Review Paper

Oxcarbazepine in the Treatment of Bipolar Disorder: A Review

Wetid Pratoomsri, MD¹, Lakshmi N Yatham, MBBS, FRCPC², David J Bond, MD, FRCPC³, Raymond W Lam, MD, FRCPC, FAPA⁴, Chang-ho Sohn, MD, PhD¹

Objective:To review the data on the efficacy of oxcarbazepine (OXC) in bipolar disorder (BD) and to provide recommendations for clinicians on the use of this medication in treating BD. Method: Using the terms oxcarbazepine and bipolar disorder, oxcarbazepine and mania, or oxcarbazepine and bipolar depression, we conducted a computer-aided search of MEDLINE for the years 1950 to 2005. Results: Case reports, retrospective chart reviews, open prospective studies, and double-blind studies reported the efficacy and effectiveness of OXC in treating BD. The data indicate that OXC has efficacy in treating acute mania and may be a useful add-on in treating acute bipolar depression and in BD prophylaxis. OXC is generally well-tolerated. Conclusion: We recommend using OXC as monotherapy or as add-on therapy in refractory mania, but we recommend it be used predominantly as an add-on treatment for other phases of BD in patients who have not improved with well-established treatments or in patients who have difficulty tolerating adequate dosages. (Can J Psychiatry 2006;51:540–545) Click here for author affiliations.  Click here for information on funding and support.  Clinical Implications OXC is effective in treating acute mania. OXC can be used as an adjunctive treatment for refractory BD. Compared with carbamazepine, OXC has fewer drug interactions and is better tolerated. Limitations The efficacy of OXC in bipolar depression has not been widely studied. It is unknown whether OXC has efficacy in the maintenance treatment of BD. Although it is recommended for use in refractory BD, the data suggesting this strategy are not supported by Level I evidence. Key Words: oxcarbazepine, bipolar disorder, mania, depression, drug interactions Résumé : L’oxcarbazépine dans le traitement du trouble bipolaire : un examen

Although lithium is considered the gold standard of treatment for BD, research and clinical experience over the past 4 decades have indicated that only a small proportion of patients with BD remain episode- or symptom-free using lithium monotherapy in long-term maintenance treatment (1,2). Thus, to improve outcomes for a substantial number of patients with BD, anticonvulsants and atypical antipsychotics are often used as alternatives or augmentation strategies to lithium. Among anticonvulsants, VPA and CBZ have proven efficacy in treating acute mania (3), and they are likely effective in maintenance treatment, although well-designed double-blind, placebo-controlled trials supporting their prophylactic efficacy are lacking. Although VPA is generally well tolerated, CBZ has significant side effects. Further, it induces CYP enzymes leading to numerous drug interactions with concomitant medications.

OXC is an anticonvulsant developed through structural variation of CBZ with the intention of avoiding metabolites that cause side effects. OXC is metabolized primarily through its reduction to an MHD form that undergoes glucorinidation. OXC is better tolerated than CBZ because it has fewer side effects. Owing to its better tolerability profile, OXC is used increasingly to treat BD.

This paper systematically reviews the pharmacology of OXC and the data on its efficacy in treating BD and provides recommendations for clinicians on the use of this medication in treating BD.

Method

Using the terms oxcarbazepine and bipolar disorder, oxcarbazepine and mania, or oxcarbazepine and bipolar depression, we conducted a computer-aided MEDLINE search for the years 1950 to 2005 . We selected related articles and scanned each article’s bibliography for additional articles. We also contacted Novartis Pharmaceuticals Canada Inc for any additional information on the medication.

