Journal of Mental Health,

April 2010; 19(2): 127–141

REVIEW

Anticonvulsants in bipolar disorder

HEINZ C. R. GRUNZE

School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UK

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Abstract
Anticonvulsant drugs are widely used in psychiatric indications. This includes alcohol and
benzodiazepine withdrawal symptoms, panic and anxiety disorders, dementia, schizophrenia, and to
some extent personality disorders. Besides pain syndromes, their main domain outside epilepsy,
however, is bipolar disorder. Carbamazepine, valproate, and lamotrigine are meanwhile recognized
mood stabilizers, but several other antiepileptic drugs have also been tried out with diverging or
inconclusive results. Understanding the mechanisms of action and identifying similarities between
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anticonvulsants effective in bipolar disorder may also enhance our understanding of the underlying
pathophysiology of the disorder.

Keywords: Psychosis, anticonvulsants, bipolar disorder, depression, mania

Introduction
Mood changes are a common symptom in epileptic patients, and some anticonvulsants
(ACs) seem to contribute to it. Whereas negative effects on mood and anxiety states
have been described quite frequently with the first generation of ACs, especially
bromium and later barbiturates, it was in the 1960s and early 1970s when first
observations were published describing the mood stabilizing effects of valpromide
(Lambert & Venaud, 1966), phenytoin (Turner, 1967) and carbamazepine (CBZ)
(Okuma, Kishimoto, Inoue, Matsumoto, & Ogura, 1973). Nowadays, the portfolio of
ACs with proven or, at least, assumed efficacy in treating mood-disordered patients is
quite respectable. This paper aims to give a condensed overview on their proposed
mechanism of action and the clinical effectiveness of different ACs in bipolar disorder
(BD). Although safety and tolerability are aspects of utmost importance, they will not
be dealt with in this article for the sake of comprehensiveness. However, it is strongly
recommended to the readers to educate themselves about the individual tolerability
and safety issues of ACs before applying them in routine practice. Recent reviews
(e.g., Singh, Muzina, & Calabrese, 2005) are a comprehensive source of information
for further reading.

Correspondence: Heinz C. R. Grunze, MD, Professor of Clinical Psychiatry, University of Newcastle, School of Neurology,
Neurobiology and Psychiatry, Leazes Wing, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
Tel: þ44 (0)191 28 25765. Fax: þ44 (0)191 222 6162. E-mail: Heinz.Grunze@ncl.ac.uk

ISSN 0963-8237 print/ISSN 1360-0567 online Ó Informa UK Ltd.

DOI: 10.3109/09638230903469186
 128 H. C. R. Grunze

Mechanism of action of ACs with respect to BD

Until the discovery of antipsychotics and lithium for the treatment of BD,
electroconvulsive therapy (ECT) was the only available, and still is the most effective
treatment not only for depression (Geddes, 2003), but also for mania (Mukherjee,
Sackeim, & Schnur, 1994). Although the decisive cellular mechanisms remain
speculative, it appears that with every application of ECT the seizure threshold increases.
Thus, ECT has, paradoxically, an anticonvulsive effect. Interestingly, manic patients also
show an increase of seizure threshold with fading manic symptomatology (Mukherjee,
1989). These observations may supply a first clinical rational for using ACs in the acute
treatment of mania.
But how may AC (and probably ECT) alter brain function? When considering the
cellular mode of action of AC, we may have to distinguish between three different levels:
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synaptic transmission, intracellular signalling and, finally, gene activation and structural
changes that increase vulnerability to relapse. Following this hierarchy, we will first
briefly touch on the impact of AC’s on the metabolism and the synaptic action of
biogenic amines.

Modulation of the action of biogenic amines by AC’s

GABA. In a genome-wide association analysis of BD, one of the most strongly associated
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polymorphisms was found within the gene encoding the GABA (A) receptor beta1 subunit,
GABRB1. In addition, also polymorphisms in the GABA A receptor subunits GABRA4,
GABRB3, GABRA5 and GABRR1 seem to be associated with BD (Craddock et al., 2010).
Although a recent magnetic resonance spectroscopy (MRS) study trying to show directly
altered GABA metabolism in Bipolar patients failed (Kaufman et al., 2009), alterations of
GABA transmission still appear to be a strong candidate for an underlying cause in BD.
Both CBZ and VPA exhibit agonistic effects on the GABAergic system. CBZ is a positive
modulator of the GABA A receptor increasing the GABA A receptor mediated chloride
current (Granger et al., 1995). VPA increases GABA release in different areas of the brain
(Emrich & Wolf, 1992). However, we also have to note that two potentially specific
GABAergic ACs, gabapentin and tiagabine, appear not as efficacious in BD. Another highly
specific GABAergic compound, vigabatrine, has even been suspected to induce affective
disorders and psychosis in epileptic patients (Sander, Hart, Trimble, & Shorvon, 1991) or
causing mania (Naumann, Supprian, Kornhuber, Lange, & Reiners, 1994). In addition,
vigabatrine seems to be unsuitable as routine treatment because of severe side effects
(retinotoxicity).

