Dr. Ghaemi is director of the Bipolar Disorder Research Program at Cambridge Hospital in Massachusetts and assistant professor of psychiatry at Harvard Medical School in Boston.

Mr. Ko is research coordinator at the Bipolar Disorder Research Program at Cambridge Hospital.

Acknowledgments: This research was supported by the National Institute of Mental Health Research Career Development Award, Grant #K-23-MH-64189.


 

Abstract

The anticonvulsant oxcarbazepine is a keto-analog of carbamazepine that has been studied as a possible treatment for bipolar disorder. European literature reports oxcarbazepine efficacy in treating manic symptoms while confirming its tolerability. Existing prophylaxis studies seem to indicate some benefit with oxcarbazepine, but small sample sizes limit the ability to generalize the findings. Naturalistic pilot data examining the treatment of bipolar disorder in a North American setting suggest some benefit with oxcarbazepine in treating a very refractory sample with depressive and rapid-cycling features. These studies are encouraging because they suggest that the drug may have some mood-stabilizing effects. However, controlled studies and more clinical experience with oxcarbazepine in the United States are required before we can assess the potential utility of the agent with any clarity.

 

Introduction

Since the 1980s, the anticonvulsant oxcarbazepine has been available for use in some parts of Europe. A handful of European studies have examined oxcarbazepine treatment of bipolar disorder, but its use in a North American setting is yet to be studied extensively. This is partly due to the fact that oxcarbazepine is relatively new to the United States; the Food and Drug Administration (FDA) first approved the drug for marketing in January 2000. In this article, we review the European literature on oxcarbazepine treatment of bipolar disorder and provide pilot data on its use in an American setting. We also provide recommendations for the clinical use of oxcarbazepine for bipolar disorder.

 

Pharmacology of Oxcarbazepine

Oxcarbazepine, a 10-keto-analog of carbamazepine, is FDA indicated for partial seizures with or without secondary generalization. The pharmacologic properties of oxcarbazepine are summarized in Table 1. A major advantage of oxcarbazepine over carbamazepine is its tolerability. Unlike carbamazepine, oxcarbazepine has not been associated with increased risk of leukopenia, aplastic anemia, agranulocytosis, elevated liver function test results, or Stevens-Johnson syndrome.

Biochemically, oxcarbazepine has a minimal effect on most major cytochrome P450 (CYP) enzymes (such as 2D6), except for mild induction of CYP 3A4.1 As such, although oxcarbazepine has fewer drug interactions than carbamazepine, it can reduce levels of oral contraceptives by up to 50% and levels of calcium channel blockers by up to 30%. Thus, particular caution should be exercised when this agent is used in women of childbearing age. Oxcarbazepine also inhibits CYP 2C19, which can increase phenytoin levels by up to 40%.1 However, oxcarbazepine does not increase lithium or valproate blood levels.

The most significant medical risk to using oxcarbazepine is its association with a 2.5% clinically significant hyponatremia rate (sodium level <125 mmol/L) based on placebo-controlled clinical trials.1 Most cases of hyponatremia occur in the first 3 months of treatment. Thus, it is probably wise to check serum sodium levels monthly in the first 3 months of treatment, and every 6–12 months thereafter. Given the potential for selective serotonin reuptake inhibitors (SSRIs) to also reduce serum sodium levels (due to an increased risk of the syndrome of inappropriate antidiuretic hormone production), patients treated with combinations of SSRIs and oxcarbazepine should be particularly carefully monitored in the early stages of treatment. However, unlike with carbamazepine, routine laboratory tests for blood levels, hepatic function, and blood counts are not necessary with oxcarbazepine.

The pharmacologic effect of oxcarbazepine is mainly related to the 10-monohydroxy (MHD) metabolite.1 Both the pro-drug and this metabolite are active agents thought to block sodium channels. No effects on neurotransmitter systems or receptors have been shown. The half-life of oxcarbazepine itself is 2 hours and that of MHD is 9 hours, thus requiring at least twice-daily dosing. Oxcarbazepine is rather quickly metabolized to mostly MHD in plasma, and MHD is poorly plasma-protein bound (only 40% bound). Blood levels increase linearly and, though dose related, have not been associated with treatment response. Thus, laboratory testing is not required to establish a therapeutic blood level. Oxcarbazepine is metabolized by the liver to MHD, then glucuronidated and excreted in the kidney. Renal impairment is associated with increased half-life of MHD, up to 19 hours. However, mild-to-moderate hepatic impairment has not been associated with changes in oxcarbazepine or MHD pharmacokinetics. The agent has not been studied in severe hepatic impairment. Effective blood concentrations of MHD are lower in children younger than 8 years of age and higher in the elderly (60–82 years of age) than in adults.

