000). In contrast to valproate and lamotrigine,
which are approved first-line medications for bipolar disorder, CBZ and OXC are generally considered alternative
agents in the management of bipolar disorder (American Psychiatric Association 2002), based on the studies
reviewed below.
Acute Mania
Twenty-three controlled studies have investigated CBZ and OXC efficacy in acute mania (Table 37–1) (Ballenger
and Post 1978; D. Brown et al. 1989; Desai et al. 1987; Emrich 1990; Emrich et al. 1985; Goncalves and Stoll 1985;
Grossi et al. 1984; Klein et al. 1984; Lenzi et al. 1986; Lerer et al. 1987; Lusznat et al. 1988; Möller et al. 1989;
Müller and Stoll 1984; Okuma et al. 1979, 1989, 1990; Post et al. 1987; Small et al. 1991; Stoll et al. 1986; Wagner
et al. 2006; Weisler et al. 2004, 2005; Zhang et al. 2007). In these studies, there is more compelling evidence for
CBZ efficacy (18 studies including 594 patients receiving CBZ) than for OXC efficacy (5 studies including 119
patients receiving OXC).
TABLE 37–1. Carbamazepine (CBZ) and oxcarbazepine (OXC) in acute mania: 23 double-blind studies
Study Design CBZ/OXC
(N)
Comparator
(N)
Duration
(days)
CBZ/OXC
response
Comparator
response
Weisler et al. 2004 CBZ vs. PBO 101 103 21 42% 22%
Weisler et al. 2005 CBZ vs. PBO 122 117 21 61% 29%
Zhang et al. 2007 CBZ vs. PBO 41 21 84 88% 57%Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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Study Design CBZ/OXC
(N)
Comparator
(N)
Duration
(days)
CBZ/OXC
response
Comparator
response
Wagner et al. 2006 OXC vs. PBO 55 55 42 42% 26%
Ballenger and Post 1978;
Post et al. 1987
PBO–CBZ–PBO 19 — 11–56 63% Frequent relapse
Emrich et al. 1985 PBO–OXC–PBO 7 — Varied 67% —
Klein et al. 1984 CBZ vs. PBO adjunct
(HAL)
14 13 35 71% 54%
Müller and Stoll 1984;
Goncalves and Stoll 1985
CBZ vs. PBO adjunct
(HAL)
6 6 21 CBZ > PBO —
Desai et al. 1987 CBZ vs. PBO adjunct
(Li)
5 5 28 CBZ > PBO —
Möller et al. 1989 CBZ vs. PBO adjunct
(HAL)
11 9 21 CBZ = PBO —
Okuma et al. 1989 CBZ vs. PBO adjunct
(NL)
82 80 28 48% 30%
Okuma et al. 1979 CBZ vs. NL (CPZ) 32 28 21–35 66% 54%
Grossi et al. 1984 CBZ vs. NL (CPZ) 18 19 21 67% 76%
Emrich 1990 OXC vs. NL (HAL) 19 19 14 OXC = HAL —
Stoll et al. 1986 CBZ vs. NL (HAL)
adjunct (CPZ)
14 18 21 86% 67%
- Brown et al. 1989 CBZ vs. NL (HAL)
adjunct (CPZ)
8 9 28 75% 33%
Müller and Stoll 1984 OXC vs. NL (HAL)
adjunct (HAL)
10 10 14 OXC = HAL —
Lerer et al. 1987 CBZ vs. Li 14 14 28 29% 79%
Small et al. 1991 CBZ vs. Li 24 24 56 33% 33%
Emrich 1990 OXC vs. Li 28 24 14 OXC = Li —
Lenzi et al. 1986 CBZ vs. Li adjunct
(CPZ)
11 11 19 73% 73%
Lusznat et al. 1988 CBZ vs. Li adjunct
(CPZ, HAL)
22 22 42 CBZ = Li —
Okuma et al. 1990 CBZ vs. Li adjunct
(NL)
50 51 28 62% 59%
Total
713 658
Response ratesa
CBZ/OXC
monotherapy
55%
(237/433)
NL monotherapy
64% (30/47)
Li monotherapy
50% (19/38)
PBO monotherapy
28% (83/296)
Response ratesa
CBZ/OXC adjunctive
59%
(106/179)
NL adjunctive
56% (15/27)
Li adjunctive
61% (38/62)
PBO adjunctive
33% (31/93)
Note. CBZ = carbamazepine; CPZ = chlorpromazine; HAL = haloperidol; Li = lithium; NL = neuroleptic; NS = not stated; OXC
= oxcarbazepine; PBO = placebo.
aWeighted means of patients with response data.
Two recent trials, which found a proprietary CBZ beaded extended-release capsule formulation (Equetro) superior
to placebo, are of particular interest because they used a randomized, double-blind, placebo-controlled paradigmPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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(Weisler et al. 2004, 2005) and yielded an FDA indication for the treatment of acute manic and mixed episodes in
patients with bipolar disorder.
These recent reports are consistent with multiple earlier studies using placebo–drug–placebo, active-comparator
(lithium or neuroleptics), and adjunctive (compared with placebo, lithium, or neuroleptics added to lithium or
neuroleptics) designs. Thus, across studies that used diverse paradigms (see Table 37–1), overall antimanic
response rates were generally comparable to those seen with lithium or neuroleptics or in other studies with
valproate (Ketter 2005). Taken together, this collection of clinical trials provides substantial evidence for the acute
antimanic efficacy of CBZ and preliminary evidence for the acute antimanic efficacy of OXC. For CBZ, this current
body of existing data appears greater than that initially considered by the FDA in approving lithium for the
treatment of acute mania.
Improvement appears to occur across the entire manic syndrome and does not seem to be due to nonspecific
sedative properties, in that patients often show dramatic clinical improvement in the absence of marked sedation.
Because CBZ and OXC are frequently used in combination with other medications in the acute treatment of mania,
knowledge of CBZ’s extensive and OXC’s more limited drug–drug interactions (as described later in this chapter) is
often required to achieve optimal outcomes.
Acute Depression
There are limited controlled data regarding the acute antidepressant effects of CBZ, and no published controlled
studies of the antidepressant effects of OXC (Table 37–2). Although CBZ appears to have weaker antidepressant
than antimanic properties, some evidence suggests that it may provide antidepressant benefit in about one-third of
treatment-resistant patients (Neumann et al. 1984; Post et al. 1986; Small 1990), and in a Chinese study, CBZ
yielded a response rate closer to two-thirds in non-treatment-resistant patients (Zhang et al. 2007). Unfortunately,
most of these studies are limited by the use of small samples of heterogeneous (both bipolar and unipolar) and
highly treatment-resistant patients. Nevertheless, double-blind off–on–off–on observations and a randomized,
double-blind, placebo-controlled trial have provided evidence of individual responsiveness in at least a subgroup of
depressed bipolar patients.
TABLE 37–2. Carbamazepine (CBZ) in acute depression: four controlled studies
Study Design CBZ
(N)
Comparator
(N)
Duration
(days)
CBZ
response
Comparator
response
Post et al. 1986 PBO–CBZ–PBO (24 BP, 11
- UP)
35 35 Median 45 34% —
Zhang et al. 2007 CBZ vs. PBO 47 23 84 64% 35%
Small 1990 CBZ/CBZ + Li vs. Li (4 BP,
24 UP)
NS NS 28 32% 13%
Neumann et al.
1984
CBZ vs. TMI (5 BP, 5 UP) 5 5 28 CBZ = TMI —
Note. BP = bipolar; CBZ = carbamazepine; Li = lithium; NS = not stated; PBO = placebo; TMI = trimipramine; UP = unipolar.
Prophylaxis
Findings from a series of 16 double-blind, randomized, open randomized, or otherwise partially controlled studies
(Ballenger and Post 1978; Bellaire et al. 1988; Cabrera et al. 1986; Coxhead et al. 1992; Denicoff et al. 1997; Di
Costanzo and Schifano 1991; Elphick et al. 1988; Greil et al. 1997; Hartong et al. 2003; Kishimoto and Okuma 1985;
Lusznat et al. 1988; Mosolov 1991; Okuma et al. 1981; Placidi et al. 1986); Post et al. 1983b; Watkins et al. 1987;
Wildgrube 1990) are consistent with a very substantial open literature suggesting that CBZ may be effective in
preventing bipolar manic and depressive episodes when administered as long-term prophylaxis, either alone or in
combination with lithium, in patients who previously had not responded to lithium (Table 37–3). CBZ may have
equal prophylactic antidepressant and antimanic efficacy, in contrast to its less potent acute antidepressant versus
antimanic effects. In contrast, there are only sparse data regarding the efficacy of OXC in the prophylaxis of
episodes in patients with bipolar disorder.