Excitatory amino acids. Inhibition of NMDA-receptor-mediated currents has been reported

for CBZ (Lampe & Bigalke, 1990) in animal studies. Chronic administration of both CBZ
and VPA reduces brain NMDA signalling via arachidonic acid (Basselin, Villacreses, Chen,
Bell, & Rapoport, 2007; Basselin, Chang, Chen, Bell, & Rapoport, 2008). LTG inhibits the
release of glutamate and aspartate. However, this appears rather to be an effect mediated by
the blockade of sodium channels then a direct effect on synthesis and release of excitatory
amino acids (Choi & Morrell, 2003). Sodium channel blockade may, in fact, have a
protective effect against NMDA-hypofunction-mediated cytotoxicity, and several ACs with
mood stabilizing properties (CBZ, VPA, LTG, phenytoin) share this mechanism (Farber,
Jiang, Heinkel, & Nemmers, 2002). It is still unclear what the contribution of action directed
 Anticonvulsants in bipolar disorder 129

against excitatory amino acids to antiepileptic potencies of these drugs is, and, even more
speculative, to efficacy in BD.

Dopamine. Catecholamines have been implied in the pathophysiology of affective disorders

for more than three decades (Buki & Goodnick, 1998), either alone or in the context of a
noradrenergic-cholinergic dysbalance theory. Genetic findings imply a role of the dopamine
D4 receptor gene (Manki et al. 1996), the dopamine transporter gene (Waldman, Robinson,
& Feigon, 1997) and the gene encoding for DARPP 32, a dopamine and cyclo-AMP
regulated phosphoprotein (Ogden et al., 2004). A dopamine hypothesis of mania has been
proposed some time ago (Diehl & Gershon, 1992) and, as a matter of fact, mainly
dopaminergic acting antipsychotics as haloperidol are still a primary choice when treating
acute mania.
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Whereas ACs seem to do little on norepinephrine turn-over (with the possible exception
of lamotrigine (LTG) (Kaster, Raupp, Binfare, Andreatini, & Rodrigues, 2007)), VPA
exerts reasonable modulatory effects on dopaminergic transmission.
VPA increases the CNS dopamine turnover in animal models (Löscher & Hoenack,
1996), an effect not seen for CBZ (Sokomba et al., 1988). However, a direct effect of VPA
on D2 receptor blockade in mania, similar as for antipsychotics, could not be verified
(Yatham et al., 2002).
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Serotonin. Although the receptor pharmacology of serotonin is probably even more complex
than the one of dopamine, there is great enthusiasm to attribute serotonin a decisive role in
BD. Serotonergic hypofunction has been implied as an underlying disturbance in mania
(Maes et al., 1997). The AA genotype of the tryptophan hydroxylase, the rate limiting
enzyme of serotonin synthesis, seems to be correlated with an enhanced risk of developing
BD (Chen et al., 2008). Lithium and most modern atypical antipsychotics used in BD work,
at least in part, by modulating serotonergic transmission. An increase of extracellular
serotonin has been observed with VPA (Whitton et al., 1985) and CBZ treatment in animal
models (Dailey et al., 1997), and in vitro for LTG (Southam et al., 1997; Wegerer,
Hesslinger, Berger, & Walden, 1997). However, it is clearly difficult to estimate the
contribution of serotonin modulation to their beneficial effects, as none of the ACs are
specific for the serotonergic system.

