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.

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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 and 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 2000.

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 al. 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.

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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 (carboxa-mide) 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.

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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.

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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 bipolar 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 epox-ide 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.

graphic112
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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.

graphic112
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 CBZ 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.

Oxcarbazepine
OXC is available in the United States as a proprietary pro-duct (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).

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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 1981; 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 phosphatidyl-inositol (PI) and adenyl-ate 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 neuro-transmission. CBZ appears to lack some actions seen 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 adenyl-ate cyclase activity stimulated by dopamine, nor-epi-neph-rine 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 (Ambrósio 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 (Ambrósio et al. 2001), and serum thyroxine (T4) concentrations (Isojärvi 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.

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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 effi-cacy 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.

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; Gonçalves 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).

Acute Mania
Carbamazepine (CBZ) and oxcarbazepine (OXC) in acute mania: 23 double-blind studies

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Acute Mania 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%

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%

D. 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 = oxcar-baz-epine; 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 paradigm (Weisler et al. 2004, 2005) and yielded an FDA indication for the treatment of acute manic and mixed epi-sodes 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.

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.

Acute Depression
Carbamazepine (CBZ) in acute depression: four controlled studies

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Acute Depression 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.

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 anti-manic effects. In contrast, there are only sparse data regarding the efficacy of OXC in the prophylaxis of episodes in patients with bipolar disorder.

Prophylaxis
Carbamazepine (CBZ) and oxcarbazepine (OXC) in prophylaxis of bipolar disorder: 16 controlled or quasi-controlled studies

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Prophylaxis 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%

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

δ3

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

δ1

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

δ5

CBZ + Li > Li

—

Mosolov 1991

CBZ vs. Li (R?)

30

30

ε1

73%

70%

Cabrera et al. 1986

OXC vs. Li (R)

4

6

δ22

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

ε2

CBZ > Li

—

Wildgrube 1990

OXC vs. Li (NR)

8

7

δ33

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).

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) hypermetab-olism 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%).

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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 develop 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 carba-maz-epine 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 (Martínez 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 clinically 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. W. Brown et al. 1992).

CBZ decreases serum T4, free T4 index, and, less consistently, triiodothyronine (T3) (Bentsen et al. 1983; Connell et al. 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 (carbamazepine) package insert 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, 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 (Rättyä 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 (Isojärvi 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 (Isojärvi et al. 2001a). However, clinically significant hypo-natremia is less common than asymptomatic hypo-natremia. 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 (Isojärvi et al. 2001b). In addition, male epileptic patients taking CBZ (but not those taking OXC) had decreased serum dehydroepiandrosterone sulfate concentrations (Rättyä et al. 2001). Switching to OXC from CBZ in male epileptic patients yielded increased serum de-hy-dro-epi-andro-ste-rone sulfate concentrations (Isojärvi et al. 1995). In healthy male volunteers, higher (ε 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).

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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 com-plex 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.

graphic113
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Stepped-care approach to bipolar depres-sion.
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 addi-tional efficacy.

graphic113
Stepped-care approach to bipolar depres-sion.
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 addi-tional efficacy.

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.

Carbamazepine
Drugs whose serum concentrations are DECREASED by carbamazepine (and oxcarbazepine)

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Carbamazepine Drugs whose serum concentrations are DECREASED by carbamazepine (and oxcarbazepine)
Antidepressants
Anticonvulsants
Dihydropyridine CCBs
Bupropion

Carbamazepine

Felodipine

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.

Carbamazepine
Drugs that INCREASE serum concentrations of carbamazepine (but not oxcarbazepine)

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Carbamazepine 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

Danazol

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 pharmaco-kinetic 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 neuro-toxicity (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 hypo-natremia (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 Löscher 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).

Interactions With Antidepressants
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 (Møller 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 mirtaza-pine (Sitsen et al. 2001), mianserin (Eap et al. 1999), sertraline (Khan et al. 2000; Pihlsgård 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 anti-depres-sants (TCAs), including amitriptyline (Leinonen et al. 1991), nortriptyline (Brøsen and Kragh-Sørensen 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 anti-psy-chotics, 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). Neuro-toxicity 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-E 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, chlor-pro-ma-zine, 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 syn-ergistic 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 anti-psy-chotics 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 anti-psy-chotic efficacy (Yatham et al. 2003). In another combination therapy study, CBZ yielded lower-than-expected blood olanza-pine 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 addi-tive central nervous system (e.g., sedation, ataxia) adverse effects. Indeed, contemporary controlled CBZ trials routinely permit some adjunctive benzodiazepine (e.g., loraz-epam) administration (Weisler et al. 2004, 2005). However, CBZ may decrease serum concentrations of clonazepam (Lai et al. 1978; Yukawa et al. 2001), alpraz-olam (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 clo-naz-epam (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; Muñoz 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 verap-amil and diltiazem, but not the dihydropyridines nifed-ipine (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 oxi-da-tive metabolism of various drugs (Hunt et al. 1989). Preliminary observations also indicate that the dihydro-pyri-dine 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 dihydro-pyri-dines (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) (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 carba-maz-epine (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 etho-suxi-mide, phenytoin, and primidone. Moreover, CBZ induces the metabolism of multiple newer anticonvulsants, including felbamate, topiramate (Sachdeo et al. 1996), tiaga-bine (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 felba-mate) 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, meth-suxi-mide, 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 cis-platin 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 (Isojärvi 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 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 al. 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 (Keränen et al. 1992a) nor the heteroinhibitor cimetidine (Keränen 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 (Krämer 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 levo-nor-ges-trel 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.

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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.