Pharmacology

OXC has a tricyclic structure like CBZ but has an extra oxygen atom at the 10 position in the centre ring, making it a 10-keto analogue of CBZ. Although there is little variation in their chemical structure, the routes of metabolism and pharmacology between OXC and CBZ are markedly different. CBZ undergoes oxidation, mediated mainly by the enzyme CYP3A4, to -CBZ-10, 11-epoxide. It then undergoes hydrolysis by the epoxide hydrolase enzyme to become 10, 11-Dihydro-10, 11-DHD (4–6). It is likely that the epoxide metabolite causes many of the side effects associated with CBZ (6). Since VPA inhibits this enzyme, blood levels of the epoxide metabolite can be increased when CBZ and VPA are administered simultaneously (7). In contrast, cytosolic arylketone reductase in the liver reduces OXC to 10, 11-dihydro-10-hydroxy-CBZ, which is known as the 10-MHD. Most of the MHD is then metabolized through glucuronide conjugation by UDP-glucuronyltransferase and excreted by the kidneys. A small amount of MHD undergoes oxidation to become an inactive DHD, which is also produced from CBZ. MHD is composed of 81% (s)-enantiomer and 19% (r)-enantiomer (6). Both OXC and MHD are active agents. Compared with CBZ, OXC has fewer drug interactions because it only minimally induces the CYP3A4,5 group and only inhibits CYP2C19 in higher dosages (5).

Absorption of OXC is rapid and complete. Maximum plasma concentration is achieved within 1 to 3 hours of a single dose (6,8). Plasma concentrations are dose-related and increase linearly. If OXC is taken twice daily, the steady state is achieved after only 3 or 4 doses. The plasma concentrations of OXC are higher in the elderly because of their reduced renal clearance; therefore, the dosage of OXC should be lower in the elderly than in younger age groups. Serum MHD increases by about 17% when OXC is taken with food. OXC is quickly metabolized in plasma, and 40% of MHD binds to plasma protein (5,6). It has few significant interactions with the drugs that compete for protein-binding sites, such as phenytoin and warfarin. The elimination half-life of MHD is 8 to 10 hours, so it should be administered twice daily. OXC and its metabolites, consisting of unchanged MHD (27%), glucuronidated MHD (49%), DHD, and unchanged OXC (< 1%), are excreted in urine (8,9).

Neurobiological Findings

OXC blocks voltage-sensitive sodium and calcium channels (5,10). While CBZ blocks L-type calcium channels, OXC blocks N-, and (or) P-, and (or) R-type calcium channels (5). OXC blocks sodium channels at a much lower concentration than that of CBZ (5). These differences may lead to different profiles of clinical response between OXC and CBZ. OXC is equally, if not more, effective at controlling seizures as CBZ (11,12). It is also effective in refractory seizure patients (12).

Efficacy

Evidence for the efficacy of OXC comes from various types of reports, including randomized controlled trials, observational prospective studies, retrospective studies, and case reports. The US Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research) Evidence Cassification System classifies studies into 3 groups: Class A (controlled trials), Class B (formal investigations with a priori methodological structure and quantitative outcome analyses), and Class C (case series, case reports, and retrospective chart review) (13,14). Studies that examined the efficacy of OXC have been categorized into these 3 classes and the evidence is summarized below.

Case Reports and Open Label Adjunctive Use Studies (Class C)

There are 4 case reports that describe the efficacy of OXC as add-on or monotherapy in a total of 7 patients with BD (15–18). The dosage range was 1200 mg to 2400 mg daily and 300 mg daily in a 6-year-old girl. The medication was well tolerated. Only one patient experienced a side effect (mild sedation).

There are 8 retrospective chart reviews reporting on the efficacy of OXC monotherapy or add-on therapy in a total of 654 patients. Response rates in these studies ranged from 50% to 100% (19–26). The dosage range was 300 mg to 3000 mg daily. Most patients in these studies had BD (96%), and the rest had a diagnosis of schizoaffective disorder or major depressive disorder. One study retrospectively assessed the efficacy of OXC (n = 27) compared with valproate (n = 27) add-on in patients with major depressive disorder, BD, and schizoaffective disorder. Results indicated that there was no overall difference in efficacy between the 2 groups as indicated by changes in scores on several rating scales (27).

