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Abstract

Objective: To review the literature on the effectiveness of anticonvulsant drugs in the management of bipolar disorder.

Methods: A selective review of the literature.

Results: Valproate is an effective drug, alone or in combination, for mania, but has limited benefit in bipolar depression. Although valproate is widely used in maintenance therapy of bipolar disorder, and secondary analyses suggest benefit, in the largest randomised maintenance trial there was only a trend favouring valproate. Lamotrigine has benefit in bipolar depression and maintenance, but not in mania. Carbamazepine is effective in mania. Other anticonvulsant drugs have been tried in mania, but with mixed results.

Conclusions: Valproate, lamotrigine and carbamazepine have a valuable place in the management of bipolar disorder.

Keywords

anticonvulsant bipolar carbamazepine lamotrigine valproate

Anticonvulsants do not have a class effect when bipolar disorder is the disease focus. Anticonvulsants have been recognized as useful in bipolar disorder since the earliest reports of efficacy for valproate in 1966 [1] and carbamazepine in 1969 [2]. Their systematic study has essentially been limited to the last 10 years, with three drugs now approved for treatment of various aspects of bipolar disorder in most countries, and several others essentially established by studies as ineffective as mood stabilizers.

Given the diverse structures and known pharmacodynamic effects of several of these drugs that were first studied and approved for epilepsies, it is not surprising that they would have diverse profiles in bipolar disorder. The inherent complexity of bipolar disorders likely contributes. Targets for drug actions include of course depression and manic symptoms. However, studies suggest that the domains of disturbed behaviour in bipolar disorder encompass depressive cognitions, motor retardation, psychic anxiety, somatic distress, hyperactivity, impulsivity, irritability, manic cognitions of elation and grandiosity, and psychosis. These different behavioural targets appear differentially responsive to anticonvulsant mood stabilizers, as well as other common treatments for bipolar disorder. This article reviews the extensive evidence for effectiveness of valproate, lamotrigine and carbamazepine, and summarizes other anticonvulsants that have been studied in bipolar disorders. Except for carbamazepine, the drugs, along with lithium have in common primary actions on signal transduction, either or both on ion channels and signal transducing systems within neurones. In this respect, they differ fundamentally from currently approved antipsychotic, antidepressant and anxiolytic drugs.

Valproate

Valproate was approved for treatment of mania in 1995, and its quick adoption as a primary treatment for mania, and more recently, maintenance treatment of bipolar disorders has been a major impetus to the study of other anticonvulsant agents in bipolar disorder. Early reports by Lambert of valproate's effectiveness, most open but some large, randomized trials gave a clear indication that benefits were prompt, robust and principally on manic symptoms [1]. Almost all regulatory studies have employed divalproex, a delayed release formulation that has improved tolerability over valproic acid and valpromide [3].

Studies and role in mania

Two placebo-controlled studies led to approval in mania. The effect size of the superiority of divalproex over placebo was large in both trials [4]. The initial effect of valproate is somewhat faster than with lithium or carbamazepine [5, 6] and similar to atypical antipsychotics [7], with improvement within the first week of treatment, and faster with loading dose strategies, or use of intravenous valproic acid [8, 9].

Valproate has been studied in combination regimens, with studies indicating some added benefits when valproate is combined with antipsychotics, or, conversely, when antipsychotics are added to patients who continue to be symptomatic with valproate treatment [10, 11]. Additionally the combined therapy regimens indicate that lower doses of the antipsychotic are adequate in combination with valproate than in monotherapy regimens [11, 12]. The studies indicate that adding a second drug when a patient continues to have manic symptoms is an effective strategy, whereas commencing treatment with two agents does not yield advantage over valproate (or lithium) alone [10].

Depression

Studies in acute depression do not indicate a clinically meaningful benefit from divalproex, although no studies indicate worsening of depression, and control of manic symptomatology is positively associated with control of depressive symptomatology [13, 14].