TABLE 37–3. Carbamazepine (CBZ) and oxcarbazepine (OXC) in prophylaxis of bipolar disorder: 16 controlled or
quasi-controlled studies
Study Design CBZ
(N)
Comparator
(N)
Duration
(years)
CBZ/OXC
response
Comparator
response
Okuma et al. 1981 CBZ vs. PBO
(B, R)
12 10 1 60% 22%Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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Study Design CBZ
(N)
Comparator
(N)
Duration
(years)
CBZ/OXC
response
Comparator
response
Ballenger and Post 1978;
Post et al. 1983b
CBZ vs. PBO
(B, M)
7 7 1.7 86% —
Placidi et al. 1986 CBZ vs. Li (B,
- R)
20 16
3 67% 67%
Watkins et al. 1987 CBZ vs. Li (B,
- R)
19 18 1.5 84% 83%
Lusznat et al. 1988 CBZ vs. Li (B,
- R)
16 15
1 56% 29%
Coxhead et al. 1992 CBZ vs. Li (B,
- R)
13 15 1 54% 47%
Bellaire et al. 1988 CBZ vs. Li (R) 46 52 1 CBZ = Li —
Greil et al. 1997 CBZ vs. Li (R) 70 74 2.5 45% 65%
Hartong et al. 2003 CBZ vs. Li (R) 50 44 2 58% 73%
Di Costanzo and Schifano
1991
CBZ + Li vs. Li
(R)
8 8
5 CBZ + Li > Li —
Mosolov 1991 CBZ vs. Li (R?) 30 30
1 73% 70%
Cabrera et al. 1986 OXC vs. Li (R) 4 6
22 75% 100%
Elphick et al. 1988 CBZ vs. Li (B,
- C)
8 11 0.75 38% 73%
Denicoff et al. 1997 CBZ vs. Li (B,
- C)
46 50 1 33% 55%
Kishimoto and Okuma 1985 CBZ vs. Li (C) 18 18
2 CBZ > Li —
Wildgrube 1990 OXC vs. Li (NR) 8 7
33 33% 67%
Total
375 373
Response ratesa
CBZ/OXC
54% (165/303)
Li
64% (185/286)
PBO
22% (2/9)
Note. B = blind; C = crossover; CBZ = carbamazepine; Li = lithium; M = mirror image; NR = not randomized; OXC =
oxcarbazepine; PBO = placebo; R = randomized.
aWeighted means of patients with response data.
In one study, the overall analysis suggested that maintenance treatment was more effective with lithium than with
CBZ (Greil et al. 1997), but subsequent analysis revealed subgroup differences. Thus, maintenance treatment was
more effective with lithium than with CBZ in patients with “classic” bipolar disorder (bipolar I disorder with no
mood-incongruent delusions or comorbidity) but tended to be more effective with CBZ than with lithium in patients
with “nonclassic” bipolar disorder (bipolar II disorder, bipolar disorder not otherwise specified, bipolar disorder
with mood-incongruent delusions or comorbidity) (Greil et al. 1998).
In another study, maintenance treatment appeared to be more effective with lithium than with CBZ in patients with
no more than 6 months’ prior exposure to either agent (Hartong et al. 2003). However, this advantage was offset
by more early discontinuations in the lithium group, so that similar proportions (about one-third) of lithium-treated
and CBZ-treated patients completed 2 years with no episode. Patients on lithium compared to CBZ tended to have a
somewhat greater risk of episodes in the first 3 months and markedly less risk of episodes after the first 3 months,
with a recurrence risk of only 10% per year with lithium after the first 3 months. Patients on CBZ had a more
consistent rate of relapse/recurrence of about 40% per year.
Some CBZ prophylaxis trials have been criticized due to methodological limitations (D. J. Murphy et al. 1989), but
such difficulties are common in maintenance studies. For example, apparently due in part to methodological
limitations, divalproex and lithium failed to separate from placebo on the primary efficacy measure in a 1-year
maintenance study (Bowden et al. 2000). Taken together, the randomized, placebo-controlled,
placebo–drug–placebo, and lithium comparator studies and trials in patients with rapid-cycling or lithium-resistant
illness constitute substantial evidence for the efficacy of CBZ (Prien and Gelenberg 1989). CBZ may be effective in
some individuals with valproate-resistant illness (Post et al. 1984b), and the CBZ plus valproate combination may
be effective in patients who show little or no response to either agent alone (Keck et al. 1992; Ketter et al. 1992).Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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In a retrospective study, although 22 of 34 (65%) patients with treatment-resistant bipolar disorder responded to
primarily adjunctive open CBZ acutely, when patients were assessed 3–4 years later, only 7 of 34 (21%) and 2 of
34 (6%) were considered probable and clear responders, respectively (Frankenburg et al. 1988). Post et al. (1990)
have suggested that loss of CBZ prophylactic efficacy over time may be related to a unique form of contingent
tolerance. In these instances, the optimal algorithm for recapturing CBZ response has not been determined.
However, techniques such as switching to another treatment regimen with a different mechanism of action or
returning later to CBZ (after a period of not taking CBZ) are worth considering, based on case reports and anecdotal
observations. Systematic clinical trials are required to better determine the efficacy of these and other approaches
for recapturing CBZ response.
Response Predictors
Predictors of CBZ and OXC response have not been adequately elucidated. CBZ appears to be effective in patients
with a history of lithium unresponsiveness or intolerance (Okuma et al. 1979; Post et al. 1987). Nonclassic bipolar
disorder (Greil et al. 1998; Small et al. 1991) and stable or decreasing episode frequency (Post et al. 1990) have
been reported to be associated with CBZ response. Studies have indicated that patients with a history of affective
illness in first-degree relatives may have preferential responses to lithium, whereas the converse may be the case
for CBZ (Ballenger and Post 1978; Post et al. 1987). Himmelhoch and colleagues (Himmelhoch 1987; Himmelhoch
and Garfinkel 1986) have suggested that patients with comorbid neurological or substance abuse problems and
inadequate lithium responses might respond to CBZ or valproate. Preliminary observations indicate that baseline
cerebral (left insula) hypermetabolism may be a marker of CBZ response (Ketter et al. 1999).
There are varying reports with respect to the relationships between CBZ response and dysphoric manic
presentations (Lusznat et al. 1988; Post et al. 1989) and illness severity (Post et al. 1987; Small et al. 1991).
Although several investigators have suggested that psychosensory symptoms (which have been hypothesized to be
due to limbic dysfunction) may indicate preferential response to CBZ and other anticonvulsants, such a relationship
has not been observed in acute therapy, and the relationship to prophylactic response remains to be delineated.
Antidepressant responses to CBZ may be seen in patients with more severe depression, more discrete depressive
episodes, less chronicity, and greater decreases in serum T4 concentrations with CBZ (Post et al. 1991, 1986).
Although the initial studies of Post et al. (1987) and Okuma et al. (1981; Okuma 1983) indicated that some
rapid-cycling patients were responsive to CBZ, other investigators found less robust results (Dilsaver et al. 1993;
Joyce 1988). As with lithium, later studies by Okuma (1993) reported a lower CBZ maintenance response rate in
rapid-cycling compared with non-rapid-cycling illness. However, even these rapid-cycling patients had a CBZ
response rate (40%) that was higher than the rates reported for other agents in other studies. Denicoff et al.
(1997) also observed that patients with a history of rapid cycling had a lower CBZ maintenance response rate
compared with those without such a history (19% vs. 54%).
SIDE EFFECTS AND TOXICOLOGY
Baseline evaluation of bipolar disorder patients includes not only psychosocial assessment but also general medical
evaluation, in view of the risk of medical processes, which could confound diagnosis or influence management
decisions, and the risk of adverse effects, which may occur with treatment. Assessment commonly includes history;
physical examination; complete blood count with differential and platelets; renal, hepatic, and thyroid function;
toxicology; pregnancy tests; and other chemistries and electrocardiogram as clinically indicated (American
Psychiatric Association 2002). Such evaluation provides baseline values for parameters that influence decisions
about choice of medication and intensity of clinical and laboratory monitoring.
