Paul J. Goodnick, MD

This article reviews the anticonvulsants that are part of the armamentarium for bipolar disorder.

At the end of this CE activity, participants should be able to:

1. Identify the anticonvulsants that have been studied for bipolar disorder.

2. Identify which anticonvulsants have proved effective for bipolar disorder.

3. Distinguish which anticonvulsant is indicated for bipolar depression

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

 This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 

. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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It is now more than 60 years since the initial use of lithium for bipolar disorder and more than 40 years since this drug was approved for treatment of bipolar disorder. However, there are significant limitations to lithium in both outpatient and inpatient settings. These include lithium’s relative lack of efficacy in rapid cycling; inconvenience of regular monitoring of serum levels as well as renal and thyroid indices; and intolerability to adverse effects. This situation led to the search for alternative therapies.

In 1967, diphenylhydantoin was found to be effective in nonepileptic emotional disorder.

 Later studies showed efficacy of carbamazepine and valproate for bipolar mania, which led to extensive testing of these drugs for other bipolar states (eg, bipolar depression, maintenance).

 In the hope that anticonvulsants could provide a class therapeutic breakthrough (ie, that the biological effect that prevented seizures might also prevent or treat mood swings), the search was on for other drugs that might be effective.

This article reviews the clinical applications for the anticonvulsants that are most often used. Consequent complications of use and recent findings for day-to-day practice are discussed, with an update on findings from research on anticonvulsants used less often, but which may be potentially beneficial.

 provides a concise biology of anticonvulsants, and 

 lists the clinical uses of anticonvulsant drugs in the US.

Carbamazepine is effective for treating mania and preventing recurrence of symptoms in patients with bipolar disorder. Randomized controlled trials (RCTs) of carbamazepine and lithium (trials were not head to head) for acute mania and maintenance showed similar improvement in Clinical Global Impressions scale measures.

 Discontinuation rates were also similar.

Valproate soon overtook carbamazepine: 10% of patients were receiving carbamazepine compared with 50% receiving lithium and 40% receiving valproate.

 Findings from a 2006 report indicate that only 6% were receiving carbamazepine.

Carbamazepine for bipolar illness is limited by the need to monitor blood cell indices, liver function tests, and serum levels.

 And carbamazepine has been associated with somnolence, dizziness, nausea, and ataxia.

 Hypersensitivity syndrome is reportedly more frequent with rapid increases in dosage.

 Complete blood cell counts are needed because of the possible risk for agranulocytosis and aplastic anemia. Tolerance to the prophylactic effects of carbamazepine has also been seen.

 In younger patients, it has been associated with a response rate of 38% to 44% in mania and mixed states

; there have been no studies in older patients.

There have been 3 recent reviews of oxcarbazepine for affective disorders.

 No differences were seen in antimanic efficacy when oxcarbazepine was compared with mood stabilizers in adults. Nor were there differences in adverse effects between oxcarbazepine and placebo: somnolence, dizziness, and ataxia appear to have been less frequent than with carbamazepine. Similar results were seen on the Bech-Rafaelsen Mania Rating Scale in patients who received 900 to 1200 mg of oxcarbazepine and those who received 15 to 20 mg of haloperidol per day.

In a study that compared oxcarbazepine with placebo for pediatric mania, differences in response did not reach statistical significance (42% vs 26%) with a comparative pattern of change in rating scale changes.

 At the same time, the rate of adverse effects was much higher in the group that received oxcarbazepine, particularly dizziness, nausea, and somnolence. There are no data on how adults treated with oxcarbazepine vs placebo responded. Consequently, there is not enough evidence for recommending oxcarbazepine. The sample sizes were small in all studies and there is no FDA approval for its use in mood states.

Divalproex was first approved by the FDA in 1994 as adjunctive treatment for mania.

 It has been extensively tested in multiple patient groups. Findings indicate that when placebo was compared with antimanic drugs, divalproex showed the best response.

 Practice guidelines in the US, UK, and Australia/New Zealand suggest using divalproex for mania as well as for maintenance and for rapid cycling.

 However, other than in the US, divalproex is not recommended for treatment of bipolar depression.

A recent review showed significant differences between divalproex and placebo in the reduction of depressive symptoms.

 The adverse effects were not significantly different, although significant weight gain was found with divalproex.

 Rapid titration to blood levels of 85 to 125 Î¼g/mL or up to 60 mg/kg has been suggested for depression.

Divalproex was found to be more effective than placebo when used for a longer duration as maintenance treatment (209 vs 143 days).