History and Discovery
Topiramate is a derivative of the naturally occurring mono-sac-cha-ride d-fructose. It was originally synthesized to be a structural analog of fructose-1,6-diphosphatase as part of a project to develop agents that inhibit gluconeogenesis by inhibiting the enzyme fructose-1,6-biphosphatase (Shank et al. 2000). To date, however, it has not been shown by clinical evidence to have direct hypoglycemic activity. Topiramate contains a sulfamate moiety. The structural resemblance of this moiety to the sulfonamide moiety in the established antiepileptic drug acetazolamide prompted researchers to evaluate topiramate for possible anticonvulsant effects. Topiramate subsequently was shown to have potent anticonvulsant properties in a broad range of preclinical epilepsy models (Shank et al. 2000).

The drug’s efficacy in patients with epilepsy was established in the early 1990s. These studies also showed that topiramate had a favorable pharmacokinetic profile, had a high therapeutic index, was not associated with hematological or hepatic abnormalities, did not require routine serum concentration monitoring, and was associated with anorexia and weight loss (rather than appetite stimulation and weight gain like some other antiepileptic drugs) (Langtry et al. 1997). Topiramate was approved by the U.S. Food and Drug Administration (FDA) for the treatment of epilepsy in 1996. It was approved for migraine prevention in adults in 2004.

Reports appearing in the late 1990s of the drug having potential beneficial effects in bipolar disorder led Johnson and Johnson Pharmaceutical Research and Development (PRD), the discoverer and manufacturer of topiramate, to conduct a large clinical study program of topiramate in the treatment of acute bipolar mania (McElroy and Keck 2004). Controlled trials of the drug in bipolar adults with manic symptoms failed to demonstrate significant separation between the topiramate and placebo groups (Chengappa et al. 2006; Kushner et al. 2006). However, topiramate has been shown to be efficacious in placebo-controlled trials in several neuropsychiatric conditions often comorbid with bipolar disorder, including, in addition to migraine, binge-eating disorder (BED), bulimia nervosa, alcohol dependence, borderline personality disorder (BPD), psychotropic-associated weight gain, and obesity.

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Structure–Activity Relations
Topiramate is a sulfamate-substituted monosaccharide derived from d-fructose (Figure 40–1). As such, it is structurally distinct from other antiepileptic medications. Its sulfamate moiety is essential for its pharmacological activity (Shank et al. 2000). It has been postulated that topiramate’s multiple pharmacological properties (which are discussed in the following section) are regulated by protein phosphorylation. Specifically, it has been hypothesized that topiramate interacts with voltage-activated sodium channels, ≥-aminobutyric acid (GABA) type A (GABAA) receptors, ±-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)/kainate glutamate receptors, and high-voltage-activated calcium channels via formation of hydrogen bonds between proton-accepting oxygens in its sulfamate moiety and proton donor groups in tetrapeptide sequences in the latter (Shank et al. 2000).

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Chemical structure of topiramate.
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Chemical structure of topiramate.
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Pharmacological Profile
Topiramate has multiple pharmacological properties that may contribute to its anticonvulsant effects, as well as its therapeutic effects in other neuropsychiatric disorders (Langtry et al. 1997; Rho and Sankar 1999; Rosenfeld 1997; Shank et al. 2000; White 2002, 2005; White et al. 2007). First, topiramate inhibits voltage-gated sodium channels in a voltage-sensitive, use-dependent manner and thus suppresses action potentials associated with sustained repetitive cell firing (Kawasaki et al. 1998; Shank et al. 2000).

Second, topiramate increases brain GABA levels, possibly by activating a site on the GABAA receptor, thereby enhancing the inhibitory chloride ion influx mediated by the GABAA receptor and potentiating GABA-evoked currents (Kuzniecky et al. 1998; Petroff et al. 2001; Simeone et al. 2006). Because this action is not blocked by the benzodiazepine antagonist flumazenil, it is thought that topiramate exerts this effect via an interaction with the GABAA receptor that is not modulated by benzodiazepines (White et al. 2000). This action may also be sensitive to GABA concentrations and GABAA receptor subunit composition (Simeone et al. 2006).

Third, topiramate antagonizes glutamate receptors of the AMPA/kainate subtype and may selectively inhibit glutamate receptor 5 (GluR5) kainate receptors (Kaminski et al. 2004). It has essentially no effect on glu-ta-mate N-methyl-d-aspartate (NMDA) receptors. AMPA/kai-nate receptors mediate fast excitatory postsynaptic potentials responsible for excitatory neurotransmission; blockade of kainate-evoked currents decreases neuronal excitability.

Fourth, topiramate negatively modulates high-voltage-activated calcium channels (Zhang et al. 2000). Of note, Shank et al. (2000) proposed that topiramate’s combined effects on voltage-activated sodium channels, GABAA receptors, AMPA/kainate receptors, and high-voltage-activated calcium channels are unique as compared with those of other antiepileptic drugs. Indeed, Schiffer et al. (2001) found that pretreatment with to-pira-mate inhibited nicotine-induced increases in mesolimbic extracellular dopamine and norepinephrine but not serotonin. They hypothesized that this property was a result of the drug’s ability to affect both GABAergic and glutamatergic function.

Fifth, topiramate has weak inhibitory actions against some carbonic anhydrase isoenzymes, including subtypes II and VI. Carbonic anhydrase is essential for the generation of GABAA-mediated depolarizing responses. By inhibiting carbonic anhydrase, topiramate has been shown to reversibly reduce the GABAA-mediated depolarizing responses evoked by either synaptic stimulation or pressure application of GABA (but not to modify GABAA-mediated hyperpolarizing postsynaptic potentials) (Herrero et al. 2002). As a result of the effects of carbonic anhydrase inhibition on intracellular pH, topiramate also may activate a potassium conductance (Herrero et al. 2002).

Finally, topiramate has been shown to have a number of other properties. These include an interaction with glycine receptor channels (Mohammadi et al. 2005), effects on mitochondrial permeability (Kudin et al. 2004), and antikindling properties in some animal models (Wauquier and Zhou 1996).