Maintenance

Although the largest randomized maintenance study showed only a trend favouring divalproex, most planned secondary analyses indicated significant superiority over placebo and equivalence or superiority to lithium [13]. These included rates of discontinuation for depression, and, compared with lithium, rates of discontinuation for intolerance, overall effectiveness, and time to development of depression (102.6 vs 59.2 days, p = 0.03) [3, 15]. Patients who were treated with divalproex during the open, acute phase had higher rates of study completion than either placebo or lithium (41%, 12% and 24%, divalproex < placebo, p = 0.002, divalproex < placebo, p = 0.04 respectively) [13]. In a second randomized, blinded maintenance, divalproex and olanzapine were similar in efficacy, with patients who were in remission at the end of week 3 significantly more likely to complete the 47 week trial (divalproex 26%, olanzapine 20%), further supporting the predictive value of early response on maintenance response [16].

Several clinical features assessable at baseline and are useful predictors of response or non-response to divalproex in monotherapy regimens. Patients with mixed mania, including low levels of concurrent depression, rather than a full depressive episode, have the same rates of response as do euphoric manics, and respond better than to lithium [17–20]. Divalproex was superior to lithium in patients with a history of poor prior response to lithium [5]. Patients with more than two prior depressive episodes had better responses to divalproex than did patients who received lithium. Manic patients with prominent irritability appear to respond better to divalproex than to lithium [21, 22] or to carbamazepine [6]. Several positive studies of divalproex have been reported in patients with irritability: cluster B personality disorders, borderline personality and schizophrenia [23–25]. Predominant hyperactivity was associated with best responses to both divalproex and lithium, whereas predominant psychosis or core depressive features predicted poor response to both [21].

Predictors of response in maintenance treatment are not necessarily the same as those in mania and data are limited. However, patients with positive acute manic response to divalproex were significantly more likely to respond to divalproex than to placebo or lithium [26]. Patients whose index manic episode was euphoric, rather than dysphoric, responded better to divalproex than to placebo, or to lithium [27].

Tolerability is generally good with divalproex, particularly in lack of emotional or physical dulling, or cognitive impairment. However, weight gain is more common at serum levels above 100 μg mL⁻¹ [13]. High serum levels are also associated with gastrointestinal adverse effects, sedation and reductions in platelet count and white blood cells [13]. Valproate can cause hair loss from chelation with zinc, which can be avoided by separating dosing from supplemental vitamins containing zinc [3]. Fetal abnormalities associated with aberrant neuronal cell development is a risk in the first trimester of pregnancy [28, 29]. Several studies indicate that there is some risk of development of polycystic ovary syndrome (PCOS), and that avoidance of weight gain is protective against PCOS [29, 30]. Valproate has beneficial effects on serum lipids [16,31–33], lowering low-density lipoprotein, triglycerides and total cholesterol and countering increases associated with atypical antipsychotic drugs [25].

Dosing of valproate benefits from serum level determinations. In mania, two studies found higher response rates with serum levels above 45 μg mL⁻¹ [5, 34]; and maintenance studies indicate that patients with serum levels between 75 and 99 μg mL⁻¹ provided significantly better outcomes than either lower or higher levels, and were superior to lithium at any serum level range [35]. A subsequent study indicates that enhanced protection against relapse occurs with higher serum levels, but that tolerability worsens with such levels (Allen, M et al. American Journal of Psychiatry, in press). For those patients whose dosing and serum levels can be maintained in the 1000 mg and below 50 μg mL⁻¹ range, adverse effects have been equivalent to those reported with placebo [36].

Valproate has mechanisms distinct from any other anticonvulsant, but has some overlapping effects with lithium. Valproate inhibits histone deacetylase, distinguishing it from lithium, lamotrigine and carbamazepine, and impacting systems associated with manic type behaviours [37]. Valproate activates extra cellular signalregulated kinase (ERK) [38, 39] with evidence that inhibition of ERK causes activation in mice similar to that observed with amphetamines [40]. Through this mechanism, valproate appears to increase expression of a protective B-cell lymphoma/leukaemia-2 gene (bcl-2) [37, 41]. Valproate, which is a short branched chain fatty acid, is incorporated into neuronal membranes and appears to substitute for naturally occurring phospholipids [42].