Carbamazepine
CBZ adverse effects appear to have substantial impact on the utility of CBZ in the treatment of bipolar disorder. For
example, in a retrospective study, 12 of 55 (22%) patients with treatment-resistant psychotic disorders (including
34 with bipolar disorder) discontinued primarily adjunctive open CBZ in the first 2 months because of adverse
effects (Frankenburg et al. 1988). Also, in a randomized, double-blind crossover maintenance study, significantly
more patients receiving CBZ (10 of 46, 22%) than those receiving lithium (2 of 50, 4%) discontinued the drug early
because of adverse effects (Denicoff et al. 1997). In a randomized open maintenance study, although
nonsignificantly more CBZ (9 of 70, 13%) than lithium (4 of 74, 5%) patients discontinued early because of
adverse effects, significantly more CBZ (26 of 33, 79%) than lithium (20 of 51, 39%) patients who completed the
study were free of adverse effects (Greil et al. 1997). Thus, adverse effects requiring discontinuation may occur
more commonly with CBZ than with other drugs, particularly during acute therapy if CBZ is rapidly introduced.
However, some patients may tolerate CBZ better than other agents, particularly during longer-term treatment, as
CBZ appears to have a low propensity to cause adverse effects such as weight gain and metabolic disturbance that
can limit the utility of some other agents (Ketter et al. 2005).
CBZ has several common dose-related adverse effects that can generally be minimized by attention to drug–drug
interactions and gradual titration of dosage or reversed by decreasing dosage. At high doses, patients can developPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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neurotoxicity with sedation, ataxia, diplopia, and nystagmus, particularly early in therapy before autoinduction and
the development of some tolerance to CBZ’s central nervous system adverse effects occur. However, in contrast to
neuroleptic treatment, CBZ therapy is not associated with extrapyramidal adverse effects. Because there is wide
interindividual variation in susceptibility to adverse effects at any given concentration, it is most useful clinically to
titrate doses against each patient’s adverse effects rather than targeting a fixed dosage or serum concentration
range.
Dizziness, ataxia, or diplopia emerging 1–2 hours after an individual dose is often a sign that the adverse-effect
threshold has been exceeded and that dosage redistribution (spreading out the dose or giving more of the dosage
at bedtime) or dosage reduction may be required. Use of extended-release formulations can also attenuate CBZ
peak serum concentrations, enhancing tolerability.
The United States prescribing information for carbamazepine includes black box warnings regarding the risks of
aplastic anemia (16 per million patient-years) and agranulocytosis (48 per million patient-years), as well as serious
dermatological reactions and the HLA-B*1502 allele. Other warnings include the risks of teratogenicity, and
increased intraocular pressure due to mild anticholinergic activity. Thus, CBZ can yield hematological (benign
leukopenia, benign thrombocytopenia), dermatological (benign rash), electrolyte (asymptomatic hyponatremia),
and hepatic (benign transaminase elevations) problems. Much less commonly, CBZ can yield analogous serious
problems. For example, mild leukopenia and benign rash occur in as many as 1 of 10 patients, with the slight
possibility that these usually benign phenomena are heralding malignant aplastic anemia and Stevens-Johnson
syndrome/toxic epidermal necrolysis, seen in approximately 1 per 100,000 and 1 to 6 per 10,000 patients,
respectively (Kramlinger et al. 1994; Tohen et al. 1995). Recent evidence indicates that the risk of serious rash may
be 10 times as high in some Asian countries and strongly linked to the HLA-B*1502 allele. Thus, the United States
prescribing information states that individuals of Asian descent should be genetically tested before initiating
carbamazepine therapy. An individual who is HLA-B*1502 positive should not be treated with CBZ unless the
benefit clearly outweighs the risk. In view of the risk of rare but serious decreases in blood counts, it is important
to alert patients to seek immediate medical evaluation if they develop signs and symptoms of possible
hematological reactions, such as fever, sore throat, oral ulcers, petechiae, and easy bruising or bleeding.
Hematological monitoring needs to be intensified in patients with low or marginal leukocyte counts, and CBZ is
generally discontinued if the leukocyte count falls below 3,000/mm3 or the granulocyte count below 1,000/mm3 .
In early 2008, the FDA released an alert regarding increased risk of suicidality (suicidal behavior or ideation) in
patients with epilepsy as well as psychiatric disorders for 11 anticonvulsants (including CBZ and OXC). In the FDA’s
analysis, anticonvulsants compared with placebo yielded approximately twice the risk of suicidality (0.43% vs.
0.22%). The relative risk for suicidality was higher in patients with epilepsy than in patients with psychiatric
disorders. As of late 2008, a class warning regarding this risk had not yet been added to the United States
prescribing information for anticonvulsants, but it is anticipated that this may occur.
In the instance of benign leukopenia, the addition of lithium can increase the neutrophil count back toward normal
(Kramlinger and Post 1990), but this strategy is not likely to be helpful for the suppression of red cells or platelets,
which is likely to be indicative of a more problematic process.
Rash presenting with systemic illness or involvement of the eyes, mouth, or bladder (dysuria) constitutes a medical
emergency, and CBZ should be discontinued immediately and the patient assessed emergently. For more benign
presentations, CBZ is generally discontinued, as there is little ability to predict which rashes will progress to more
severe, potentially life-threatening problems. However, in rare instances of resistance to all medications except
CBZ, a repeat trial of CBZ with a course of prednisone has usually been well tolerated (J. M. Murphy et al. 1991; Vick
1983). If there is evidence of systemic allergy, fever, or malaise, prednisone is less likely to be helpful. A
substantial number of patients with CBZ-induced rashes may not have a rash on reexposure (even without
prednisone coverage), but if a rash again develops, it usually appears more rapidly than in the first occurrence.
Only 25%–30% of the patients who develop a rash while taking CBZ also develop a rash (cross-sensitivity) with
OXC.
Due to the risk of rare hepatitis, patients should be advised to seek medical evaluation immediately if they develop
malaise, abdominal pain, or other marked gastrointestinal symptoms. In general, CBZ (like other anticonvulsants)
is discontinued if liver function tests exceed three times the upper limit of the normal range (Martinez et al. 1993).
CBZ may affect cardiac conduction and should be used with caution in patients with cardiac disorders such as heart
block. A baseline electrocardiogram is worth considering if the patient has a positive cardiac history.
Conservative laboratory monitoring during CBZ therapy includes baseline studies and reevaluation of complete
blood count, differential, platelets, and hepatic indices initially at 2, 4, 6, and 8 weeks, and then every 3 months
(American Psychiatric Association 1994, 2002). Most of the serious hematological reactions occur in the first 3
months of therapy (Tohen et al. 1995). In contemporary clinical practice, somewhat less focus is placed on
scheduled monitoring; instead, monitoring as clinically indicated (e.g., when a patient becomes ill with a fever) is
emphasized. Patients who have abnormal or marginal indices at any point merit careful scheduled and clinicallyPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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indicated monitoring. The United States prescribing information for the beaded extended-release capsule CBZ
formulation that was recently approved for the treatment of acute mania includes monitoring baseline complete
blood count, platelets, ±reticulocytes, ±serum iron, and hepatic function tests; closely monitoring patients with low
or decreased white blood cell count or platelets; and considering discontinuation of CBZ if there is evidence of bone
marrow depression (“Equetro” 2008). Serum CBZ concentrations are typically assessed at steady state and then as
clinically indicated (e.g., by inefficacy or adverse effects).
Dividing or reducing doses, moving doses in relation to mealtimes, and changing formulations can attenuate
CBZ-induced gastrointestinal disturbances. CBZ suspension may have more proximal absorption and thus
exacerbate upper gastrointestinal (nausea and vomiting) or attenuate lower gastrointestinal (diarrhea) adverse
effects. The reverse holds for extended-release preparations.
Weight gain and obesity are important clinical concerns in the management of bipolar disorder. Medications and the
hyperphagia, hypersomnia, and anergy commonly seen in bipolar depression can contribute to this important
obstacle to optimal outcomes. CBZ is less likely than lithium (Coxhead et al. 1992; Denicoff et al. 1997) or valproate
(Mattson et al. 1992) to yield weight gain. In one study, CBZ caused weight gain in depressed (but not manic)
patients, an effect that seemed to be related to the degree of relief of depression (Joffe et al. 1986b). Nevertheless,
in view of its relatively favorable effect on weight, CBZ may provide an important alternative to other mood
stabilizers for patients who struggle with weight gain and obesity.
CBZ can induce hyponatremia that may be tolerated well by some younger patients but can be particularly
problematic in the elderly. If confusion develops in an elderly patient, serum sodium should be assessed. In rare
instances water intoxication and seizures can occur. In some cases, hyponatremia can be effectively counteracted
with the addition of lithium or the antibiotic demeclocycline (Ringel and Brick 1986).