Effects of ACs on intracellular messaging systems

Activation of receptors of biogenic amines initializes a cascade of intracellular signalling
that finally leads to the expression of early genes. ACs may, however, interfere with this
cascade on different levels of the signalling pathways, either from inside of the cell or by
blocking transmembraneous ion fluxes. Modulation of sodium currents have already
been mentioned as a mechanism that may protect against NMDA hypofunction-
mediated neurotoxicity (Farber et al., 2002). In addition, a deranged intracellular
calcium homeostasis may be a common feature in BD (Dubovsky & Franks, 1983). It
should be noted that some authors also suggest a special sensitivity of the Na, K ATPase
in bipolar patients towards calmodulin and calcium (Kassir & Meltzer, 1991) which
would enhance hyperactivating effects by an increased intracellular calcium release.
Finally, excessive intracellular calcium may cause neuronal loss by activating calcium
dependent proteases and phospholipase A.
 130 H. C. R. Grunze

Potentially beneficial effects of ACs through interference with intracellular calcium

signalling have been reported for various pathways. A decreased Na, K ATPase activity has
been described as a state marker in acutely ill bipolar patients as it is not seen in healthy
relatives (Antia, Smith, Wood, & Aronson, 1995). Besides lithium, also CBZ is capable to
stimulate the Na, K ATPase causing a reduction of intracellular calcium (Wood, Elphick, &
Grahame-Smith, 1989). Similar to lithium, CBZ and VPA also reduce the activity of protein
kinase A and C by reducing cAMP dependent protein phosphorylation. This reduces, in
turn, also the gene expression of proteins responsible for neurotransmission (Jensen &
Mork, 1997). Especially protein kinase C (PKC) inhibition might be a crucial antimanic
mechanism of action, and the PKC inhibitor tamoxifen has also proven antimanic efficacy in
clinical trials (Yildiz, Guleryuz, Ankerst, Ongur, & Renshaw, 2008).
However, ACs may also affect voltage dependent calcium channels directly. This has been
demonstrated in vitro for CBZ (Walden, Altrup, Reith, & Speckmann, 1993), VPA
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(Macdonald & Kelly, 1995) and LTG (Wegerer et al., 1997). In addition, another action on
ion channels by CBZ, VPA and LTG, potentially important for the suppression of seizures,
include the facilitation of an early transient potassium outward current (Grunze, Greene,
Möller, Meyer, & Walden, 1998; Olpe, Kolb, Hausdorf, & Haas, 1991; Walden et al.,
1993). It is, at this moment, purely speculative whether this action contributes also to mood
stability.

Effects of ACs on cellular resilience

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During the last decade, it has been demonstrated that not only lithium, but also VPA and, in
part, CBZ regulate numerous factors enhancing cellular plasticity and resilience, including
inositol biosynthesis (MIP synthase), cyclic adenine monophosphate (c-AMP) response
element- binding protein, brain- derived neuotrophic factor (BDNF), the extracellular
signal-regulated kinase pathway, the arachidonic acid pathway, the cytoprotektive protein
bcl-2 and mitogen-activated protein kinases (Bachmann et al., 2005; Chen & Manji, 2006;
Chen, Huang, Zeng, & Manji, 2001; Chen et al., 2006; Rao, Bazinet, Rapoport, & Lee,
2007; Shaltiel et al., 2004; Williams, Cheng, Mudge, & Harwood, 2002).
The inositol phospholipid pathway might be more sensitive (and, by this, vulnerable) in
bipolar patients (Moscovich, Belmaker, Agam, & Livne, 1990). The impact of lithium on
cellular plasticity and resilience by targeting inositol monophosphatases (IMPases) and
myo-inositol uptake has been acknowledged for a while (Berridge & Irvine, 1989; van Calker
& Belmaker, 2000); it is more recently that we became aware of the inhibitory effects of VPA
and CBZ on inositol turnover (Lubrich & van Calker, 1999). VPA is also capable of
inhibiting the synthesis of inositol monophosphate (Vaden, Ding, Peterson, & Greenberg,
2001). This also means a downstream reduction of the activation rate of Ca2þ calmodulin
kinase II (CAM kinase II), a enzyme critically involved in long term synaptic changes
(Lisman, 1994) and of myristoylated alanine- rich C kinase substrate (MARCKS)
implicated in synaptic neurotransmission and cytoskeletal restructuring (Lenox & Watson,
1994), thus inhibiting structural changes of neurons in the course of the disease.
However, other mechanisms may be at least of equal importance for the mood-stabilizing
action of ACs. Glycogen synthase kinase -3 (GSK-3) is a serine/threonine kinase that
appears to be a major regulator of apoptosis, neuronal resilience and circadian rhythmicity.
It is deactivated by numerous signalling pathways, including protein kinase A and C. VPA,
and also some antidepressants, are capable of inhibiting GSK-3 (Chen, Huang, Jiang, &
Manji, 1999; Zarate, Jr., Singh, & Manji, 2006), either directly or by interfering with one of
the downstream mechanisms that normally would activate GSK-3. As GSK-3 may also play
 Anticonvulsants in bipolar disorder 131