Lamotrigine

Depression

Lamotrigine has been approved for maintenance treatment principally in the control of depressive symptomatology. Lamotrigine was first systematically studied in an open 6 month trial of patients in all phases of the illness. Although some evidence of efficacy occurred in manic patients, the overall benefit was directed toward depressive symptoms, both in rapid cycling and non-rapid cycling patients [43, 44]. Subsequently two-blinded, placebo-controlled trials indicated significantly greater antidepressant efficacy for lamotrigine over placebo in bipolar I depressed patients [45, 46]. A factor analysis of the Hamilton Depression Rating Scale indicated that the principle dimensions benefited were depressive cognitions and motor retardation (Mitchell P et al: personal communication 2006). The second of these two studies also found lamotrigine to be superior to gabapentin [46].

Maintenance

Two 18-month placebo-controlled randomized, double-blind studies have established that lamotrigine is effective in treatment of bipolar depression. The two had similar designs, with one enrolling currently or recently manic patients, the other enrolling recently depressed patients [47, 48]. The effect size for the superiority of lamotrigine was large in both studies, whereas lithium did not differentiate from placebo, even with a planned combined analysis of the two studies [49]. In the two studies lamotrigine was not superior to placebo in delaying time to intervention for mania; however, when the two were combined for analysis, the lamotrigine advantage over placebo was significant (p = 0.04).

As was the case for valproate, there was a positive relationship between control of manic and depressive symptoms with lamotrigine, indicating that when lamotrigine was effectively controlling depressive symptoms, manic symptoms were also likely to be controlled [47]. The magnitude of lamotrigine's benefit was greatest in initially manic patients, in part because the studies indicated, consistent with other evidence, that depression is highly likely to recur regardless of presenting episode type, whereas manic recurrence was largely limited to patients who had been enrolled while recently or currently manic [47]. Lamotrigine was somewhat less likely to be effective if depressive severity was initially greater in the open phase and if patients were experiencing a mixed manic episode [50]. Lamotrigine was also effective on some but not all measures in a 6-month study in rapid cycling patients. Whereas bipolar I patients did not differ significantly if treated with lamotrigine or placebo, bipolar II patients had significantly longer time to intervention for a new episode if treated with lamotrigine compared with placebo [51].

Lamotrigine was minimally associated with side effects. In some studies, headache has been more frequent than with placebo [45]. Rates of severe rash have been less than one per thousand patients treated in the blinded and open studies in bipolar disorder [52]. The hazard ratio for early discontinuation of lamotrigine versus lithium favoured lamotrigine [53].

Mania

Lamotrigine was ineffective in alleviating acutely manic symptoms in blinded, placebo-controlled trials, including ones where lithium was superior to placebo [54].

Lamotrigine appears to require doses in the 100– 400 mg day⁻¹ range for most patients. If patients are concurrently treated with valproate, as both drugs are metabolized by glucuronidation in the liver, doses of lamotrigine should be reduced. Current recommendations are that initial lamotrigine dosing be 25 mg qod for 2 weeks, with an increase to 25 mg daily for 2 weeks, then somewhat more rapid increases to a dose generally not above 200 mg day⁻¹ [55]. In the face of concurrent carbamazepine or oxcarbazepine use, initial dosing should commence with 50 mg day⁻¹, and steady state dosing be in the 200–600 mg day⁻¹ range [55]. Lamotrigine metabolism is also slowed by progesterone components of birth control pills. Therefore, caution should be observed in dosing lamotrigine when women are concurrently taking birth control pills. Dosage may need to be increased during the portion of the cycle that the woman is taking the contraceptives, but reduced during periods of treatment that are not associated with taking the medication. The half-life of lamotrigine is approximately 30 days, therefore once daily dosing is adequate for most patients.

Lamotrigine has been associated with reduction of weight in patients with initially high body mass index scores (<30), which differed significantly from weight changes at 1 year's treatment with placebo or lithium, both of which were associated with weight gain [56].