CBZ increases plasma high-density lipoprotein (HDL) (O’Neill et al. 1982) and total cholesterol (D. W. Brown et al.
1992) concentrations. However, because the ratio of HDL to total cholesterol does not change (O’Neill et al. 1982),
CBZ-induced increases in total cholesterol are not likely to be clinically problematic in regard to atherosclerosis (D.
- Brown et al. 1992).
CBZ decreases serum T4, free T4 index, and, less consistently, triiodothyronine (T3) (Bentsen et al. 1983; Connell et
- 1984; Haidukewych and Rodin 1987; Joffe et al. 1986a) but does not substantially alter serum thyroid-binding
globulin, reverse T3, basal thyroid-stimulating hormone (TSH) concentrations (Bentsen et al. 1983; Connell et al.
1984), or somatic basal metabolic rates (Herman et al. 1991). In contrast to lithium, the TSH response to
thyrotropin-releasing hormone is blunted (Joffe et al. 1986a) or unaltered (Connell et al. 1984) with CBZ therapy,
and clinical hypothyroidism during treatment with CBZ is exceedingly rare.
CBZ is teratogenic (Pregnancy Category D) and is associated with low birth weight, craniofacial deformities, digital
hypoplasia, and (in approximately 3% of exposures) spina bifida (Jones et al. 1989; Rosa 1991). For the latter,
folate supplementation may attenuate the risk, and fetal ultrasound studies may allow early detection. In rare
patients with severe mood disorders, clinicians may determine in consultation with a gynecologist that the benefits
of treating with CBZ outweigh the risks in comparison with other treatment options (Sitland-Marken et al. 1989).
CBZ is present in breast milk at concentrations about half those present in maternal blood but may not accumulate
in fetal blood (Froescher et al. 1984; Kuhnz et al. 1983; Pynnönen et al. 1977; Shimoyama et al. 2000). Clinicians
may prefer to avoid the putative risks of exposing infants to CBZ in breast milk (Frey et al. 2002) and discourage
breast-feeding in women taking CBZ (“Carbatrol” 2008; “Tegretol” 2008).
Oxcarbazepine
Adverse effects may limit the use of OXC, as with CBZ. In a retrospective study, adverse events were noted in
one-third of 947 epilepsy patients (Friis et al. 1993). However, OXC may have tolerability advantages over CBZ, in
part perhaps related to the absence of the CBZ-E metabolite. For example, in a 1-year randomized, double-blind
study of 235 patients with newly diagnosed epilepsy, OXC monotherapy yielded fewer severe adverse effects than
CBZ monotherapy (Dam et al. 1989). OXC and valproate may have similar tolerability; in a 1-year randomized,
double-blind study of 249 patients with newly diagnosed epilepsy, monotherapy with these agents had similar rates
of adverse effects (Christe et al. 1997). Importantly, OXC yielded anticonvulsant effects similar to those of CBZ and
valproate in the above-mentioned studies.
Much less is known about the tolerability of OXC in bipolar disorder patients. In randomized, double-blind studies of
monotherapy for acute mania, the proportions of patients experiencing adverse effects were lower with OXC 2,400
mg/day (2 of 19, 10%) than with high-dose haloperidol 42 mg/day (7 of 19, 37%) and were not statistically
different with OXC 1,400 mg/day (8 of 29, 28%) compared with lithium 1,100 mg/day (5 of 27, 19%) (Emrich
1990). A retrospective study of open OXC in acutely manic inpatients found that by the time of discharge, only 6 of
200 (3%) had discontinued the medication because of adverse effects (3 due to hyponatremia) or potential
drug–drug interactions (3 due to concomitant treatment with hormonal contraceptives) (Reinstein et al. 2002).
However, in another retrospective study of primarily depressed patients with treatment-resistant bipolar disorder,Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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7 of 13 (54%) patients discontinued primarily adjunctive OXC because of adverse effects (Ghaemi et al. 2002).
OXC appears to yield less neurotoxicity and rash than CBZ. In a retrospective study of 947 epilepsy patients, OXC
adverse effects most frequently involved the central nervous system and included dizziness, sedation, and fatigue,
each of which was noted in 6% of patients (Friis et al. 1993). Rash was seen in 6% of patients, half of whom had
previously experienced CBZ allergic reactions. About 75% of patients with a rash on CBZ will tolerate OXC.
Importantly, OXC has not been associated with blood dyscrasias, lacks a boxed warning in the prescribing
information, and does not appear to require hematological monitoring.
As noted earlier for CBZ, in early 2008 the FDA released an alert regarding increased risk of suicidality (suicidal
behavior or ideation) in patients with epilepsy as well as psychiatric disorders for 11 anticonvulsants (including
OXC and CBZ). As of late 2008, a class warning regarding this risk had not yet been added to the United States
prescribing information for anticonvulsants, but it is anticipated that this may occur.
OXC, like CBZ, may produce transaminase elevations and gastrointestinal adverse effects but is associated with less
weight gain than valproate (Rattya et al. 1999). In addition, OXC may have less impact on lipids than does CBZ; in
12 male patients with epilepsy, switching to OXC from CBZ yielded decreased serum total cholesterol (but not HDL
cholesterol or triglyceride) concentrations (Isojarvi et al. 1994).
Hyponatremia occurs with OXC (Friis et al. 1993) and may be the main adverse effect that occurs more commonly
than with CBZ. In one study of 10 male epileptic patients who switched to OXC monotherapy from CBZ
monotherapy, mean serum sodium concentrations decreased—in 2 of 10 (20%), below the reference range
(Isojarvi et al. 2001a). However, clinically significant hyponatremia is less common than asymptomatic
hyponatremia. In a retrospective study of inpatients with acute mania, OXC yielded serum sodium concentrations
below the reference range in 24 of 200 (12%), but only 3 of 200 (1.5%) discontinued as a result of hyponatremia
with serum sodium less than 125 mmol/L (Reinstein et al. 2002).
In comparison with CBZ, OXC has less impact on blood concentrations of thyroid and sex hormones, likely because
of its less marked hepatic enzyme induction. In one study, only 24% of 29 male epileptic patients taking
OXC—versus 45% of 40 taking CBZ—had low serum total and/or free T4 (but not T3 and thyrotropin) concentrations
(Isojarvi et al. 2001b). In addition, male epileptic patients taking CBZ (but not those taking OXC) had decreased
serum dehydroepiandrosterone sulfate concentrations (Rattya et al. 2001). Switching to OXC from CBZ in male
epileptic patients yielded increased serum dehydroepiandrosterone sulfate concentrations (Isojarvi et al. 1995). In
healthy male volunteers, higher ( 900 mg/day) but not lower (<900 mg/day) dosages of OXC appeared to yield
increased levels of testosterone and gonadotropins (Larkin et al. 1991). Importantly, as noted below (see
“Drug–Drug Interactions”), OXC induction of female hormone metabolism is sufficient to decrease the efficacy of
hormonal contraceptives (Fattore et al. 1999; Klosterskov Jensen et al. 1992).
OXC, in contrast to CBZ, has not to date been associated with congenital malformations in humans (FDA Pregnancy
Category C). This could be merely related to fewer OXC exposures. However, the absence of the CBZ-E metabolite
could render OXC less teratogenic; in mice, CBZ-E (but not OXC) yielded two- to fourfold increases in malformations
compared with placebo (Bennett et al. 1996). As with CBZ, in rare patients with severe mood disorders, clinicians
may determine in consultation with a gynecologist that the benefits of treating with OXC outweigh the risks in
comparison with other treatment options.
OXC is present in breast milk, and as with CBZ, clinicians may prefer to avoid the putative risks of exposing infants
to OXC in breast milk and discourage breast-feeding in women taking OXC (“Trileptal” 2008).
DRUG–DRUG INTERACTIONS
Combination therapy is common in bipolar disorder, with up to two-thirds of patients receiving more than one
medication (Kupfer et al. 2002). Patients with treatment-resistant illness may require a stepped-care approach
(Figure 37–2) and appear to be receiving increasingly complex medication regimens (Frye et al. 2000). CBZ and, to
a lesser extent, OXC have clinically significant drug–drug interactions, which increase the complexity of managing
patients with bipolar disorder.