Four open prospective studies reported that OXC was an effective adjunctive treatment in patients with BD and schizoaffective disorder. VeliKonja and Heinrich studied 20 patients with mania or schizoaffective disorder (28). Of these, 10 patients received OXC 900 mg daily plus haloperidol, and 10 patients received only haloperidol. Patients in both groups improved; however, the dosage of haloperidol in the OXC group was about one-half that of the haloperidol-only group (12.3 mg daily, compared with 24.9 mg daily, respectively). Muller and Stoll found that 600 mg to 3000 mg daily of OXC was effective as add-on therapy in 48 patients with mania, with 83% of patients showing good to very good response (4). Another short-term study reported that OXC add-on therapy of 300 mg to 2400 mg daily was not only effective in treating mania but also effective in treating the depressive phase of BD (29). Benedetti and others conducted a longer-term (4- to 12-month follow-up), open, add-on study in 4 patients with mania, 8 patients with depression, and 8 patients with a mixed-episode of BD. Of their patients, 61% met criteria for response according to their Clinical Global Improvement scores and their Mania scores on the BRMRS (30).

Open-Label Monotherapy Studies (Class B)

Hummel and others conducted an open trial with a nonrandom on-off-on design to examine the efficacy of OXC in 12 patients with mild to moderate mania (31). All patients were treated for 14 days with OXC as monotherapy. They were then crossed over to a 7-day drug-free period and were finally switched back to another 14-day period of OXC treatment. The dosage of OXC was titrated within 1 week to the final range of 900 mg to 2100 mg according to tolerability and therapeutic response. Of the 12 patients, 3 (25%) at the end of the first phase and 4 (33%) at the end of the final phase met the criteria for response, which was defined as a $ 50% reduction in scores on the YMRS. Further, the mean YMRS scores at the end of the OXC treatment periods were lower than the scores at the end of the drug-free period.

In a single-blind, active-comparator trial, Reinstein and colleagues assessed the efficacy and safety of OXC, compared with VPA (32). This study randomly assigned 57 patients with manic or schizoaffective BD treated for at least 8 weeks with VPA to either continue treatment with VPA or switch to OXC for 10 weeks. Of these patients, 23 who were switched to OXC at baseline and 19 who continued taking VPA completed the study. The patients who switched to OXC were titrated off VPA as tolerated over a 7-day period. The starting dosage of OXC was 150 mg twice daily, and it was further increased to between 300 mg and 1200 mg twice daily according to clinical response and side effects. The maximum dosage ranges of VPA and OXC were 1000 mg to 4000 mg daily and 1200 mg to 2400 mg daily, respectively. The CARS-M was performed at baseline, Week 5, and Week 10. There were significant reductions in CARS-M scores (that is, an OXC reduction of 2.91 points and a VPA reduction of 3.15 points) in both groups, with no significant differences between groups. Interestingly, 83% of patients in the OXC group showed a reduction in CARS-M scores, compared with 53% of patients in the VPA group, but the difference was not statistically significant. These results suggest that OXC and VPA have similar effects in the treatment of mania.

Double-blind Monotherapy Trials (Class A)

Emrich and others conducted the first double-blind, placebo-controlled ABA design study (A representing placebo and B representing medication) (33,34). Of the VPA group, 5 patients were studied, and of the OXC group, 6 patients were studied, one of whom underwent 2 trials. The duration of each treatment phase was varied and unknown to the patients and the psychiatrists who assessed them. The IMPS was used to evaluate the clinical response. The maximum dosages of OXC were 1800 mg daily (6 patients) and 2100 mg daily (1 patient). The IMPS scores were reduced significantly by 49.9%, SD 26.1%, during the OXC phases, compared with the placebo phases, which suggests that OXC has therapeutic efficacy in acutely ill patients with affective and schizoaffective disorder. Further, the efficacy of OXC was comparable to that observed with VPA.

Double-blind Active Comparator Trials (Class A)

OXC was compared with VPA, haloperidol, and lithium in double-blind active comparator trials.

In a preliminary trial, Emrich and others reported that, according to similar reductions in IMPS rating scores, the efficacy of OXC (n = 7) was similar to that of VPA (n = 5) (33,34).