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Pharmacokinetics and Disposition
Topiramate has a favorable pharmacokinetic profile (Bialer et al. 2004; Doose and Streeter 2002; Langtry et al. 1997; Rosenfeld 1997; Shank et al. 2000). It is rapidly and almost completely absorbed after oral administration, with bioavailability estimated to be about 80%. Peak plasma concentrations are reached within 2–4 hours. Plasma concentration increases in proportion to dose over the pharmacologically relevant dose range.

The volume of distribution of topiramate is inversely proportional to the dose, with the drug distributed primarily to body water. It is minimally protein-bound (9%–17%).

Topiramate is minimally metabolized by the liver in the absence of hepatic enzyme–inducing drugs. It inhibits cyto-chrome P450 (CYP) enzyme 2C19 but not other hepatic CYP enzymes. Topiramate is excreted mostly unchanged (approximately 70%) in the urine. The nonrenal (hepatic) clearance of topiramate increases two- to threefold when the drug is administered with hepatic enzyme–inducing drugs such as carbamazepine and phenytoin. Six minor metabolites have been identified (Shank et al. 2000).

Topiramate’s elimination half-life is 19–25 hours, with linear pharmacokinetics in the dose range of 100–1,200 mg. The pharmacokinetics of topiramate in children are similar to those in adults, except that clearance is 50% higher, resulting in 33% lower plasma concentrations. Moderate or severe renal failure is associated with reduced renal clearance and increased elimination half-life of topiramate. Moderate or severe liver impairment is associated with clinically insignificant increased plasma concentrations of the drug.

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Mechanism of Action
Although the mechanism of topiramate’s anticonvulsant action is unknown, it has been hypothesized to be due to some combination of the drug’s multiple pharmacological properties (Rho and Sankar 1999; Shank et al. 2000; White 2002, 2005; White et al. 2007).

As discussed, these include state-dependent blockade of voltage-activated sodium channels, enhancement of GABA activity at the GABAA receptor via interaction with a nonbenzodiazepine receptor site, antagonism of the AMPA/kainate glutamate receptor, antagonism of high-voltage-activated calcium channels, and inhibition of carbonic anhydrase. For example, the drug’s anticonvulsant profile, as well as its benefits in substance use and eating disorders, has been hypothesized to be due to its dual actions on the GABAergic and glutamatergic systems (Johnson et al. 2003, 2005; McElroy et al. 2003, 2007b; Rho and Sankar 1999; Schiffer et al. 2001). By contrast, carbonic anhydrase inhibition is thought by some not to play a large role in topiramate’s anticonvulsant properties despite acetazolamide’s clinical efficacy as an antiepileptic because of topiramate’s much weaker potency as an inhibitor (Rho and Sankar 1999). Others, however, have suggested that topiramate’s inhibition of carbonic anhydrase contributes to its anticonvulsant properties via reduction of GABAA-mediated depolarizing responses and/or activation of a potassium conductance (Herrero et al. 2002).

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Indications and Efficacy
FDA-Approved Indications
Topiramate is currently indicated by the FDA as initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures; as adjunctive therapy for adults and pediatric patients ages 2–16 years with partial-onset seizures or primary generalized tonic-clonic seizures; and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome (van Passel et al. 2006). It is also indicated for the prophylaxis of migraine headache in adults (Brandes 2005; Bussone et al. 2006).

Other Indications
Topiramate is not currently approved by the FDA for use in the treatment of any psychiatric disorder. Because the drug was widely used off-label in the treatment of bipolar disorder after it came to market (see subsection “Bipolar Disorder” below), Johnson and Johnson PRD, the discoverer of topiramate, conducted a large study program of topiramate in adults with acute bipolar mania. These placebo-controlled studies failed to demonstrate a significant benefit of topiramate over placebo on the Young Mania Rating Scale (YMRS) (Chengappa et al. 2001a; Kushner et al. 2006; McElroy and Keck 2004). In contrast, a placebo-controlled trial in pediatric mania, which was prematurely discontinued in the aftermath of the failed adult trials, did show significant efficacy results favoring topiramate based on a retrospective analysis of 56 patients (Delbello et al. 2005).

Topiramate has been studied in the treatment of a variety of other neuropsychiatric disorders, many of which co-occur with bipolar disorder. Data from placebo-controlled clinical trials suggest that topiramate is efficacious in BED with obesity (McElroy et al. 2003, 2007b), bulimia nervosa (Hedges et al. 2003; Hoopes et al. 2003; Nickel et al. 2005b), alcohol dependence (Johnson et al. 2003, 2007), psychotropic-induced weight gain (Ko et al. 2005; M. K. Nickel et al. 2005b), obesity (McElroy et al. 2008), and neuropathic pain (Raskin et al. 2004). These and other studies will be reviewed below.

Bipolar Disorder
Five randomized, placebo-controlled studies have shown that topiramate monotherapy is not efficacious in the short-term treatment of acute manic or mixed episodes in adults with bipolar I disorder (Kushner et al. 2006; McElroy and Keck 2004). All five studies used week 3 as the primary endpoint; in addition, three studies had a week 12 secondary endpoint, two studies had lithium comparator groups, and all trials measured weight as a secondary outcome. Analyses of the 3-week data from all five trials were consistent. In each trial, the primary efficacy outcome—the change from baseline to week 3 in the YMRS score—failed to show a statistically significant separation between topiramate and placebo. There was also no drug–placebo separation in the three trials with week 12 data. By contrast, in the two trials in which lithium was used, lithium did show statistical superiority to placebo. To-pira-mate, however, showed significant separation from placebo in weight loss, whereas lithium was associated with statistically significant weight gain.

Similarly, in the only placebo-controlled study of adjunctive topiramate in bipolar disorder, 287 outpatients experiencing a manic or mixed episode (by DSM-IV [American Psychiatric Association 1994] criteria) and a YMRS score ε 18 while taking therapeutic levels of valproate or lithium showed similar reductions (40%) in baseline YMRS scores for both topiramate and placebo after 12 weeks (Chengappa et al. 2006). Topiramate, however, was again associated with significant weight loss as compared to placebo.