FIGURE 37–2. Stepped-care approach to bipolar depression.Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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Composite schema of results from three different studies in which patients with bipolar depression received carbamazepine
(CBZ) monotherapy (Post et al. 1986), lithium (Li) added to CBZ (Kramlinger and Post 1989b), and a monoamine oxidase
inhibitor (MAOI) added to CBZ±Li (Ketter et al. 1995b). Each successive intervention yielded additional efficacy.
Carbamazepine
The pharmacokinetic properties of CBZ are typical of older enzyme-inducing anticonvulsants used by neurologists
but atypical among medications prescribed by psychiatrists and necessitate special care when treating patients
concurrently with other medications (Ketter et al. 1991a, 1991b). Three major principles appear to contribute
importantly to CBZ drug–drug interactions:
CBZ is a robust inducer of catabolic enzymes (including CYP3A3/4) and decreases the serum concentrations
of many medications, including CBZ itself (Table 37–4). CBZ induces not only CYP3A3/4 and conjugation but also
presumably other cytochrome P450 isoforms that remain to be characterized. Thus, CBZ decreases the serum
concentrations not only of CBZ itself (autoinduction) but also of many other medications (heteroinduction). CBZ-induced
decreases in serum concentrations of certain concurrent medications can render them ineffective (see Table 37–4).
Moreover, if CBZ is discontinued (or, in some instances, if replaced with OXC), serum concentrations of these other
medications can increase, potentially leading to adverse effects.
CBZ metabolism (which is primarily by CYP3A3/4) can be inhibited by certain enzyme inhibitors, yielding
increases in serum CBZ concentrations and CBZ intoxication (Table 37–5; see Figure 37–1, top). Autoinduction
makes CBZ particularly vulnerable to the effects of enzyme inhibitors. Thus, a variety of agents that inhibit CYP3A3/4 can
yield increased serum CBZ concentrations and intoxication (see Table 37–5; see Figure 37–1, top).
CBZ has an active epoxide (CBZ-E) metabolite (see Figure 37–1, top). Valproate inhibits epoxide hydrolase,
yielding increased serum CBZ-E (but not CBZ) concentrations and intoxication (see Table 37–5). Free CBZ may also
increase because of valproate-induced displacement of CBZ protein binding.
TABLE 37–4. Drugs whose serum concentrations are DECREASED by carbamazepine (and oxcarbazepine)
Antidepressants Anticonvulsants Dihydropyridine CCBs
Bupropion Carbamazepine
FelodipinePrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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Citalopram Ethosuximide Nimodipine
Mirtazapine Felbamate
Sertraline
Lamotrigine
Immunosuppressants
Tricyclics Levetiracetam (?) Cyclosporine (?)
Oxcarbazepine Sirolimus
Antipsychotics
Phenytoin Tacrolimus
Aripiprazole Primidone
Chlorpromazine (?) Tiagabine
Muscle relaxants
Clozapine Topiramate Atracurium
Fluphenazine (?) Valproate Cisatracurium
Haloperidol Zonisamide Doxacurium
Olanzapine
Mivacurium
Quetiapine
Analgesics
Pancuronium
Risperidone Alfentanil Pipercuronium
Thiothixene (?)
Buprenorphine
Rocuronium
Ziprasidone (?) Fentanyl (?) Vecuronium
Levobupivacaine
Anxiolytics/sedatives
Methadone
Steroids
Alprazolam (?) Tramadol Dexamethasone
Buspirone
Hormonal contraceptives
Clonazepam
Anticoagulants
Mifepristone
Eszopiclone (?) Warfarin Prednisolone
Midazolam
Anti-infectives Others
Stimulants
Caspofungin
Paclitaxel
Methylphenidate Delavirdine Quinidine
Modafinil Doxycycline
Repaglinide
Praziquantel Theophylline (?)
Protease inhibitors Thyroid hormones
Note. Boldface italic type indicates that serum concentration of the medication may decrease to a clinically significant extent
not only with carbamazepine but also with oxcarbazepine, hindering efficacy of the agent.
CCBs = calcium channel blockers; (?) = Unclear clinical significance.
TABLE 37–5. Drugs that INCREASE serum concentrations of carbamazepine (but not oxcarbazepine)
Antidepressants
Calcium channel blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Anti-infectives
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristin/dalfopristin
Others
Azole antifungals
Acetazolamide
Fluconazole
Cimetidine
Itraconazole
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Ketoconazole
Grapefruit juice
Omeprazole
Macrolide antibiotics
d-Propoxyphene
Clarithromycin
Ritonavir
Erythromycin
Ticlopidine (?)
Troleandomycin
Valproate (increases CBZ-E)
Note. (?) = Unclear clinical significance.
Thus, CBZ has a wide variety of pharmacokinetic drug–drug interactions that are in excess of and different from
those seen with lithium or valproate. Knowledge of CBZ drug–drug interactions is crucial in effective management,
and patients should be instructed to consult their pharmacist when prescribed other medications by other
physicians. Advances in molecular pharmacology have characterized the specific cytochrome P450 isoforms
responsible for metabolism of various medications. This may allow clinicians to anticipate and avoid
pharmacokinetic drug–drug interactions and thus provide more effective combination pharmacotherapies. Below,
we review CBZ drug interactions with other medications, with agents of particular interest in the management of
mood disorders indicated in boldface type. The reader interested in detailed reviews of CBZ drug–drug interactions
may find these in other articles (Ketter et al. 1991a, 1991b).
Interactions With Mood Stabilizers
The combination of CBZ plus lithium is frequently used in bipolar disorder and may provide additive or synergistic
antimanic (Kramlinger and Post 1989a) and antidepressant (Kramlinger and Post 1989b) effects. The combination
is generally well tolerated, with merely additive neurotoxicity (McGinness et al. 1990), which can be minimized by
gradual dose escalation. Pharmacokinetic interactions between these drugs do not occur, because lithium is
excreted by the kidney, with no hepatic metabolism. Adverse effects of lithium and CBZ can be either additive or
complementary, so that combination therapy decreases the serum concentrations of thyroid hormones in an
additive fashion (Kramlinger and Post 1990), whereas lithium-induced increases in leukocytes and neutrophils
override the common benign decreases in these indices seen with CBZ (Kramlinger and Post 1990). However, there
is no evidence that lithium can alter the course of the rare severe bone marrow suppression caused by CBZ (Joffe
and Post 1989). Also, the diuretic effect of lithium overrides the antidiuretic effect of CBZ (Klein 1987). Thus, CBZ
will not reverse lithium-induced diabetes insipidus, but lithium attenuates CBZ-induced hyponatremia (Klein 1987;
Vieweg et al. 1987).
Reports suggest that the CBZ plus valproate combination not only is tolerated but also may show psychotropic
synergy (Keck et al. 1992; Ketter et al. 1992; Tohen et al. 1994). However, the effective use of these two
medications together requires a thorough knowledge of their drug interactions, which can be simplified into the
general principle that usual doses of CBZ should be reduced. Valproate inhibits CBZ metabolism (Macphee et al.
1988) and also displaces CBZ from plasma proteins, increasing the free CBZ fraction that is active and available to
be metabolized (Macphee et al. 1988; Moreland et al. 1984). Depending on which effect predominates, total serum
CBZ concentrations can rise (Moreland et al. 1984) or fall (Rambeck et al. 1987) or remain unchanged (Brodie et al.
1983; Kutt et al. 1985; Macphee et al. 1988). Valproate inhibits epoxide hydrolase, increasing the serum CBZ-E
concentration, at times without altering the total serum CBZ concentration (Brodie et al. 1983; Rambeck et al.
1987).
Thus, these interactions can potentially confound clinicians, because patients can have neurotoxicity due to
elevated serum CBZ-E or free CBZ concentrations despite having therapeutic serum total CBZ concentrations (Kutt
et al. 1985). CBZ decreases serum valproate concentrations (Kondo et al. 1990), and its discontinuation can yield
increased serum valproate concentrations and toxicity (Jann et al. 1988). CBZ enzyme induction also increases the
formation of the active valproate metabolite, 2-propyl-4-pentenoic acid (4-ene-valproate) (Kondo et al. 1990),
which may be hepatotoxic and also may add to teratogenicity (Nau and Loscher 1986; Scheffner et al. 1988).
Although fatal hepatitis in infants treated with combinations of valproate with other anticonvulsants is of great
concern (Scheffner et al. 1988), the risk of combined therapy is much lower in adults (Dreifuss et al. 1989). As a
general rule, clinicians should clinically monitor patients receiving the CBZ plus valproate combination for adverse
effects and consider decreasing the CBZ dose in advance (because of the expected displacement of CBZ from
plasma proteins and increase in CBZ-E) and possibly increasing the valproate dose (because of expected
CBZ-induced decrements in valproate).