It is generally thought that doses of oxcarbazepine need to be about one third higher than those of carbamazepine for similar effects. Research has suggested that many of the side effects of carbamazepine, which are lower with oxcarbazepine, have to do with the major metabolite 10,11-epoxide.2 In a study of 20 healthy volunteers, a single dose of oxcarbazepine (600 mg) was compared with carbamazepine (400 mg). Each dose led to fatigue in 7 of 10 persons in each group, but dizziness was lower in the oxcarbazepine group than in the carbamazepine group (2/10 versus 7/10, respectively; P<.05). Overall, reported tolerance of oxcarbazepine was greater than that of carbamazepine.2

In the epilepsy clinical trials that led to oxcarbazepine’s FDA indication, the most common side effects reported in one trial (N=172) with monotherapy at 2,400 mg/day (compared with a control group given 300 mg/day) included headache (31% versus 15% in controls), dizziness (28% versus 8% in controls), nausea (22% versus 7% in controls), and fatigue (21% versus 5% in controls). Discontinuation rates due to side effects were much higher in combination treatment clinical trials than in oxcarbazepine monotherapy studies; 1% or fewer patients discontinued in monotherapy studies, compared with 65% in combination treatment studies (using the same dose of 2,400 mg/day in both cases). Sedation and ataxia markedly increased the likelihood of discontinuation.

Oxcarbazepine has a lower rash rate than carbamazepine. A study conducted in Denmark found that skin rash reactions to carbamazepine resolved in 75% of patients with epilepsy after treatment was switched to oxcarbazepine.3 Thus, it is estimated that 25% of individuals who experience rash with carbamazepine will also experience it with oxcarbazepine. In a placebo-controlled monotherapy study (N=104), rash was reported in 4% of oxcarbazepine-treated subjects, compared with 2% of controls.

Oxcarbazepine is a pregnancy category C drug, with fetal abnormalities noted in animals treated at doses similar to recommended human doses.1 Fertility was also impaired in animal studies. Oxcarbazepine and MHD are excreted in human breast milk, with a milk:plasma concentration ratio of 0:5. This agent should probably be avoided during preconception, pregnancy, and breast-feeding.

There are no other known serious medical risks associated with oxcarbazepine, although studies in rats suggest increased 2-year rates of hepatocellular adenomas or carcinomas at doses near human recommended doses. In more than a decade of human use in Europe, no known increase in cancer risk has been reported with this agent.

 

European Studies of Bipolar Disorder

Clinical effectiveness studies with oxcarbazepine are summarized in Table 2.

Treatment of Acute Mania

In an open pilot study2 in which 48 patients with acute mania were treated with oxcarbazepine alone, 50% (n=24) were maintained on 600–900 mg/day, 37.5% (n=9) on 1,200–1,500 mg/day, and 6% (n=3) on 1,800–3,000 mg/day. Neuroleptics or lithium were needed in only 7 patients (15%), and oxcarbazepine was used by itself or only with hypnotic agents in the remaining 41 patients (85%). Patients were followed for a mean of 39 days, and based on clinicians’ assessments, 83% had a marked improvement and 94% tolerated the medication without adverse reactions.
 

A double-blind, placebo-controlled study used an on-off-on design in six acutely manic patients.4 All patients received an oxcarbazepine dose of 1,800 mg/day, and one patient received a second trial at 2,100 mg/day. The only side effect reported was dizziness at the higher dose (2,100 mg/day). A 49.9% reduction in manic symptoms (using the Inpatient Multidimensional Rating Scale—a psychopathology measure13) was shown on the drug, compared with only a 26.1% reduction off the drug (P<.10).
 

Another controlled study in mania (N=20) involved double-blind randomized treatment for 2 weeks to either oxcarbazepine (900–1,200 mg/day) or haloperidol (15–20 mg/day).2 Using the Bech-Rafaelsen Mania Scale (BRMS), both groups experienced equal and marked improvement in manic symptoms (from an initial mean score ~20 to a final mean score ~8). This study strongly suggests that the onset of action of oxcarbazepine rivals that of neuroleptic agents. Side-effect data were not reported.
 

A third double-blind study6 compared 19 manic patients on oxcarbazepine with 19 manic patients on haloperidol at high doses (2,400 mg/day of oxcarbazepine versus 42 mg/day of haloperidol). Both drugs were equally effective in 2 weeks of treatment, with reductions in the BRMS score from about 22 initially to less than 10 at 2 weeks. Although notable adverse effects occurred in 35% of haloperidol-treated patients, only 10% of oxcarbazepine-treated patients experienced adverse effects (n=3; one each with vomiting, lack of coordination, and parkinsonian symptoms). The researchers judged tolerability of oxcarbazepine to be excellent in 18%, good in 76%, moderate in 6%, and poor in none. In comparison, 25% of the haloperidol group was judged to have moderate or poor tolerability.
 