Despite the negative results of the adult acute mania trials, numerous clinical reports suggest that topiramate may have a role in the management of bipolar disorder. In the only placebo-controlled study of topiramate in pediatric bipolar I disorder, 56 children and adolescents (6–17 years) with manic or mixed episodes were randomly assigned to topiramate (n = 29) or placebo (n = 27) for 4 weeks (Delbello et al. 2005). Initially designed to enroll approximately 230 subjects, the study was prematurely discontinued when the adult mania trials were negative. Decrease in mean YMRS score from baseline to final visit using last observation carried forward (LOCF) was not statistically different between treatment groups ( 9.7 ± 9.65 for topiramate vs.  4.7 ± 9.79 for placebo, P = 0.152). However, a post hoc repeated-measures linear regression model of the primary efficacy analysis showed a statistically significant difference in the slopes of the linear mean profiles (P = 0.003).

No placebo-controlled study of topiramate has yet been done in acute bipolar depression. Results from an 8-week single-blind comparison trial in which 36 outpatient adults with bipolar depression were randomly assigned to receive either topiramate (mean dosage = 176 mg/day; range = 50–300 mg/day) or bupropion SR (sustained release) (mean dosage = 250 mg/day; range = 100–400 mg/day) suggested that the drug might have antidepressant properties in some bipolar patients (McIntyre et al. 2002). The percentage of patients meeting a priori response criteria (50% or greater decrease from baseline in mean total score on the 17-item Hamilton Rating Scale for Depression [Ham-D]) was significant for both topiramate (56%) and bupropion SR (59%). There were no cases of manic switching with either drug. Moreover, numerous open-label reports have described patients with milder forms of bipolarity (i.e., “soft” bipolar spectrum disorders), including those with mixed states or rapid cycling, that respond to topiramate (McElroy and Keck 2004; McElroy et al. 2000; McIntyre et al. 2005).

Finally, a number of open-label reports have described the successful topiramate treatment of bipolar disorder with various comorbid psychiatric or general medical disorders (“complicated” bipolar disorder). Comorbid psychiatric conditions in which improvement was seen included alcohol abuse; anxiety disorders such as obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD); eating disorders such as bulimia nervosa, BED, and anorexia nervosa; impulse-control disorders; and catatonia (Barzman and Delbello 2006; Guille and Sachs 2002; Huguelet and Morand-Collomb 2005; McDaniel et al. 2006; McElroy et al. 2008; Shapira et al. 2000). Comorbid general medical conditions in which improvement was seen included obesity, psychotropic-induced weight gain, type 2 diabetes mellitus, tremor, and Tourette’s disorder (Chengappa et al. 2001b; Guille and Sachs 2002; McIntyre et al. 2005; Vieta et al. 2002).

These observations call for controlled studies of topiramate in pediatric bipolar disorder, acute bipolar depression, bipolar II disorder and other “softer” forms of bipolar disorder, and complicated bipolar disorder. No controlled maintenance or prophylactic treatment studies of topiramate in bipolar disorder have yet been completed.

Depressive Disorders
In the only controlled study of topiramate in a depressive disorder, 64 females with DSM-IV recurrent major depressive disorder were randomly assigned to topiramate (n = 32) or placebo (n = 32) for 10 weeks (C. Nickel et al. 2005a). Topiramate was superior to placebo in reducing depressive and anger symptoms (as assessed by the Ham-D [P = 0.02] and the State-Trait Anger Expression Inventory [STAXI; P < 0.001 on all scales]), respectively, and on most scales of the SF-36 Health Survey (all Ps between 0.15 and  0.001). The reduction in expression of anger correlated significantly with changes on the Ham-D. Five subjects (2 topiramate, 3 placebo) were lost to follow-up. Weight loss was greater in the topiramate group by 4.2 kg (P < 0.001). All subjects tolerated topiramate well, and there were no suicidal events.

Psychotic Disorders
Two randomized, placebo-controlled studies of topiramate targeting psychopathology in psychotic disorders have been conducted. In the first, 26 patients with treatment-resistant schizophrenia had topiramate (gradually increased to 300 mg/day) or placebo added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods (Tiihonen et al. 2005). In the intent-to-treat analysis, topiramate was superior to placebo in reducing general psychopathological symptoms as assessed by the Positive and Negative Syndrome Scale (PANSS), but no significant improvement was observed in positive or negative symptoms.

In the second study, 48 patients with schizoaffective disorder, bipolar type, were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100–400 mg/day) or placebo (Chen-gappa et al. 2007). Patients who had achieved ε 20% decrease from baseline in their PANSS total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. Study medication dosage was continued unchanged from the earlier 8-week study period. Adjunctive topiramate (nearly 275 mg/day) did not show increased efficacy relative to placebo on the PANSS (the primary outcome measure) or on any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than did placebo-treated patients, but they also experienced higher rates of paresthesias, sedation, word-finding difficulty, sleepiness, and forgetfulness.

Case reports regarding topiramate’s effectiveness as an adjunct treatment in schizophrenia have been inconsistent, with improvement, no change, and deterioration in clinical state all being described (Citrome 2008). However, there are several case reports of the successful use of topiramate to treat catatonia in patients with chronic psychotic disorders (McDaniel et al. 2006).