CBZ increases lamotrigine metabolism and approximately halves blood lamotrigine concentrations. Thus,
lamotrigine doses can be doubled with this combination. In addition, CBZ combined with lamotrigine may have
additive neurotoxicity, probably due to a pharmacodynamic interaction. CBZ even appears to affect OXC
metabolism; in patients with epilepsy, CBZ yielded decreased serum MHD concentrations (McKee et al. 1994).
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Antidepressants are commonly combined with mood stabilizers in the treatment of bipolar disorder. Because CBZ
can increase metabolism of some antidepressants, and because some antidepressants can inhibit CBZ metabolism,
dosage adjustments may be necessary in combination therapy.
Selective serotonin reuptake inhibitors (SSRIs) have fewer adverse effects than do older antidepressants, but
paroxetine and fluoxetine potently inhibit CYP2D6 (but not CYP1A2), and fluvoxamine inhibits CYP1A2 (but not
CYP2D6). The atypical antidepressant nefazodone, norfluoxetine, and to a lesser extent fluvoxamine appear to
inhibit CYP3A4 (Brosen 1994). Fluoxetine (Grimsley et al. 1991; Pearson 1990), fluvoxamine (Fritze et al. 1991),
and nefazodone (Ashton and Wolin 1996; Laroudie et al. 2000; Roth and Bertschy 2001) have been reported to
inhibit CBZ metabolism, causing increased CBZ concentrations and toxicity, although evidence to the contrary also
has emerged for fluoxetine and fluvoxamine (Spina et al. 1993). Viloxazine (Pisani et al. 1984, 1986) and perhaps
trazodone (Romero et al. 1999) can also increase CBZ levels.
Taken together, these observations suggest that fluoxetine, fluvoxamine, and nefazodone may increase CBZ
concentrations, possibly by inhibition of CYP3A4. In addition, parkinsonian symptoms have been reported after
addition of fluoxetine to CBZ (Gernaat et al. 1991). In contrast, sertraline (Rapeport et al. 1996), paroxetine
(Andersen et al. 1991), citalopram (Moller et al. 2001), and mirtazapine (Sitsen et al. 2001) do not appear to alter
CBZ metabolism. CBZ appears to decrease serum concentrations of racemic citalopram, including those of the active
enantiomer escitalopram (Steinacher et al. 2002). CBZ also appears to induce the metabolism of mirtazapine
(Sitsen et al. 2001), mianserin (Eap et al. 1999), sertraline (Khan et al. 2000; Pihlsgard and Eliasson 2002), and to
some extent trazodone (Otani et al. 1996), but not viloxazine (Pisani et al. 1986). The combination of CBZ with
mirtazapine is of potential concern given that mirtazapine has been associated with rare agranulocytosis, and CBZ
could induce metabolism of this drug, decreasing plasma mirtazapine concentrations.
Patients receiving CBZ and bupropion have extremely low serum bupropion concentrations and high
hydroxybupropion (metabolite) concentrations (Ketter et al. 1995a). Because hydroxybupropion is active, the
clinical impact of this dramatic decrease in the bupropion-to-hydroxybupropion ratio is probably not problematic,
and the combination of CBZ and bupropion may often be effective and well tolerated.
Theoretical grounds have been stated for concern about combining CBZ with monoamine oxidase inhibitors
(MAOIs) (“Carbatrol” 2008; “Tegretol” 2008; Thweatt 1986). CBZ may increase rather than decrease serum levels
of transdermal selegiline and its metabolites (“Emsam” 2008), and higher CBZ doses were needed in five patients
taking tranylcypromine than in four taking phenelzine to yield similar serum CBZ concentrations (Barklage et al.
1992). However, case reports (Joffe et al. 1985; Yatham et al. 1990) and a series of 10 patients (Ketter et al.
1995b) suggest that the addition of phenelzine or tranylcypromine to CBZ may be well tolerated, does not affect
CBZ pharmacokinetics, and may provide relief of resistant depressive symptoms in some patients. However, the
antituberculosis drug isoniazid, which is also an MAOI, increases CBZ levels.
CBZ appears to induce the metabolism of tricyclic antidepressants (TCAs), including amitriptyline (Leinonen et al.
1991), nortriptyline (Brosen and Kragh-Sorensen 1993), imipramine (C. S. Brown et al. 1990), desipramine
(Baldessarini et al. 1988), doxepin (Leinonen et al. 1991), and clomipramine (De la Fuente and Mendlewicz 1992),
so that if patients fail to respond to standard doses of TCAs, TCA and metabolite concentrations should be checked.
CBZ-induced decreases in tertiary-amine TCA concentrations could be mediated by CYP3A4 induction, because this
isoenzyme (as well as CYP1A2 and CYP2D6) has been implicated in the N-demethylation of imipramine but not
desipramine (Lemoine et al. 1993; Ohmori et al. 1993). The mechanism of possible CBZ induction of
secondary-amine TCA metabolism remains to be determined. Spina et al. (1994) suggested that induction of
CYP2D6 (the isoenzyme responsible for TCA 2-hydroxylation) may be the operative process, although no other
medication has been observed to definitely yield significant induction of this isoenzyme.
Interactions With Antipsychotics
Combinations of antipsychotics with mood stabilizers are commonly required in treatment of severe mania
(American Psychiatric Association 2002). Newer antipsychotics are preferred over older antipsychotics in the
management of bipolar disorder because of their better tolerability (American Psychiatric Association 2002). CBZ
can be used effectively in combination with antipsychotics, although clinicians need to be aware of potential
drug–drug interactions.
CBZ increases haloperidol metabolism (Ereshefsky et al. 1986; Jann et al. 1989; Kahn et al. 1990), dramatically
lowering its blood concentrations. Haloperidol metabolism is complex (Tsang et al. 1994), and the mechanism of
CBZ induction of this metabolism remains to be determined. Some patients have improvement in psychiatric status
or fewer neuroleptic adverse effects during combination treatment, while others show deterioration in psychiatric
status (Jann et al. 1989; Kahn et al. 1990). Neurotoxicity possibly related to receiving the combination of CBZ and
haloperidol has been very rarely reported (Brayley and Yellowlees 1987). There is weaker evidence that CBZ may
increase the metabolism of other first-generation antipsychotic agents, including fluphenazine (Ereshefsky et al.
1986; Jann et al. 1989), chlorpromazine (Raitasuo et al. 1994), and thiothixene (Ereshefsky et al. 1986), but not
thioridazine (Tiihonen et al. 1995), and that loxapine, chlorpromazine, and amoxapine may increase CBZ-EPrint: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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concentrations (Pitterle and Collins 1988). Thioridazine does not yield clinically significant changes in serum CBZ or
CBZ-E concentrations (Spina et al. 1990). Also, animal studies suggest that promazine, chlorpromazine, perazine,
chlorprothixene, and flupenthixol may increase CBZ concentrations (Daniel et al. 1992). In view of the above,
serum antipsychotic medication concentrations should be checked if patients fail to respond to standard dosages of
antipsychotic agents during combination therapy with CBZ.
Combination of clozapine with CBZ is not recommended in view of the hypothetical possibility of synergistic bone
marrow suppression (“Carbatrol” 2008; “Tegretol” 2008). However, these drugs have been used in combination in
some European centers, one of which reported that CBZ decreases clozapine (a CYP2D6 substrate [Fischer et al.
1992]) concentrations (Raitasuo et al. 1993). Thus, clinicians wishing to combine a psychotropic anticonvulsant
with clozapine should consider valproate, lamotrigine, or another anticonvulsant rather than CBZ, except under
unusual circumstances.
CBZ increases metabolism of olanzapine (Linnet and Olesen 2002; Lucas et al. 1998), risperidone (Ono et al. 2002;
Spina et al. 2000; Yatham et al. 2003), quetiapine (Grimm et al. 2006), aripiprazole (Physicians’ Desk Reference
2008), and ziprasidone (Miceli et al. 2000). Although the clinical significance of CBZ-induced decreases in
ziprasidone serum concentrations remains to be determined, CBZ interactions with other atypical antipsychotics
can be clinically significant. For example, in a recent acute mania combination therapy study, CBZ decreased serum
risperidone plus active metabolite concentrations by 40%, interfering with antipsychotic efficacy (Yatham et al.