 In addition, fewer patients who received divalproex vs placebo discontinued because of symptom relapse (71% vs 50%).

 Compared with placebo, divalproex was more effective in preventing relapse of any mood swing (27% fewer manic relapses and 60% fewer depression relapses).

 And, it may be as effective as lithium in reducing the risk of suicide during ongoing treatment; the rate of suicide events was equivalent in both groups over a double-blind treatment period of 2.5 years.

 Other findings suggest that combining divalproex with quetiapine in patients with mixed symptoms may improve outcomes.

Limiting factors for divalproex include the need to monitor serum levels, weight, blood cell counts, liver function tests, and menstrual history (because of the risk of polycystic ovarian syndrome).

 There is also twice the rate of malformations in pregnancy, as well as the risk of ammonemia during maintenance treatment.

There have been 3 double-blind trials of divalproex in the pediatric population

: in a comparison trial of divalproex and quetiapine, better results were seen with quetiapine; results from another trial showed equivalent benefits for divalproex and lithium for maintenance therapy; and the last trial found no difference from placebo in prophylaxis.

Five studies in older patients were reviewed; 4 consisted of retrospective analyses.

 Study results show that 59% met criteria for improvement despite a wide range of concentrations (25 to 120 Î¼g/mL); one study showed similar response rates for lithium and valproate (82% and 75%, respectively). This may suggest that valproate is effective across a wide range of serum levels.

The last of the anticonvulsants with extensive research for use in mania is lamotrigine.

 Initial studies with an approximate sample size of 30 showed similar response rates for lithium and lamotrigine.

 However, large-scale attempts to replicate these results failed.

Lamotrigine was compared with placebo, olanzapine/fluoxetine, gabapentin, venlafaxine, and citalopram in RCTs of bipolar depression treatment. One placebo-controlled study showed significant benefit for the lamotrigine (200 mg/d) group.

 Significant improvement was seen in the group that received dosages higher than 50 mg/d. A meta-analysis found that lamotrigine was more effective in patients who had more severe baseline symptoms (Hamilton Depression Rating Scale score above 24).

 Lamotrigine was found to be as effective as venlafaxine and citalopram in one trial. Results of another trial showed that lamotrigine was less effective than the olanzapine/fluoxetine combination. Overall, a 2012 review that followed the release of updated US guidelines in 2005 concluded that lamotrigine had only a modest effect for depression.

Two long-term studies (1.5 years), with an entry criterion of either mania or depression, found that the onset of depression was delayed with lamotrigine compared with placebo.

 Lithium, used as an active control, did not delay onset of depression. However, the rate of relapse into mania was much lower for those who received lithium. Further evaluation showed that mixed state and more than 2 depressive episodes in the past 3 years predicted a better response to lamotrigine.

Compared with placebo, lamotrigine was found to be more effective for rapid cycling in patients with bipolar II but not for those with bipolar I (ie, in patients with greater and more severe depression than mania).

 However, adding lamotrigine to lithium or divalproex did not reduce depression severity in rapid cycling.

 Moreover, findings from another study indicate that the combination of lamotrigine and quetiapine increased euthymia from 0% to 46%.

In a pediatric open-label study, 54% of patients treated with lamotrigine had symptom response.

 In older adults, lamotrigine augmentation at a mean dosage of 150.9 mg/d for 12 weeks led to significant improvement on the Montgomery-Ãsberg Depression Rating Scale.

 By the end of the treatment period, 57% met remission criteria and 65% met response criteria.

 pointed out the importance of monitoring for Stevens-Johnson syndrome as well as watching for possible weight gain. The risk of hypersensitivity syndrome is lower than with carbamazepine and is reduced by titrating slowly. Adverse effects include somnolence, hyperphagia, dry mouth, and weight gain.

 There is a risk of overdose with lamotrigine, and although overdoses are usually benign, they can lead to complete heart block and death.

Adverse effects in the pediatric population include stomach upset, rash, and headaches.

 The most commonly reported adverse effects in older adults are reduced sleep time (25%), weight loss (21%), and polyuria/polydipsia (19%); rash that may have been due to lamotrigine resolved on discontinuation.

 Older patients (more than 55 years of age) who received maintenance treatment with lamotrigine at a mean dosage of 240 mg/d were found to have fewer adverse effects than patients who took lithium.

It must be noted that if lamotrigine is combined with valproate, levels of lamotrigine are doubled and those of valproate fall 25%.