Eating Disorders
Five randomized, placebo-controlled studies have shown that topiramate reduces binge eating and excessive body weight in 640 subjects with bulimia nervosa (n = 2 studies, 99 subjects) or BED (n = 3 studies, 541 subjects). In the first study in bulimia nervosa, a 10-week trial in 69 subjects, topiramate (median dosage = 100 mg/day; range = 25–400 mg/day) was superior to placebo in reducing the frequency of binge and purge days (days during which at least one binge-eating or purging episode occurred; P = 0.004); decreasing scores on the bulimia/uncontrollable overeating (P = 0.005), body dissatisfaction (P = 0.007), and drive for thinness (P = 0.002) subscales of the Eating Disorder Inventory; decreasing scores on the bulimia/food preoccupation (P = 0.019) and dieting (P = 0.031) subscales of the Eating Attitudes Test; and reducing body weight (mean decrease of 1.8 kg for topiramate vs. 0.2 kg mean increase for placebo; P = 0.004) (Hedges et al. 2003; Hoopes et al. 2003). Binge-eating/purging remission rates were 32% for topiramate and 6% for placebo (P = NS). Dropout rates were 34% for topiramate and 47% for placebo. In the second study, 60 subjects with DSM-IV bulimia nervosa for at least 12 months received 10 weeks of topiramate (titrated to 250 mg/day in the sixth week) (n = 30) or placebo (n = 30) (Nickel et al. 2005b). Topiramate was associated with significant decreases in binge/purge frequency (defined as a > 50% reduction; 37% for topiramate and 3% for placebo), body weight (difference in weight loss between the 2 groups = 3.8 kg), and all of the SF-36 Health Survey scales (all Ps < 0.001). Five (17%) subjects on topiramate and 6 (20%) subjects on placebo were dropouts.

In the first controlled study in BED, 61 subjects with DSM-IV BED and obesity (defined as a body mass index [BMI] ε 30) received topiramate (n = 30) or placebo (n = 31) for 14 weeks (McElroy et al. 2003). Topiramate was significantly superior to placebo in reducing binge frequency, as well as global severity of illness, obsessive-compulsive features of binge-eating symptoms, body weight, and BMI. Topiramate-treated subjects experienced a 94% reduction in binge frequency and a mean weight loss of 5.9 kg, whereas placebo-treated subjects experienced a 46% reduction in binge frequency and a mean weight loss of 1.2 kg. The dropout rate, however, was high—14 (47%) subjects receiving topiramate and 12 (39%) subjects receiving placebo failed to complete the trial.

The second controlled study of topiramate in BED was a multicenter trial in which subjects with DSM-IV BED and ± 3 binge-eating days per week, a BMI ranging from 30 kg/m2 to 50 kg/m2, and no current psychiatric disorders or substance abuse were randomly assigned in a 1:1 ratio to topiramate or placebo for 16 weeks (McElroy et al. 2007b). Of 407 subjects enrolled, 13 failed to meet inclusion criteria; 95 topiramate and 199 placebo subjects were therefore evaluated for efficacy. Topiramate significantly reduced binge-eating days per week ( 3.5 ± 1.9 vs.  2.5 ± 2.1), binge episodes per week ( 5 ± 4.3 vs.  3.4 ± 3.8), weight ( 4.5 ± 5.1 kg vs. 0.2 ± 3.2 kg), and BMI ( 1.6 ± 1.8 kg/m2 vs. 0.1 ± 1.2 kg/m2) compared with placebo (all Ps < 0.001). The drug also significantly decreased measures of obsessive-compulsive symptoms, impulsivity, hunger, and disability. Fifty-eight percent of topiramate-treated subjects achieved remission compared with 29% of placebo-treated subjects (P < 0.001). Discontinuation rates were 30% in each group; adverse events were the most common reason for topiramate discontinuation (16%; placebo, 8%).

The third controlled study of topiramate in BED was another multicenter trial in which 73 patients with BED and obesity were randomly assigned to 19 sessions of cognitive-behavior therapy in conjunction with topiramate (n = 37) or placebo (n = 36) for 21 weeks (Claudino et al. 2007). Compared with patients given placebo, patients given topiramate showed a significantly greater rate of reduction in weight, the primary outcome measure, over the course of treatment (P < 0.001). Topiramate recipients also showed a significant weight loss ( 6.8 kg) relative to placebo recipients ( 0.9 kg). Rates of reduction of binge frequencies and scores on the Binge Eating Scale and BDI did not differ between the groups, but a greater percentage of topiramate-treated patients (31 of 37) than of placebo-treated patients (22 of 36) attained remission of binge eating (P = 0.03). There was no difference between groups in completion rates, although one topiramate recipient withdrew because of an adverse effect.

In open studies, topiramate has also been reported to have long-term therapeutic effects in BED with obesity; to reduce symptoms of BED, bulimia nervosa, and an-orexia nervosa with comorbid mood disorders; and to reduce nocturnal eating and overweight in patients with night-eating syndrome and sleep-related eating disorders (Guille and Sachs 2002; McElroy et al. 2008; Winkelman 2006). However, there is a report of topiramate possibly “triggering” a recurrent episode of anorexia nervosa in a woman with epilepsy and several reports of eating disorder patients misusing the drug to lose weight (McElroy et al. 2008).

Substance Use Disorders
Four randomized, placebo-controlled studies suggest that topiramate may have therapeutic effects in alcohol, cocaine, and nicotine dependence. Two studies examined topiramate in alcohol dependence. In the first, 150 subjects with alcohol dependence were randomly assigned to topiramate (n = 75; up to 300 mg/day) or placebo (n = 75) for 12 weeks (Johnson et al. 2003). All subjects received compliance enhancement therapy. At study end, subjects receiving topiramate, compared with those on placebo, had 2.88 (95% CI =  4.50 to  1.27) fewer drinks per day (P = 0.0006), 3.10 (95% CI =  4.88 to  1.31) fewer drinks per drinking day (P = 0.0009), 27.6% fewer heavy drinking days (P = 0.0003), 26.2% more days abstinent (P = 0.0003), and a log plasma gamma-glutamyl transferase (GGT) ratio of 0.07 ( 0.11 to  0.02) less (P = 0.0046). Changes in craving were also significantly greater with topiramate than with placebo. In the second study, 371 subjects were randomly assigned to topiramate (up to 300 mg) or placebo, along with a weekly compliance enhancement intervention, at 16 sites for 14 weeks (Johnson et al. 2007). Topiramate was significantly superior to placebo in reducing the percentage of heavy drinking days and other drinking outcomes, such as drinks per drinking day, percentage of days abstinent, and log plasma GGT ratio (all Ps δ 0.002).