Two double-blind trials reported the efficacy of OXC, compared with haloperidol. Müller and Stoll randomized 20 patients with acute mania to OXC 900 mg to 1200 mg daily or to haloperidol 15 mg to 20 mg daily for a 2-week period (4). The change in manic symptoms was measured with the BRMRS. The mean BRMRS scores decreased from 20 to 8 in both groups at the end point, with reductions somewhat greater in the OXC group at the end of Week 1, which suggests a slightly faster onset of action for OXC.

In another trial, Emrich compared the efficacy of OXC and haloperidol in treating 38 patients with acute mania (35). The primary outcome measure was the change in BRMRS scores, and the duration of study was 2 weeks. The mean dosage of OXC was 2400 mg daily, and the mean haloperidol dosage was 42 mg daily. The effect of OXC was comparable to that of haloperidol, as indicated by similar reductions in BRMRS scores. The incidence of side effects, however, was 3.5-fold greater in the haloperidol group, compared with the OXC group.

The same methodology was employed to compare OXC with lithium in 52 patients with acute mania (35). The mean dosage of OXC in this sample was 1400 mg daily and that of lithium was 1100 mg daily. The results showed similar improvement in both groups’ manic symptoms.

Adverse Events

Overall

OXC and its metabolite, MHD, have fewer side effects than CBZ and are generally well tolerated. In most trials, the side effects were usually transient and occurred mostly at the beginning of treatment. The reported side effects consist of nausea, vomiting, sedation, blurred vision, dizziness, headache, fatigue, diarrhea, constipation, ataxia, hyponatremia, and skin lesions. There are minimal effects on cognitive function and there is no effect on the hematological system (36). In Emrich’s study, 35% of patients taking haloperidol and 10% of patients taking OXC reported side effects. Emrich also found that both lithium and OXC were similarly tolerated as side effects were noted in 28% of patients taking OXC and in 19% taking lithium (35). All patients in Reinstein and others’ study (32) and 94% of patients in Muller and Stoll’s study (4) reported no side effects with OXC.

Dermatologic System

Rash occurred in 3% to 10% of patients who took OXC (6), which is lower than the rate reported with CBZ (7% to 10%). Patients who have a hypersensitivity reaction to CBZ have a 25% to 30% chance of developing a hypersensitivity to OXC (5). Therefore, a person who develops exfoliative dermatitis from CBZ should also avoid OXC (38). Patients should stop taking OXC if a hypersensitivity reaction occurs (5).

Electrolytes

Hyponatremia has been reported to occur in 3% to 51% of epileptic or psychiatric patients taking OXC (26,38–42). It is rare (0.2%) in children (43). Most patients with hyponatremia are asymptomatic and do not need to change the treatment. Elderly individuals and those taking diuretics are at an increased risk of hyponatremia. The symptoms include weakness, lethargy, dizziness, nausea, hiccups, cramping, confusion, headache, seizure, and coma. Hyponatremia can result in death.

Weight

Reinstein and others’ study of 57 psychiatric patients reported that 70% lost weight, 26% gained weight, and 4% had no weight change (32). Hummel and others found that 1 of 12 patients (8%) gained weight (31), and another study found that 8 of 18 psychiatric patients (44%) gained weight (30). One chart review found that 2 of 13 patients with BD (15%) gained weight (20).

Nervous System and Gastrointestinal System

The reported side effects in psychiatric patients include fatigue (16%), dizziness (7%), vertigo (25%), nausea and vomiting (15% to 16.7%), ataxia (8%), sedation (40% to 67%), insomnia (11.1%), tremor (27.8%), headache (5% to 7%), twitching (2%), dry month (11.1%), constipation (16.7%), paresthesia (2%), diplopia (2%), and cognitive difficulties (5% to 23%). Chest discomfort was mentioned as a side effect in one report, but the frequency was not provided (19–21,30,31). It is important to note that some of the patients experiencing side effects were taking other medications in addition to OXC.