Lamotrigine appears to be well tolerated and compatible with concurrent lithium, valproate, antipsychotic and antidepressant drug use [57].

Lamotrigine has a unique mechanism of activity that involves use-dependent blocade of sodium channel activity [58]. Whereas a number of other anticonvulsants, including carbamazepine, have some sodium channel blockade, this is not associated with use dependency for drugs other than lamotrigine. The effects of lamotrigine result in some downstream effects on other intraneuronal systems, including inhibition of glutaminergic activity [59, 60].

Carbamazepine

Mania

Carbamazepine has been recently approved for treatment of mania in the US following completion of the first two randomized, parallel group, placebo-controlled studies of the drug. An extended release formulation was employed, which yields some improved tolerability. In the one study carbamazepine was significantly superior in efficacy at day 21, but not at earlier week 1 or 2 [61]. In the second study, carbamazepine was superior by an observed case analysis at weeks 1 through 3 [62]. In a small randomized, blinded comparison with valproate, both studies were efficacious, with earlier, broader efficacy associated with valproate, and more adverse effects associated with carbamazepine use [6].

Adverse effects associated with carbamazepine include diplopia, uncoordination, sedation, weight gain (less than with divalproex or lithium), benign rash in as many as 1/3 of patients, hypersensitivity syndrome including features of Stevens Johnson syndrome (0.1–0.5%), leucopenia 10–20%, and rarely aplastic anemia or agranulocytosis [63, 64]. Rates of neural tube defects are increased in the first trimester of pregnancy. Cholesterol levels are increased both acutely and over a 6-month period [62, 65].

Carbamazepine induces the 3A4 system of hepatic enzymes, thereby increasing rates of metabolism for a substantial number of drugs, including psychotropic drugs. In general carbamazepine should be avoided in combined regimens of drugs. If it is necessary to use carbamazepine in combination regimens, serum level determinations should be used to determine that dosage of drugs with which it is combined are adequate [66]. The congener oxcarbazepine has less induction effects on hepatic enzymes [67] and may be reasonably considered as an alternative to carbamazepine, but has not been systematically studied in bipolar disorder [68].

Carbamazepine has been studied in one large randomized, open maintenance trial, in comparison to lithium. On the primary outcome measures, lithium was generally superior to carbamazepine [69]. On several secondary analyses of subsets of patients, there were trends for superiority of carbamazepine among patients with atypical features and older patients [70].

Carbamazepine is generally dosed from 200 to 600 mg day⁻¹, in divided doses, with better tolerability for some side effects with extended release preparations. Although some suggestive evidence of an efficacious and relatively well-tolerated serum level range between 4 and 12 Ug mL⁻¹ has been reported, no adequate studies provide support for use of serum levels for other than adher-ence/toxicity purposes.

Carbamazepine shares the same molecular structure as tricyclic antidepressants, and therefore has some overlapping pharmacodynamic effects. Carbamazepine does affect sodium channels, but does not have most of the signal transducing effects recently established for lithium and valproate [71]. Carbamazepine does reduce cytosolic phospholipase A2, a property also observed with lithium, and thereby decreasing arachidonic acid turnover of brain phospholipids, a mechanism suggested as relevant to mood-stabilizing properties [72].

Other anticonvulsants studied in bipolar disorder

The following section briefly reviews the limited evidence for other anticonvulsants. In general these studies, and open trial use indicate limited if any benefits of all of the listed drugs. Two caveats are relevant. In some instances, a drug has been studied for only one aspect of bipolar disorder, for example, manic states. Therefore, it is possible that evidence regarding some other aspect of the illness, for example, depression, prophylactic efficacy, has simply not been developed. Second, some interest in the drugs is certainly driven by benefits that they have on ancillary symptomatology in bipolar disorders, for example, the antianxiety effects of gabapentin, and that adjunctive use for these purposes can be justified, despite their lacking of overall mood stabilizing properties.