In the study in cocaine dependence, 40 subjects were randomly assigned to topiramate (titrated gradually over 8 weeks to 200 mg/day) or placebo for 13 weeks (Kampman et al. 2004). Topiramate-treated subjects were more likely to be abstinent from cocaine after week 8 compared with placebo-treated subjects (P = 0.01). They were also more likely to achieve 3 weeks of continuous abstinence from cocaine (P = 0.05).

In the first of two controlled studies in smoking cessation, topiramate (n = 45) was superior to placebo (n = 49) in 94 male and female subjects with comorbid alcohol dependence (Johnson et al. 2005). This study was a subgroup analysis of the first controlled study of topiramate in alcohol dependence (Johnson et al. 2003). In the second study, the drug (n = 43) was superior to placebo (n = 44) for smoking cessation in male (n = 38), but not female (n = 49), subjects who had no associated psychopathology (Anthenelli et al. 2008).

There have also been case reports of the successful use of topiramate in opiate and benzodiazepine withdrawal, but these uses will need to be evaluated in placebo-controlled trials (Michopoulos et al. 2006; Zullino et al. 2004).

Anxiety Disorders
Topiramate has been evaluated in one controlled study of PTSD. Thirty-eight patients with non-combat-related PTSD were randomly assigned to flexible doses of topiramate (median dosage = 150 mg/day, range = 25–400 mg/day) or placebo for 12 weeks (Tucker et al. 2007). No significant difference was found on the primary efficacy measure, the total Clinician-Administered PTSD Scale (CAPS) score. However, significant or near significant effects were found in favor of topiramate on the eight-item Treatment Outcome PTSD scale (TOP-8) (decrease in overall severity 68% vs. 41.6%; P = 0.025) and endpoint Clinical Global Impression Scale—Improvement (CGI-I) scores (1.9 ± 1.2 vs. 2.6 ± 1.1; P = 0.055).

Open-label studies suggest that topiramate may have therapeutic effects in generalized social phobia and OCD (Mula et al. 2007). In contrast, there are case reports of patients experiencing panic attacks apparently induced by topiramate (Damsa et al. 2006).

Borderline Personality Disorder
Three placebo-controlled studies, all conducted by the same group, have evaluated topiramate in DSM-IV-defined BPD. In the first, 29 female subjects were randomly assigned in a 2:1 ratio to topiramate (n = 21, analysis based on 19) or placebo (n = 10) for 8 weeks (M. K. Nickel et al. 2004). Topiramate dosage was increased to 250 mg/day over 6 weeks. At study end, significant improvement on four subscales of the STAXI (state–anger, trait–anger, anger–out, and anger–control) was observed for topiramate compared with placebo. In the second study, 42 male subjects with BPD received topiramate (n = 22) or placebo (n = 20) for 8 weeks (M. K. Nickel et al. 2005a). Similar to the study in females, significant improvement on the same four subscales on the STAXI was found for topiramate compared with placebo. In the third study, 56 women with BPD received topiramate (n = 28) or placebo (n = 28) for 10 weeks (Loew et al. 2006). Topiramate was titrated to 200 mg/day over 6 weeks and then held constant. Topiramate was superior to placebo on the somatization, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and Global Severity Index subscales of the Symptom Checklist (SCL-90-R) (all Ps < 0.001); all eight scales of the SF-36 Health Survey (all Ps < 0.01); and four of eight scales of the Inventory of Interpersonal Problems (all Ps < 0.001). Four patients (1 on topiramate, 3 on placebo) dropped out. In all three studies, topiramate was associated with significantly greater weight loss then placebo. It was also well tolerated, and there were no psychotic or suicidal adverse events.

Psychotropic-Associated Weight Gain
Two placebo-controlled studies suggest that topiramate reduces antipsychotic-induced weight gain in schizo-phrenia. In one study, 66 inpatients with schizophrenia receiving antipsychotic medication and “carrying excess weight” were randomly assigned to topiramate 100 mg/day, topiramate 200 mg/day, or placebo for 12 weeks (Ko et al. 2005). Body weight, BMI, and waist and hip circumference decreased significantly in the topiramate 200 mg/day group compared with the topiramate 100 mg/day and placebo groups. Scores on the Clinical Global Impression Scale—Severity of Illness (CGI-S) and the Brief Psychiatric Rating Scale (BPRS) were also significantly decreased, but the decreases were not thought to be clinically meaningful. In the other study, 43 women with mood or psychotic disorders who had gained weight while receiving olanzapine were given topiramate (n = 25) or placebo (n = 18) for 10 weeks (Nickel et al. 2005b). Weight loss was significantly greater (by 5.6 kg) in the topiramate group. Topiramate-treated subjects also experienced significantly greater improvement in measures of health-related quality of life and psychological impairment.

One placebo-controlled study and two randomized comparison trials suggest that topiramate may be superior to placebo and at least as effective as bupropion and si-bu-tramine in psychotropic-associated weight gain in bipolar patients. In the controlled study in bipolar I manic or mixed patients receiving lithium or valproate, adjunctive topiramate was ineffective for manic symptoms but was associated with significantly greater reductions in body weight compared with placebo ( 2.5 vs. 0.2 kg, respectively; P < 0.001) and BMI ( 0.84 vs. 0.07 kg/m2, respectively; P < 0.001) (Chengappa et al. 2006). In a single-blind comparator trial in 36 outpatients with bipolar depression, adjunctive bupropion and topiramate showed similar rates of antidepressant response (59% vs. 56%), but topiramate was associated with a greater mean weight loss (5.8 kg vs. 1.2 kg) (McIntyre et al. 2002). In a 24-week open-label, flexible-dose comparison trial, 46 euthymic outpatients with a bipolar disorder (types I, II, or not otherwise specified [NOS]) who had a BMI ε 30 kg/m2, or a BMI ε 27 with obesity-related medical comorbidities, and psychotropic-asso-ciated weight gain (defined as a weight gain of 10 lbs [4.5 kg] since initiation of their current psychotropic regimen) were randomly assigned to receive topiramate (n = 28; 25–600 mg/day) or sibutramine (n = 18; 5–15 mg/day) for 24 weeks (McElroy et al. 2007a). Patients receiving either drug lost comparable amounts of weight (2.8 ± 3.5 kg for topiramate and 4.1 ± 5.7 kg for sibutramine) and displayed similar rates of weight loss (0.82 kg/week and 0.85 kg/week, respectively). However, only 4 (22%) patients receiving sibu-tra-mine and 6 (21%) patients receiving topiramate completed the trial. In addition, the attrition patterns for the two drugs were different, with patients discontinuing topiramate doing so early in treatment and patients discontinuing sibutramine doing so throughout treatment.