a crucial role in Alzheimer’s disease, the development of GSK-3 inhibitors is currently a

major effort in pharmaceutical companies.
Another more recently discovered effect of VPA is its action on the chaperones GRP 78,
GRP 94 and calreticulin. These endoplasmatic reticulum (ER) stress proteins bind calcium
and are protective against cell death. Chronic treatment with VPA increases the synthesis of
all three chaperones in rat C6 glioma cells, thus contributing to calcium homeostasis in the
ER (Wang, Bown, Chen, & Young, 2001).
A possible explanation for the delayed onset of action of several mood stabilizers (and
antidepressants) is that they affect gene regulation in critical neuronal circuits. VPA might
do so by acting as a histone deacetylase (HDAC) inhibitor (which may also, on the negative
side, cause teratogenicity when taken during early pregnancy). This inhibition of HDAC has
a multitude of downstream effects which, in summary, increase cellular plasticity and
resilience (for a detailed review, see Zarate, Jr. et al., 2006 or Bachmann, Schloesser, Gould,
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& Manji, 2005).

Effects of ACs on HPA axis activity

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis has been demon-
strated both in acutely ill and remitted bipolar patients (Watson, Gallagher, Ritchie, Ferrier,
& Young, 2004). Little is known about direct effects of VPA and CBZ on HPA axis
function. In the case of VPA, they may be rather unfavourable as they have been implied in
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polycystic ovary syndrome, although they may moderately decrease ACTH hypersecretion
(Kasperlik-Zaluska, Zgliczynski, Jeske, & Zdunowski, 2005). Inhibitory effects of LTG on
CRH release have been described in animals (Tringali, Aubry, Navarra, & Pozzoli, 2006)
and it has been speculated that this, together with inhibition of ACTH (Jezova, 2005), may
contribute to LTGs antidepressant and mood stabilizing effects.

Sensitization and kindling – behavioural models for the recurrent pattern of BD?
Several aspects of depressive symptomatology can be approached in behavioural animal
studies, i.e., learned helplessness paradigms or olfactory bulbectomized rats (Grunze,
Schüle, Casey, & Baghai, 2008; Harkin, Kelly, & Leonard, 2006). Some animal models do
also resemble aspects of mania, e.g., administration of D-amphetamine, and VPA appears
capable of preventing oxidative stress and DNA damage in this model (Andreazza et al.,
2008). However, it still appears difficult to explain specific characteristics of BD, such as
opposing mood deflections and increasing vulnerability over the course of illness, in a
conclusive model. Although still speculative in several aspects, sensitization and kindling as
described by Post and Weiss (1996) may be helpful in understanding BD, starting from a
molecular level and evolving towards behavioural changes.
Kraepelin (1921) noticed that a marked psychosocial stressor is likely to precede the first
affective episode, whereas subsequent episodes coincide only with minor or no notable life
events. Over time, the frequency of episodes tends to increase, in some patients finally to
autonomous rapid cycling, with decreasing efficacy of mood stabilizing drugs (Roy-Byrne,
Post, Uhde, Porcu, & Davis, 1985).
Post and co-workers (1981) developed a model of cocaine- induced behavioural
sensitization (CIBS). Cocaine administration causes hyperlocomotion in rats and
hypomanic-like symptoms in man. Repeated cocaine administration, however, may cause
a shift of symptomatology toward signs of dysphoric mania (which has a high incidence in
BD as shown by several studies (Goodwin & Jamison, 2007)) or even paranoid symptoms.
 132 H. C. R. Grunze