Gabapentin

Two negative studies have been published. The first utilized a crossover design to study a mixed group of bipolar and unipolar patients in different illness states. For subsets of patients with predominantly manic and depressive symptoms, gabapentin was not superior to placebo, whereas lamotrigine was superior to both placebo and gabapentin [46]. A second multicentre study added gabapentin or placebo to an ongoing lithium regimen in patients who were symptomatically manic despite current lithium treatment. Gabapentin plus lithium was not superior to lithium alone in the 10-week randomized, blinded study [73]. Gabapentin has demonstrated antianxiety properties in patients with social phobia, therefore the frequent anxiety symptomatology observed both in depressed and manic/hypomanic bipolar patients may benefit from adjunctive gabapentin, although systematic studies on this point have not been published.

Tiagabine

A few negative open reports on tiagabine, some suggesting worsening of depression and sedative reports in bipolar patients, have been published [74, 75].

Levetiracetam

One small randomized add-on study of levitiracetam was conducted, but no results have been published. No other published studies suggest a role in bipolar disorder treatment.

Topiramate

Four blinded, randomized placebo-controlled studies of topiramate as monotherapy in acute mania have been completed, with the results currently in press [76]. In none of the studies was topiramate superior to placebo. Some of the studies included lithium as an active comparator, and lithium was superior to placebo and to lithium. In a recently completed 12-week, randomized, double-blind comparison of continued valproate or lithium plus placebo, versus valproate or lithium plus topiramate, there was no evidence of difference for the combination treatment versus valproate or lithium alone. The study required that patients have continued evidence of a manic episode despite at least 6 weeks' treatment with valproate or lithium. Therefore, the design enriched the sample for patients unlikely to have full benefit from either mood stabilizer. Doses of topiramate averaged 255 mg day⁻¹, and serum levels at the end of the study for both valproate (53 μg mL⁻¹) and lithium (0.8 mEq L⁻¹ were adequate [77]. Therefore, this study, coupled with the monotherapy trials, establish that topiramate does not have antimanic properties. Topiramate has shown efficacy in binge eating disorders [78] and as a treatment to facilitate alcoholism withdrawal programs [79]. These studies provide some indirect evidence that components of bipolar disorder with impulsive, or compulsive behaviours might be adjunctively benefited by topiramate.

Zonisamide

No published systematic study of zonisamide in bipolar disorder is available. Two characteristics of the drug have resulted in some use in bipolar disorders adjunctively, but do not provide evidence of antimanic or antidepressant properties. Zonisamide is associated with some sedative, sleep inducing properties at doses of 100–400 mg. Therefore, it has been employed in the frequently serious sleep disruption common in bipolar disorder. Also, zonisamide, similar to topiramate, is sometimes associated with appetite suppression and moderate weight loss. Given the frequency of obesity in bipolar patients, and the wide range of treatments (olanzapine, other antipsychotic drugs, lithium, valproate, carbamazepine, SSRIs) that are associated with weight gain, zonisamide and topiramate have had some adjunctive use in bipolar disorder for purposes of addressing weight gain.

Phenytoin

A small study is suggestive of a benefit for phenytoin in mania in bipolar disorder; however, no subsequent reports, even of case series, have provided reasons to expect substantial benefit from it in management of bipolar disorders [80].

Other drugs that modulate neuronal signal transduction

Given the evidence for some overlapping signal transducing properties of lithium and valproate, including on systems that are arguably relevant to manic symptomatology, it is reasonable that newly developed drugs, whether called anticonvulsants or not, that appear to have mechanisms on neuronal intracellular signalling and ion channel mediated actions should be considered in preclinical and clinical testing for their potential effects on aspects of bipolar symptomatology.

Footnotes

This paper was presented at the Joint CINP/ASPR meeting, held in Brisbane, December 2005.

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Anticonvulsants in Bipolar Disorder

Abstract

Keywords

Valproate

Studies and role in mania

Depression

Maintenance

Lamotrigine

Depression

Maintenance

Mania

Carbamazepine

Mania

Other anticonvulsants studied in bipolar disorder

Gabapentin

Tiagabine

Levetiracetam

Topiramate

Zonisamide

Phenytoin

Other drugs that modulate neuronal signal transduction

Footnotes

References