Several open-label, prospective trials suggest that initiating treatment with the combination of topiramate with either risperidone or olanzapine may successfully stabilize mood in patients with bipolar disorder while preventing weight gain (Bahk et al. 2005; Vieta et al. 2003, 2004). Finally, topiramate has also been used to treat weight gain in patients with major depression receiving antidepressants, patients with anxiety disorders receiving selective serotonin reuptake inhibitors, and patients with autism receiving antipsychotics (McElroy et al. 2008).

Obesity
Nine randomized, placebo-controlled trials have evaluated topiramate (Astrup et al. 2004; Bray et al. 2003; Eliasson et al. 2007; Stenlöf et al. 2007; Tonstad et al. 2005; Toplak et al. 2007; Tremblay et al. 2007; Wilding et al. 2004) or a controlled-release (CR) formulation of to-piramate (Rosenstock et al. 2007) for weight loss in subjects with obesity. In one study, subjects were required to have comorbid essential hypertension (Tonstad et al. 2005); in four studies, subjects were required to have concurrent type 2 diabetes (Eliasson et al. 2007; Rosenstock et al. 2007; Stenlöf et al. 2007; Toplak et al. 2007). In all nine studies, topiramate was superior to placebo for weight loss at all doses (range 64–400 mg/day) and at all endpoints (range 28 weeks to 1 year) evaluated. The four long-term studies (duration 40 weeks to 1 year) showed that topiramate was associated with weight loss that increased up to 1 year without plateauing (Astrup et al. 2004; Eliasson et al. 2007; Stenlöf et al. 2007; Wilding et al. 2004). In the study of topiramate in obese subjects with comorbid hypertension, there were significant decreases in diastolic, but not systolic, blood pressure in the two groups receiving topiramate compared with the placebo group. In the four studies of topiramate in obese subjects with comorbid type 2 diabetes, topiramate-treated patients showed significant decreases in glycosylated hemo-globin (HbA1c) compared with placebo-treated patients.

Neuropathic Pain and Other Neurological Conditions
Five randomized, placebo-controlled studies of topiramate in painful diabetic neuropathy have produced mixed results. Three similarly designed trials in 1,259 subjects with moderate or extreme pain evaluating topiramate at 100 mg, 200 mg, or 400 mg/day did not find statistical separation on the 100-mm Visual Analog Scale (VAS) after 18–22 weeks of treatment (Thienel et al. 2004). Across all studies, 24% of topiramate-treated subjects and 8% of placebo-treated subjects discontinued treatment due to adverse events; groups did not differ in the occurrence of serious adverse events.

The other two controlled studies showed separation between topiramate and placebo in 345 subjects (Raskin et al. 2004). In the larger trial (N = 323), subjects with a pain visual analog (PVA) scale score of at least 40 (on a scale of 0 [no pain] to 100 mm [worst possible pain]) were given topiramate (up to 400 mg/day; n = 214) or placebo (n = 109) for 12 weeks (Raskin et al. 2004). Topiramate was associated with significantly greater reductions in the PVA scale score (P = 0.038), the worst pain intensity score (P = 0.003), and sleep disruption (P = 0.020). Topiramate also reduced body weight ( 2.6 vs. +0.2 kg for placebo; P < 0.001) without disrupting glycemic control.

Regarding other neurological conditions, topiramate has been shown superior to placebo in controlled trials in preventing pediatric migraine (Winner et al. 2005) and treating essential tremor (Ondo et al. 2006). Open data suggest that topiramate may have beneficial effects in cluster headache (Pascual et al. 2007).

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Side Effects and Toxicology
The side-effect profile of topiramate may vary with the patient’s illness, mood state, and concomitant medications. The most common side effects of topiramate in the initial dose-ranging studies in patients with epilepsy when used in combination with other antiepileptic drugs at dosages of 200–1,000 mg/day were related to the central nervous system and included dizziness, somnolence, psychomotor slowing, nervousness, paresthesias, ataxia, difficulty with memory, difficulty with concentration or attention, confusion, and speech disorders or related speech problems (Langtry et al. 1997; Shorvon 1996). Other side effects were nystagmus, depression, nausea, diplopia, abnormal vision, anorexia, language problems, and tremor. When used as monotherapy in patients with epilepsy, the most common side effects were dizziness, anxiety, paresthesias, insomnia, somnolence, myalgia, anorexia, nausea, dyspepsia, and diarrhea. The most common side effects of topiramate in the large registration trials for migraine (which used total daily doses of 50, 100, and 200 mg) were paresthesias, fatigue, memory difficulties, concentration/attention problems, and mood problems (Bussone et al. 2006). In the monotherapy trials in adult mania, paresthesias, decreased appetite, dry mouth, and weight loss were more common with topiramate than placebo (Kushner et al. 2006). In the adolescent mania trial, the most common adverse events occurring with topiramate were decreased appetite, nausea, diarrhea, paresthesias, somnolence, insomnia, and rash (Delbello et al. 2005). In the obesity trials, events related to the central or peripheral nervous systems or to psychiatric disorders were most commonly reported (Rosenstock et al. 2007). These included paresthesias; fatigue; difficulty with attention, concentration and/or memory; taste perversion; and anorexia. Overall, paresthesias and cognitive complaints are the most troublesome adverse events (van Passel et al. 2006).