Lesion experiments in the amygdala show that CIBS involves different neuromodulatory
changes depending on the duration and frequency of cocaine administration. Thus, not only
the symptomatology can shift, but also the neuronal pathways involved, becoming
independent from a direct action on the amygdala. Furthermore, cocaine is also capable
to influence neuromodulators in a similar fashion as stress, i.e., an increase of CRF, ACTH,
cortisol, cytokines, catecholamines and indoleamines.
Relating these findings to intracellular, transcriptional processes, we note another
important analogy to stress sensitization. Both conditions, CIBS and repeated stress, lead
at the end of the intracellular signal transducing cascade to the expression of immediate early
genes (c-fos and zif-268) in the amygdala and related limbic structures as well as late effector
genes (LEG) (Smith, Makino, Kvetnansky, & Post, 1995). The composition of early genes
and their occupation of the AP 1 receptor are partially specific for different stressors, e.g.,
electroconvulsive seizures or cocaine, as well as for mode of application, i.e., acute, repetitive
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or chronic. This may give a molecular background for speculations why psychosocial
stressors may cause symptoms of depression more likely, whereas others, like acute pain, do
not. Whereas early immediate genes activation primarily induces expression of genes, such as
neurotransmitter transporter genes, and finally modulates the acute symptomatology,
induction of LEG’s as neurotropins and nerve growth factor (NGF) will modulate synaptic
connectivity and nerve end sprouting, thus giving rise to neuroanatomical changes.
Taken together, CIBS may be a useful model to study acute events and long term changes
in symptomatology caused by episodes of affective disorders. However, to explain the aspect
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of sequential unfolding of episodes with increasing autonomy from the stressor, the
amygdala kindled rat appears to be a suitable model. Kindling reflects a cumulative and
progressive unfolding of physiological and behavioural changes in response to repeated
stimulation over time which eventuates in seizures, first triggered and then occurring
spontaneously. Although epileptic seizures may have some mechanisms in common with
affective disorders (Gajwani et al., 2005), they are still two different conditions. But the
rough anatomical substrate is similar, as the amygdaloid complex plays a key role in both
disorders. Repeated electrical stimulation of the basolateral amygdala decreases the
threshold for epileptic seizures, finally often leading to spontaneous epileptic activity. The
correlate on the synaptic level is an increase of both NMDA and non- NMDA receptor
mediated glutamatergic transmission with a parallel decrease of inhibitory GABAergic
transmission (Rainnie et al., 1992). On the level of expression of early genes and
neuropeptides, an increase of c-fos and TRH mRNA has been observed (Rosen et al.,
1992). With full manifestation of seizures, these changes on the synaptic level and substrate
expression also involve the contralateral, non- stimulated amygdala complex. It is assumed
that, similar to electrical kindling, recurrent affective episodes cause analogous long- term
changes in neuronal networks, such as lowering the threshold for any consecutive episode.
This hypothesis is backed up by a clinical study of Goldberg and Harrow (Goldberg &
Harrow, 1994). Although having overall a comparable total number of previous episodes,
patients who had a pattern of close periodicity of episodes in the past showed an increased
relapse risk during follow up, interpreted as an indicator of a previous kindling process
(Goldberg, Garno, & Harrow, 2005).
Different ACs efficacious in BD do exert antikindling properties, e.g., CBZ, VPA and
LTG. However, they all may develop contingent tolerance leading to insufficient
suppression of seizures in the kindling model (Post & Weiss, 1996). On a clinical level,
this may correspond to tolerance or drug resistance observed with long- term treatment and/
or discontinuation of mood stabilizers as observed in some bipolar patients (Post & Weiss,
2004).
 Anticonvulsants in bipolar disorder 133

Clinical effectiveness of ACs in BD

Several ACs have been tested in BD over the last decades. Currently licensed in this
indication or at least used with good evidence are VPA, CBZ and LTG, but also phenytoin,
oxcarbazepine, levetiracetam, topiramate, zonisamide and gabapentin may be beneficial in
selected patients.

Carbamazepine
CBZ has been traditionally used in bipolar patients who were not sufficiently responding to
lithium. It has proven antimanic (Owen, 2006) and prophylactic efficacy (Smith et al.,
2007). Data on antidepressant efficacy of CBZ are much less robust and suggest, at its best,
a mild to moderate effect (Post et al., 1996).
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For mania, several comparator studies against lithium, VPA and first generation
antipsychotics have been conducted. The impression of these studies was that CBZ was
overall equally effective as comparators, with a probably slightly slower onset of response
compared to neuroleptics (Brown et al., 1989) and VPA (Vasudev et al., 2000), but slightly
faster acting than lithium (Small et al., 1996).
Comparing the prophylactic efficacy of CBZ against lithium, the two most recent studies
suggest superiority of lithium treatment (Greil et al., 1997; Hartong et al., 2003). However,
CBZ appeared to be the better alternative for atypical manifestations of BD, such as a rapid
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cycling course, frequent recurrences of dysphoric or psychotic mania or other comorbid

psychiatric or neurological conditions (Greil et al., 1998). In patients insufficiently
responsive to lithium, addition of CBZ can greatly enhance prophylactic efficacy as shown
in a large controlled study (Denicoff et al., 1997).