A fourth double-blind study6 examined 28 acutely manic patients on oxcarbazepine (mean dose=1,400 mg/day) with a control group of 24 patients receiving lithium (mean dose=1,100 mg/day) over 2 weeks. Again, efficacy was similar with both agents; there was improvement in the BRMS score from ~27 initially to ~11 at endpoint. Twenty-eight percent of the oxcarbazepine group had adverse effects, compared with 18.5% in the lithium group. However, this difference was not statistically significant. Two patients experienced hypotension, sedation, and sialorrhea. One patient each experienced skin rash, sedation, vertigo, akathisia, slurred speech, and oculogyric movements. Researchers judged the two medications to be equally tolerable, with excellent tolerability reported in 79% of both groups and good tolerability in 14% of the oxcarbazepine group, compared with 13% of the lithium group. Only 3% of the oxcarbazepine group and 6% of the lithium group were thought to have tolerated the medications poorly.
 

An open-label German study5 treated 10 hospitalized patients with acute psychotic mania or schizoaffective psychosis with 900 mg/day of oxcarbazepine, along with neuroleptics. All patients showed improvement with 3 weeks of treatment, including psychotic and agitated symptoms. Lower mean haloperidol doses (12.3 mg/day) were lower in the oxcarbazepine group, compared with a matched control group (24.9 mg/day). Factor analyses of global psychopathology ratings provided evidence for improvement in manic-like symptoms and in hostility and paranoid symptoms. No statistically significant improvement in hallucinatory symptoms was seen. Electroencephalograms were monitored in this study, and only one case of some slowing with generalized theta waves was noted. Only one patient dropped out due to a rash (this person was excluded from the analysis).
 

Prophylaxis Treatment

The only controlled prophylaxis study (open, not double-blind) was conducted in 10 patients, 4 of whom were randomized to oxcarbazepine and 6 to lithium.7 In the oxcarbazepine group, two depressive relapses and one manic relapse were noted over 10 months of follow-up, compared with two manic relapses and one depressive relapse in the lithium group over 12 months of follow-up. In mirror-image comparisons of relapse before and after treatment with the two drugs, both groups also appeared to improve similarly. Interestingly, all four oxcarbazepine-treated patients (versus only one lithium-treated patient) discontinued treatment eventually, three due to noncompliance and one due to leukopenia. Side effects were limited despite this dropout rate. However, the small numbers greatly limit the ability to interpret these results. It should also be noted that four other lithium-refractory patients who were nonrandomly assigned to oxcarbazepine treatment (mean dose=1,050 mg/day, for a mean duration of 16 months) appeared to do rather well, with only two depressive relapses in that time frame.
 

Another prophylaxis study, which was open but uncontrolled, assessed outcome in nine lithium nonresponders who received add-on treatment with oxcarbazepine. Six patients were treated with 600 mg/day, two with 900 mg/day, and one with 1,200 mg/day; mean duration of treatment was 5.4 months. Naturalistic treatment with neuroleptics and antidepressants was allowed. No robust benefit was seen overall in terms of reduction in the number of mood episodes, but a few patients appeared to have reduced severity of symptoms and fewer hospitalizations. Standardized outcome measures were not used. Side effects were reported to be limited and transient, with some dizziness, sedation, and ataxia. One patient dropped out after 2 months of treatment due to dizziness, nausea, and headache. Interestingly, lithium-related polyuria improved in two patients treated with adjunctive oxcarbazepine, and thyrotropin-releasing hormone stimulation test results normalized on oxcarbazepine plus lithium in three patients who previously had abnormal results when treated with lithium alone.8
 

Other Studies

A recent scientific report from Italy focused on the effect of switching patients from carbamazepine to oxcarbazepine.9 Thirteen patients reported to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition14 criteria for bipolar disorders or cyclothymia were treated openly with oxcarbazepine; nine of the patients had been switched from carbamazepine. All carbamazepine-treated patients had to be switched to oxcarbazepine due to hepatic or blood count abnormalities, dermatitis, electrocardiogram abnormalities, or noncompliance. Overall, liver-function test results and hematologic parameters improved into the normal range on oxcarbazepine. The researchers also reported improvement in mood based on the Global Assessment Scale in all patients, all of whom were also treated with SSRIs at 8-week follow-up. Details regarding the clinical indications for treatment and statistical comparisons were not provided.
 