The central nervous system and gastrointestinal effects of topiramate are usually mild to moderate in severity and often decrease or resolve with time or dosage reduction (Meador et al. 2003; Shorvon 1996). Also, they may be minimized by slow titration of topiramate dosage (Biton et al. 2001). However, topiramate may be associated with more cognitive impairment than some of the other new antiepileptic drugs (Martin et al. 1999; Meador et al. 2003).

Infrequent but serious side effects of topiramate include nephrolithiasis, an ocular syndrome of acute myopia with secondary angle-closure glaucoma, oligohydrosis and hyperthermia, and metabolic acidosis (van Passel et al. 2006). The incidence of nephrolithiasis has been estimated to be 1.5% (Shorvon 1996). In the epilepsy trials, more than 75% of the patients who developed renal stones elected to continue treatment with topiramate (Reife et al. 2000). Nephrolithiasis is thought to be related to topiramate exerting carbonic anhydrase inhibition in the kidney (Welch et al. 2006).

The secondary angle-closure glaucoma associated with topiramate is characterized by acute onset of bilateral blurred vision and ocular pain (Fraunfelder and Fraunfelder 2004; Fraunfelder et al. 2004). Ophthalmological findings include bilateral myopia, conjunctival hyperemia, anterior chamber shallowing, and increased intraocular pressure. Most cases have occurred within 1 month of topiramate initiation and fully resolve with drug discontinuation. Peripheral iridectomy or laser iridotomy are not effective. The syndrome has been attributed to sulfamate-induced ciliary body edema.

There were no clinically relevant changes in hepatic, renal, or hematological parameters in the registration trials of topiramate, and laboratory monitoring was initially thought not to be required (Reife et al. 2000; Sachdeo and Karia 2002). In addition, no treatment-related changes in physical or neurological examinations (except body weight loss; see next paragraph), in the electrocardiogram, or in ophthalmological or audiometric test results were noted. However, as a carbonic anhydrase inhibitor, topiramate reduces serum bicarbonate levels, and it is believed that this is the mechanism underlying reports of reversible metabolic acidosis in some patients (Sachdeo and Karia 2002; van Passel et al. 2006; Welch et al. 2006). It is now recommended that baseline and periodic serum bicarbonate levels be measured in patients receiving to-pira-mate. A case of liver failure in a young woman with epi-lepsy after addition of topiramate to carbamazepine (Bjøro et al. 1998) and a case of significant liver enzyme elevation in another young woman with bipolar disorder and obesity after addition of topiramate to divalproex sodium, benztropine, risperidone, clonazepam, and an oral contraceptive (Doan and Clendenning 2000) have been reported. To date, no cases of liver failure have been reported with topiramate monotherapy.

A growing concern is the psychiatric adverse-event profile of antiepileptic drugs in patients with epilepsy, including whether such drugs cause suicidality and psychosis. Although some data suggest that a subgroup of epilepsy patients may be susceptible to such psychiatric adverse events, other data indicate that topiramate may be associated with depression in epilepsy patients, especially during rapid titration (Mula and Sander 2007). There are also isolated reports of the drug inducing mood and anxiety symptoms in psychiatric patients (Damsa et al. 2006; Klufas and Thompson 2001). Moreover, one obesity study reported eight (6.2%) suicidal-related events occurring in topiramate-treated subjects versus none in placebo-treated subjects (Rosenstock et al. 2007).

Body weight loss in patients enrolled in clinical trials for epilepsy was reported as an adverse event in 7% of the patients receiving topiramate 200–400 mg/day and 13% of the patients receiving topiramate 600–1,000 mg/day, compared with 3% of the placebo-treated patients (Reife et al. 2000). Weight loss was associated with anorexia and was more common in heavier patients. Degree of weight loss was dose related; mean weight loss was 1.1 kg in patients receiving less than 200 mg/day of topiramate and 5.9 kg in patients receiving 800 mg/day or more (Langtry et al. 1997). Weight reduction usually plateaued after 15–18 months of treatment (Rosenfeld et al. 1997b).


Drug–Drug Interactions
Although topiramate is minimally metabolized by the liver, its clearance can be increased by the coadministration of hepatic enzyme–inducing drugs (Bialer et al. 2004; Gidal 2002; Langtry et al. 1997; Rosenfeld et al. 1997a; van Passel et al. 2006). Thus, carbamazepine and phenytoin may substantially decrease topiramate levels. Conversely, topiramate has mild enzyme-inducing properties and may enhance metabolism of ethinyl estradiol. Available data suggest that at topiramate doses of 200 mg/day or lower, this induction is insignificant, but at doses greater than 200 mg/day, induction becomes dose dependent and occurs to a great extent (Bialer et al. 2004). Women taking combination oral contraceptive agents therefore need to be counseled about this potential interaction.

There have been reports of topiramate causing increased lithium levels (Abraham and Owen 2004). This effect appears to be rarely clinically significant. Indeed, pharmacokinetic studies suggest that topiramate may slightly decrease serum lithium concentrations (Bialer et al. 2004).


Conclusion
Five controlled monotherapy trials and one adjunctive therapy trial indicate that topiramate is not efficacious in the treatment of acute bipolar mania in adults. However, clinical reports suggest that topiramate may be effective in other aspects of bipolar disorder, including juvenile mania, bipolar depression, “soft” forms of bipolar spectrum disorder, and bipolar disorder with comorbid conditions. Moreover, placebo-controlled trials suggest that topiramate is efficacious in binge-eating disorder, bulimia nervosa, alcohol dependence, borderline personality disorder, psychotropic-induced weight gain, and obesity. Further controlled clinical trials of topiramate in mood, eating, substance use, and personality disorders are needed to more clearly delineate its role as a psychotropic agent.