2003). In another combination therapy study, CBZ yielded lower-than-expected blood olanzapine concentrations,
and even though this was addressed in part by more aggressive olanzapine dosage, the efficacy of the olanzapine
plus CBZ combination was still not significantly better than that of CBZ monotherapy in the treatment of acute
mania (Tohen et al. 2008). In two patients, quetiapine appeared to increase CBZ-E levels (Fitzgerald and Okos
2002). The effects of clozapine, olanzapine, risperidone, ziprasidone, and aripiprazole on CBZ pharmacokinetics
remain to be established.
Interactions With Anxiolytics and Sedatives
CBZ is commonly administered along with benzodiazepines in patients with bipolar disorder, with merely additive
central nervous system (e.g., sedation, ataxia) adverse effects. Indeed, contemporary controlled CBZ trials
routinely permit some adjunctive benzodiazepine (e.g., lorazepam) administration (Weisler et al. 2004, 2005).
However, CBZ may decrease serum concentrations of clonazepam (Lai et al. 1978; Yukawa et al. 2001), alprazolam
(Arana et al. 1988; Furukori et al. 1998), clobazam (Levy et al. 1983), and midazolam (Backman et al. 1996),
potentially decreasing the efficacy of these agents. CBZ-induced decreases in certain benzodiazepine
concentrations could be mediated by induction of CYP3A4, as this isoenzyme has been implicated in the metabolism
of clonazepam (Seree et al. 1993), triazolam (Kronbach et al. 1989), midazolam (Gascon and Dayer 1991; Kronbach
et al. 1989), and possibly alprazolam (Greenblatt et al. 1993; von Moltke et al. 1993). The newer hypnotics
eszopiclone and zolpidem may have drug interactions with CBZ, as these agents appear to be more susceptible than
zaleplon to drugs that induce CYP3A4 (Drover 2004). On the other hand, clonazepam (Lander et al. 1975;
Lehtovaara et al. 1978) and clobazam (Goggin and Callaghan 1985; Munoz et al. 1990) appear to have variable
effects on CBZ metabolism. Of interest, CBZ may be effective in ameliorating benzodiazepine withdrawal symptoms
(Ries et al. 1989).
Interactions With Stimulants
The use of stimulants in bipolar disorder is circumscribed largely because of concerns about the risk of abuse and
mood destabilization. CBZ appears to decrease serum concentrations of methylphenidate and modafinil.
Interactions With Calcium Channel Blockers
Of clear clinical importance, elevated serum CBZ concentrations and neurotoxicity have been reported during
concurrent treatment with the nondihydropyridines verapamil and diltiazem, but not the dihydropyridines
nifedipine (Brodie and MacPhee 1986; Price and DiMarzio 1988) and nimodipine. (This is easily remembered by the
“N” rule: Not Nifedipine or Nimodipine.) These observations are consistent with the finding that verapamil and
diltiazem, but not nifedipine, inhibit the hepatic oxidative metabolism of various drugs (Hunt et al. 1989).
Preliminary observations also indicate that the dihydropyridine nimodipine may not substantially influence CBZ
kinetics and that the addition of CBZ to nimodipine may yield therapeutic synergy (Pazzaglia et al. 1993, 1998).
Enzyme-inducing anticonvulsants such as CBZ appear to decrease serum concentrations of dihydropyridines such as
nimodipine (Tartara et al. 1991) and felodipine (Capewell et al. 1988; Zaccara et al. 1993), presumably by induction
of CYP3A4, given that this isoenzyme mediates metabolism of nimodipine, felodipine, nifedipine, and nicardipine, as
well as a variety of other dihydropyridines (Guengerich et al. 1991).
Interactions With Substances of Abuse
In view of the high comorbidity of bipolar disorder and alcohol abuse, knowledge of interactions between ethanol
and CBZ is of clinical utility. Ethanol is a CYP2E1 substrate (Gonzalez et al. 1991) and inducer (Hansson et al.
1990). Although ethanol and CBZ do not have pharmacokinetic interactions (Dar et al. 1989; Pynnönen et al. 1978)Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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(presumably because of their metabolism by different CYP families), CBZ attenuates alcohol withdrawal symptoms
(Malcolm et al. 1989), a potentially useful property given the risk of alcohol abuse in bipolar disorder patients.
Combination therapy with disulfiram and CBZ is well tolerated and does not cause clinically significant changes in
serum CBZ and CBZ-E concentrations (Krag et al. 1981).
Tobacco smoking (which induces CYP1A [Guengerich 1992]) does not alter CBZ metabolism (Bachmann et al.
1990), and CBZ does not alter caffeine (a CYP1A2 substrate [Fuhr et al. 1992]) pharmacokinetics (Wietholtz et al.
1989).
Preliminary clinical studies suggested that CBZ attenuated acute cocaine effects and seizures and possibly cocaine
craving (Halikas et al. 1989; Kuhn et al. 1989; Sherer et al. 1990), but later controlled studies generally failed to
support these observations (Cornish et al. 1995; Kranzler et al. 1995; Montoya et al. 1994).
Interactions With Anticonvulsants
As noted above, CBZ induces the metabolism of carbamazepine (autoinduction) and oxcarbazepine (McKee et al.
1994), as well as the mood-stabilizing anticonvulsants valproate and lamotrigine. CBZ also induces the metabolism
of several older anticonvulsants, including ethosuximide, phenytoin, and primidone. Moreover, CBZ induces the
metabolism of multiple newer anticonvulsants, including felbamate, topiramate (Sachdeo et al. 1996), tiagabine
(Samara et al. 1998), zonisamide (Ojemann et al. 1986), and possibly levetiracetam (May et al. 2003), but not
gabapentin (Radulovic et al. 1994) or pregabalin (Brodie et al. 2005). In contrast, none (aside from felbamate) of
these newer anticonvulsants yields clinically significant changes in CBZ pharmacokinetics (Brodie et al. 2005; Gidal
et al. 2005; Gustavson et al. 1998; McKee et al. 1994; Radulovic et al. 1994; Ragueneau-Majlessi et al. 2004;
Sachdeo et al. 1996). However, the anticonvulsants phenytoin, phenobarbital, primidone, methsuximide, and
felbamate decrease serum CBZ concentrations. In addition, CBZ may have a pharmacodynamic interaction with
levetiracetam (Sisodiya et al. 2002).
Interactions With Nonpsychotropic Drugs
Drug–drug interactions between CBZ and other (nonpsychotropic) drugs are also of substantial clinical importance.
CBZ induces metabolism of diverse medications, raising the possibility of undermining the efficacy of steroids such
as hormonal contraceptives, dexamethasone, prednisolone, and mifepristone. In women taking CBZ, oral
contraceptive preparations need to contain at least 50 g of ethinylestradiol, levonorgestrel implants are
contraindicated because of cases of contraceptive failure, and medroxyprogesterone injections need to be given
every 10 rather than 12 weeks (Crawford 2002). CBZ also induces metabolism of methylxanthines such as
theophylline and aminophylline; antibiotics such as doxycycline; antivirals such as protease inhibitors;
neuromuscular blockers such as pancuronium, vecuronium, and doxacurium; analgesics such as methadone;
immunosuppressants such as sirolimus and tacrolimus; and the anticoagulants warfarin and possibly dicumarol
(see Table 37–4).
Similarly, a variety of medications can increase serum CBZ concentrations and yield clinical toxicity, including
isoniazid, azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin,
protease inhibitors such as ritonavir and nelfinavir, hypolipidemics such as gemfibrozil and nicotinamide, and the
carbonic anhydrase inhibitor acetazolamide (see Table 37–5). In addition, other medications such as cisplatin and
doxorubicin may decrease serum CBZ levels, potentially yielding inefficacy.
Oxcarbazepine
In contrast to CBZ, OXC has fewer clinically significant drug–drug interactions. Differences in three major areas
appear to contribute importantly to differences between OXC and CBZ drug–drug interactions:
OXC is only a modest to moderate enzyme (CYP3A4) inducer, which yields clinically significant decreases in
serum concentrations of some medications (see Table 37–4). OXC yields minor enzyme heteroinduction (but not
autoinduction), which is clearly less robust than that seen with CBZ. For example, in healthy male volunteers, measures
of enzyme activity such as antipyrine metabolism and urinary 6- -hydroxycortisol excretion concentrations were unaltered
with OXC (Larkin et al. 1991), and in male epileptic patients, switching to OXC from CBZ yielded decreased antipyrine
clearance (Isojarvi et al. 1994). In some instances, OXC compared to CBZ induction is substantially less robust, so that
switching from OXC to CBZ (or vice versa) will make adjustments of doses of other medications necessary. The extent of
OXC induction of metabolism of other drugs is often clinically insignificant but is clinically significant for hormonal
contraceptives. Serum concentrations of some of the medications (in boldface italic type) listed in Table 37–4 may
decrease to a clinically significant extent with OXC, hindering efficacy of such agents. OXC decreases serum
concentrations of female hormones, presumably mediated by heteroinduction of CYP3A, sufficiently to compromise the
efficacy of hormonal contraceptives (Fattore et al. 1999) and to require higher doses. In contrast, induction of conjugation
is more limited, yielding only modest clinical effects on clearance of drugs such as valproate and lamotrigine. Finally, OXC
inhibits CYP2C19 (Tripp et al. 1996) and thus may increase serum phenytoin concentrations.