North American Studies of Oxcarbazepine in Bipolar Disorder

Treatment of Depression and Rapid Cycling

The European literature on oxcarbazepine mostly focuses on mania, with a few small prophylaxis studies and no published data on depression. Since its indication for use in epilepsy in the US, oxcarbazepine has been increasingly used for psychiatric purposes as well.
 

In a recent study for the Stanley Foundation Bipolar Network, 12 manic patients received oxcarbazepine alone in an open on-off-on design (14 days on, 7 days off, 14 days on).10 Using the Young Mania Rating Scale (YMRS), 42% were judged responders (with the standard definition of ≥50% improvement on the YMRS). Side effects occurred in four patients (30%) and constituted the usual findings of sedation and nausea. The most severely manic and psychotic patients appeared to experience less improvement in their YMRS scores on oxcarbazepine monotherapy.
 

Another recent large study11 compared oxcarbazepine (n=30) with divalproex sodium (n=30) in an open-label, prospective, nonrandomized fashion. All patients were acutely manic and assessed at 5 and 10 weeks with the Clinician-Administered Rating Scale for Mania (CARS-M). The two drugs were similar in efficacy, but there was more weight gain and cognitive side effects (based on the Mini Mental State Examination) with divalproex. While the results suggest enhanced tolerability with oxcarbazepine, the study was not randomized and therefore the drug’s efficacy data should be viewed with caution.
 

We also report preliminary data here on our experience using this agent for the treatment of mostly depressive and rapid-cycling symptoms in patients with bipolar disorder. Our research group has recently completed a chart review of oxcarbazepine treatment of refractory bipolar disorder in a naturalistic North American setting. The charts of 13 outpatients treated with oxcarbazepine were examined and clinical response was assessed retrospectively using the Clinical Global Impressions Scale– Improvement. All patients had failed treatment with at least one previous mood stabilizer, and most were experiencing depressive or rapid-cycling symptoms. The mean maintenance dose of oxcarbazepine was ~600 mg/day, and patients were followed for a mean duration of treatment of ~3 months. Mild-to-moderate improvement was seen in about one half of patients. The most common side effect was sedation, occurring in slightly more than one half of patients. Although the efficacy of oxcarbazepine remains to be established in larger, controlled studies with monotherapy in a North American setting, these naturalistic data suggest some benefit in this very refractory, difficult-to-treat sample with depressive and rapid-cycling features.12
 

Clinical Recommendations

Based on the previously mentioned research in bipolar disorder, the typical dose range for oxcarbazepine appears to be 600–1,200 mg/day in divided doses, although it seems tolerable and often effective in doses as high as 3,000 mg/day. Most of the controlled studies conducted with this agent have occurred in the 1980s and have been limited to studies of acute mania. Only one placebo-controlled study has been conducted, and that study used an on-off design (rather than the typical randomized, parallel group design) in only six subjects. Nonetheless, that report suggested benefit, and double-blind comparisons suggest similarity in efficacy with haloperidol (two studies) or lithium (one study), with the same or lower rates of side effects. Despite the suggestiveness of these studies, straightforward, placebo-controlled, parallel-design data would be more compelling.
 

Long-term benefit with oxcarbazepine has only been assessed in two small, open, prospective studies, one of which was controlled with a lithium comparison group. However, the extremely small size of these studies and their lack of standardized outcome criteria make them extremely difficult to interpret.
 

No studies have yet been published on the use of oxcarbazepine for depressive symptoms of bipolar disorder or for the rapid-cycling subtype. However, our recent pilot data12 suggest some benefit, albeit mild to moderate, in a very refractory population which had previously failed at least one fair trial of lithium, valproate, or carbamazepine.
 

Although far from definitive, these studies are encouraging. They suggest that oxcarbazepine may have some antimanic and/or mood-stabilizing effects. Further, its chemical similarity to carbamazepine, a well-proven antimanic and mood-stabilizing agent, provides some biochemical rationale for the likely efficacy of oxcarbazepine.
 

Perhaps most importantly, in practical terms, oxcarbazepine rather clearly appears to be better tolerated than carbamazepine and possesses fewer drug interactions. Given that most patients with bipolar disorder do not respond to a single mood stabilizer and thus require polypharmacy with two or more agents, the availability of oxcarbazepine for adjunctive use with lithium, valproate, or other agents provides a potentially useful alternative. Our initial pilot American data suggest that the limiting factor to its use in this setting may be sedation.
 

Conclusions

In summary, more clinical experience with oxcarbazepine in the US is required before we can assess the potential utility of this agent (particularly for depressive and prophylactic benefit) with any clarity. It has been available in Europe for almost two decades and researchers there have produced some double-blind evidence, albeit limited, that oxcarbazepine is an effective antimanic agent. Given its biochemical similarity to carbamazepine, future research may find evidence of broad utility in bipolar disorder.  PP
 

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