Clinical Recommendations

The above literature suggests that OXC is effective in treating acute mania and that it may also have some efficacy in treating acute bipolar depression and refractory BD, as well as in the maintenance treatment of BD. Until further data are available from double-blind studies, however, we recommend that OXC be used in clinical practice as monotherapy or in combination with other medications for patients with acute mania who failed to improve with standard approved treatments such as lithium, VPA, and atypical antipsychotics. We further recommend OXC be used predominantly as an add-on treatment for other phases of BD in patients for whom wellestablished treatments have failed or in patients who have difficulty tolerating adequate dosages.

The therapeutic dosage range of OXC is 300 mg to 3000 mg daily in 2 divided doses (4,19,20,22), and the commonly prescribed dosages are usually between 600 mg and 2400 mg daily (4,6,32,33,28). The titration strategy and dosages that are used to treat individuals with epilepsy are similar to those used to treat individuals with affective disorders (6). The starting dosage in patients with mood disorders should be 150 mg twice daily and should increase every few days to a maximum of 2400 mg daily, depending on clinical response and side effects (30,32,44). Owing to the fact that it appears to have similar efficacy to haloperidol (4,35), lithium (35), and VPA, OXC can be used as a monotherapy or as an add-on therapy in patients with acute mania who have not responded to or cannot tolerate lithium, VPA, or antipsychotics (32). The addition of OXC to other psychotropic medications, including lithium, antidepressants, and other mood stabilizers, is also an effective strategy in refractory bipolar (19–23,25,27,30) and schizoaffective disorders (21,27,32–34,45).

OXC, unlike CBZ, does not induce its own metabolism (46); thus, when OXC is taken for a long time, the blood level is stable. As OXC and MHD only minimally inhibit the CYP enzyme system, they have fewer drug interactions than CBZ. However, they can induce specific isoenzymes (that is, CYP3A4 and CYP3A5) of the CYP3A family. These enzymes are responsible for the metabolism of CBZ, oral contraceptives, and dihydropyridine calcium channel blockers (5,9). Thus OXC can reduce levels of oral contraceptives by up to 50% and can reduce levels of calcium channel blockers by up to 30%. The blood level of CBZ is also reduced by OXC. Patients must be cautious when taking these medications concomitantly with OXC. Moreover, at higher dosages (that is, > 2400 mg daily), OXC can inhibit CYP2C19 . Substitution of OXC for CBZ can increase plasma concentrations of phenytoin and VPA by about 20% to 30%. However, the addition of OXC at a dosage of up to 600 mg daily does not significantly change any pharmacokinetic properties of CBZ, VPA, or phenytoin (47). OXC has no significant plasma level interactions with VPA, lamotrigine, antipsychotics, tricyclic antidepressants, lithium, benzodiazepine, verapamil, erythromycin, dextropropoxyphene, or warfarin (8,48).

OXC is generally safe and does not need hematological or hepatic monitoring. Routine monitoring of OXC levels is not indicated as there is currently no evidence to support an association between serum level and clinical response. Because of hyponatremia, monitoring serum sodium levels is recommended, preferably every 6 months or as clinically indicated, especially in those concomitantly taking salt-reducing medications or those with preexisting renal diseases.

Funding and Support

Dr Yatham is supported by the Michael Smith Foundation Senior Scholar Award

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Author(s)

Manuscript received January 2006, revised, and accepted March 2006.

1. Clinical Research Fellow, Mood Disorders Centre of Excellence, University of British Columbia, Vancouver, British Columbia.

2. Professor, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Director, Mood Disorders Clinical Research Unit, University of British Columbia, Vancouver, British Columbia.

3. Consultant Psychiatrist, Mood Disorders Centre of Excellence, University of British Columbia, Vancouver, British Columbia.

4. Professor and Head, Division of Clinical Neuroscience, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Director, Mood Disorders Centre of Excellence, University of British Columbia, Vancouver, British Columbia.

Address for correspondence: LN Yatham , Director, Mood Disorders, Clinical Research Unit, University of British Columbia, 2255, Wesbrook Mall, Vancouver, BC V6T 2A1

e-mail: yatham@interchange.ubc.ca

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