OXC metabolism (which is primarily by arylketone reductase) generally is not susceptible to enzyme
inhibitors. The absence of autoinduction and the robust actions of cytosol reductases that mediate conversion to MHD
2.Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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appear to render OXC metabolism not susceptible to the common phenomenon of inhibition by other agents seen with
CBZ. Thus, the medications listed in Table 37–5 that can elevate serum CBZ concentrations and yield neurotoxicity do
NOT appear to have such interactions with OXC.
OXC has an active (MHD) metabolite (see Figure 37–1, bottom middle). However, MHD metabolism, unlike CBZ-E
catabolism, is not inhibited by valproate, presumably due to the lack of involvement of epoxide hydrolase in MHD
disposition. Thus, coadministration of valproate does NOT yield toxicity related to increased MHD.
Interactions With Mood Stabilizers
OXC, in contrast to CBZ, does not induce valproate metabolism. In patients with epilepsy, OXC did not significantly
alter valproate (or CBZ) area under the concentration–time curve (McKee et al. 1994), and switching to OXC from
CBZ yielded increased serum total valproate concentration-to-dose ratios and increased valproate-related adverse
effects (Battino et al. 1992). Also, in rats, valproate did not significantly alter OXC pharmacokinetic parameters
(Matar et al. 1999).
OXC, in comparison with CBZ, also appears to have less robust effects on lamotrigine metabolism; in women with
epilepsy, OXC was associated with a 29% and CBZ a 54% decrease in serum lamotrigine concentrations (May et al.
1999). The clinical significance of this interaction remains to be established and could vary across patients (Theis et
- 2005). Lamotrigine does not appear to alter OXC pharmacokinetics (Theis et al. 2005). A possible
pharmacodynamic interaction has been reported with OXC and lamotrigine (Sabers and Gram 2000).
In addition, carbamazepine induces OXC metabolism, yielding decreased serum MHD concentrations (McKee et al.
1994). The presence or absence of pharmacokinetic interactions between OXC and lithium remains to be
established.
Interactions With Antidepressants
OXC, in contrast to CBZ, may not robustly induce citalopram metabolism; switching to OXC from CBZ in two patients
yielded increased serum citalopram concentrations (Leinonen et al. 1996).
Interactions With Antipsychotics
OXC, unlike CBZ, may not robustly induce antipsychotic metabolism; switching to OXC from CBZ in six patients with
schizophrenia or organic psychosis who were taking haloperidol, chlorpromazine, or clozapine yielded 50%–200%
increases in serum neuroleptic concentrations and additional extrapyramidal symptoms (Raitasuo et al. 1994). OXC
does not cause clinically significant alterations in serum olanzapine or risperidone concentrations (Rosaria
Muscatello et al. 2005).
Interactions With Anxiolytics and Sedatives
OXC may decrease serum concentrations of benzodiazepines.
Interactions With Calcium Channel Blockers
OXC appears to decrease serum concentrations of dihydropyridine calcium channel blockers (which are CYP3A4
substrates) to some extent. Although OXC reduced felodipine area under the concentration–time curve by 28% in
healthy volunteers, this effect was much smaller than that previously reported with CBZ (Zaccara et al. 1993). In a
retrospective study, 16 inpatients with acute mania who were taking calcium channel blockers had no clinically
significant changes in blood pressure when treated with concurrent OXC (Reinstein et al. 2002).
Interactions With Nonpsychotropic Drugs
OXC, compared with CBZ, also appears to have fewer interactions with nonpsychotropic drugs. Thus, neither the
CYP3A4 inhibitor erythromycin (Keranen et al. 1992a) nor the heteroinhibitor cimetidine (Keranen et al. 1992b)
appears to alter OXC pharmacokinetics in healthy volunteers. Also, OXC does not appear to robustly induce warfarin
metabolism; in healthy volunteers receiving steady-state warfarin, OXC did not significantly alter prothrombin time
(Kramer et al. 1992).
However, as noted earlier in this chapter, OXC appears to have a clinically significant interaction with hormonal
contraceptives; in healthy female volunteers, OXC appeared to decrease ethinylestradiol and levonorgestrel derived
from hormonal contraceptives by up to about 50% (Fattore et al. 1999; Klosterskov Jensen et al. 1992).
OXC, like CBZ, may decrease serum concentrations of the analgesic buprenorphine, the anticancer agent paclitaxel,
and the antidiabetic agent repaglinide. As previously noted, OXC also yields decreases in serum concentrations of
the dihydropyridine calcium channel blocker felodipine (which is also a CYP3A4 substrate). In contrast to CBZ, the
CYP3A4 inhibitor erythromycin and the antidepressant viloxazine do not yield clinically significant increases in
serum OXC concentrations.
OXC may modestly decrease serum concentrations of topiramate (May et al. 2002) and levetiracetam (May et al.
2003). In addition, the anticonvulsants CBZ, phenytoin, phenobarbital, and primidone may induce OXC metabolism.
Finally, OXC can increase serum phenytoin concentrations, presumably by inhibiting the activity of CYP2C19.Print: Chapter 37. Carbamazepine and Oxcarbazepine http://www.psychiatryonline.com/popup.aspx?aID=419526&print=yes…
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CONCLUSION
In the past, because of lack of an FDA indication, complexity of use, and methodological concerns regarding earlier
efficacy studies, CBZ was generally considered an alternative rather than a first-line intervention in bipolar
disorder. However, the recent approval of a proprietary CBZ beaded extended-release capsule formulation
(Equetro) for the treatment of acute manic and mixed episodes in patients with bipolar disorder and the low
propensity of CBZ to cause weight gain and metabolic problems seen with some other agents may lead clinicians to
reassess its role in the management of patients with bipolar disorder (Ketter et al. 2005). This long-acting
preparation in some patients with bipolar disorder can be given as a single nighttime dose, which will enhance
compliance and minimize daytime side effects.
OXC, compared with CBZ, has more limited evidence of efficacy in bipolar disorder but has enhanced tolerability and
fewer drug–drug interactions. For example, with CBZ (but not OXC), common benign leukopenia is difficult to
distinguish from what may be a harbinger of the very rare serious aplastic anemia, and patients and caregivers
need to monitor carefully for symptoms of this adverse effect. In addition, CBZ (and to a lesser extent OXC) in
combination therapy induces metabolism of other drugs, sometimes undermining their efficacy unless doses are
adjusted. Also, other drugs (such as erythromycin or verapamil) can inhibit CBZ (but not OXC) metabolism, causing
CBZ toxicity. Instructing patients to alert their other caregivers and pharmacists that they are receiving CBZ may
help avoid drug interactions. Informing patients of several of the common interactions can further assist in the
warning process, as other practitioners may inadvertently introduce commonly used drugs such as erythromycin
with the attendant risk of CBZ toxicity.
CBZ and OXC are important treatment options for bipolar disorder patients who experience inadequate responses to
or unacceptable adverse effects with lithium and valproate. Awareness of CBZ and OXC pharmacology and potential
drug–drug interactions will provide clinicians with the opportunity to enhance outcomes when managing bipolar
disorder with these agents.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Anticonvulsants: Understanding Epilepsy and Seizure Management
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Understanding Epilepsy: A Neurological Perspective
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Seizure Management: Strategies and Approaches
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Introduction to Anticonvulsants: Mechanisms of Action
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Quiz: Epilepsy and Seizure Fundamentals
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The Role of Carbamazepine and Oxcarbazepine in Treatment
Pharmacology of Carbamazepine: Mechanisms and Clinical Applications
Pharmacology of Oxcarbazepine: Mechanisms and Clinical Applications
Comparative Analysis: Carbamazepine vs. Oxcarbazepine in Clinical Practice
Advanced Case Studies and Conclusion: Optimizing Treatment Strategies with Carbamazepine & Oxcarbazepine
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