 Unfortunately, until there is more evidence, the clinical role of lamotrigine appears to be best limited to combination treatment and to prevention of relapse into depression.

Is there any role for other anticonvulsants (eg, gabapentin, levetiracetam, tiagabine, topiramate, zonisamide)? Gabapentin, once thought to be a possible alternative for treatment of mania, failed in randomized clinical trials and is now mostly used for treatment of pain and anxiety.

Levetiracetam reduced manic symptoms in 7 of 16 patients; however, there were multiple adverse effects.

 Reports of positive findings led to an RCT on bipolar depression. Although patients received a mean dosage of 1132 mg/d for 6 weeks, there was no evidence of symptom response.

No randomized trials have been identified for the use of tiagabine for acute treatment. A Cochrane review, however, indicates that tiagabine may lead to syncope or seizure.

 Similar results were found regarding its use for maintenance therapy.

There have been 4 failed randomized clinical trials of topiramate for the treatment of mania, although one RCT showed benefit of 176 mg/d of topiramate as an add-on treatment of bipolar depression.

 There was a mean weight loss of 5.8 kg over the 8-week trial. Results for the comparator bupropion sustained-release were similar clinically, with less mean weight loss. A meta-analysis by Liu and colleagues

 focused on 2 open-label trials and 1 pediatric RCT. The open-label studies focused on weight gain effects counteracted by bupropion. However, in one of the trials, a reduction of symptom severity was also seen. One trial had only modest statistical power so it could only report a numerical difference in response (35% vs 22%). The adverse effects of bupropion included decreased appetite, nausea, and weight loss. However, rapid dose escalation produced cognitive memory impairment.

Zonisamide results are mixed. The results from 2 trials showed efficacy for mania5; however, when patients were randomized to either adjunctive zonisamide or placebo, there were no significant outcome differences.

 An 8-week open-label trial in 20 patients aged 23 to 53 years with bipolar depression showed significant improvement in multiple ratings; however, there was a 50% dropout rate because of sedation, nausea, and dizziness.

 There was an average weight loss of 3.79 lb.

More studies, particularly RCTs, are indicated for topiramate and zonisamide. Perhaps mostly for completeness and historical reasons, RCTs on gabapentin are also indicated. Initially believed to be a possible alternative for treatment of mania and other forms of bipolar disorder, gabapentin failed in con-trolled trials; however, it may prove effective in other areas of clinical practice.

Despite all the initial excitement for anticonvulsants as a “class effect” to treat bipolar disorder in the mid-1990s, evidence has shown that only a few anticonvulsants are effective and safe. Of 9 candidates for investigation of clinical utility in treatment, we have a situation in which despite guidelines suggesting the use of perhaps as many as 3 agents for mania, 2 for bipolar depression, and 4 for maintenance treatment, a careful review of the data is disappointing.

Of the 3 agents suggested for treatment of mania (carbamazepine, oxcarbazepine, and divalproex), carbamazepine’s utility is limited by its adverse effects, the need for monitoring serum levels, and the risk of agranulocytosis and aplastic anemia. The evidence for the use of its close relative, oxcarbazepine, is inadequate. The results of the comparative studies of oxcarbazepine versus placebo showed numerical but not statistical superiority.

A careful review of results of the trials of the 2 agents suggested for bipolar depression shows that lamotrigine clearly did better than placebo in 1 of 4 RCTs, but not as well as the olanzapine/fluoxetine combination. Only divalproex showed results sufficient to suggest its use for treatment of both mania and bipolar depression.

Lamotrigine effectiveness appears limited to its FDA indication for relapses of bipolar depression symptoms. Results for the other anticonvulsants for bipolar disorder have been negative: they were ineffective (gabapentin, levetiracetam), there were tolerance problems (tiagabine, zonisamide), or there was insufficient evidence for effectiveness (topiramate, zonisamide).

Divalproex, despite its need for monitoring as well as a number of adverse effects, appears safe and effective for mania, bipolar depression, and prophylaxis of relapses in both pediatric and geriatric populations. More work is needed with topiramate and zonisamide to establish possible future use.

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Dr Goodnick is Professor of Clinical Psychiatry at Georgetown University School of Medicine in Washington, DC, and Clinical Education Director at the Veterans Affairs Medical Center in Washington, DC.

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Articles

Clinical applications for the most commonly used anticonvulsants are reviewed here, along with complications and recent findings for day-to-day practice.  Also: an update on findings from research on anticonvulsants used less often, but which may be potentially beneficial. 

Paul J. Goodnick, MD

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