Valproate
This paper uses ‘‘valproate’’ (VPA) as the common generic name for the different
preparations tested in BD, e.g., valproic acid, sodium valproate, divalproate, divalproex
sodium, and valpromide. As far as pharmacokinetics and pharmacodynamics are concerned,
only valproic acid finally reaches and penetrates the blood-brain barrier. Although
tolerability is enhanced with extended release preparations these small differences do not
justify grouping valproic acid derivatives as different medications.
VPA is nowadays recommended as a first line treatment for acute mania (Grunze
et al., 2009). The antimanic activity of VPA was first reported by Lambert (Lambert &
Venaud, 1966). Superiority against placebo has consequently been shown in several
double-blind controlled monotherapy and add-on studies (Bowden et al., 1994; Bowden
et al., 2006; Müller-Oerlinghausen et al., 2000; Pope et al., 1991); however, it failed to
separate from placebo in only mild-to-moderate mania (Tohen et al., 2008). In
comparator trials, VPA showed equal efficacy as lithium (Bowden et al., 1994; Bowden
et al., 2008; Freeman et al., 1992), haloperidol (McElroy et al., 1996) and in one study
against olanzapine (Zajecka et al., 2002), but not in two others (Tohen et al., 2008;
Zajecka et al., 2002). Compared to lithium, VPA appears especially effective in
conditions less responsive to lithium such as mixed states (Swann et al., 1997). In
comparison to CBZ, VPA appeared overall to be more efficacious in mania (Vasudev
et al., 2000). For bipolar depression, two small placebo controlled study have been
published showing significant effects (Davis et al., 2005; Ghaemi et al., 2007), but
confirmative studies are still missing.
 134 H. C. R. Grunze

The only large scale randomized maintenance study comparing VPA against placebo and
lithium carried out so far could not proof efficacy either for VPA or lithium for the primary
outcome criterion (time to any mood episode). Looking for secondary outcome parameters,
however, clinically useful information was detected, e.g., VPA was significantly better than
placebo in preventing new depressive episodes. In addition, patients who were previously
responsive to VPA when treated for an acute episode also performed better when
randomized on VPA maintenance treatment compared to when randomized on lithium or
placebo. However, when reanalysing this study together with other, smaller studies a meta-
analysis was able to support prophylactic efficacy of VPA at least for depressive relapses
(Smith et al., 2007).

Lamotrigine
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Different from CBZ and VPA, LTG seems to exert its main strength in the prophylaxis
of bipolar depression. The two controlled acute mania studies with LTG were both
negative. Of the sponsored Phase III studies in acute bipolar depression, only one study
showed a positive result in a secondary outcome parameter (Calabrese et al., 1999),
whereas four further studies failed to separate from placebo. However, a recent add-on
study could prove the antidepressant efficacy of LTG in combination with lithium (Van
der Loos et al., 2007). In direct (but underpowered) comparison to other treatment
modalities of acute bipolar depression, LTG was equally as effective as citalopram
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(Schaffer et al., 2006), but less effective than tranylcypromine (Nolen et al., 2007). LTG
was also less effective than the olanzapine/fluoxetine combination in a comparator trial,
but appeared better tolerated and safer as far as the metabolic profile was concerned
(Brown et al., 2006).
The main area of application of LTG in BD is maintenance treatment. Two double-
blind, randomized maintenance trials over 18 months proved efficacy of LTG when
compared to placebo and lithium. Both LTG and lithium were superior to placebo.
Looking for differential rates of relapse, LTG was more effective in preventing new
depressive episodes, whereas lithium was better in preventing manic episodes (Goodwin
et al., 2004).

Other ACs
Several other ACs have been proposed as having efficacy in BD, but none of them has been
studied enough to allow the conclusion that efficacy and tolerability were within the same
range as the drugs previously reviewed in more detail. Additionally, for some, substantial
evidence of marginal or unsatisfactory tolerability exists, and/or evidence of lack of
difference from placebo in mania trials is conclusive.
Phenytoin has demonstrated antimanic and prophylactic properties, but no antidepressant
action in randomized, placebo controlled studies (Bersudsky, 2006; Mishory et al., 2000;
Mishory et al., 2003) This has been readily interpreted as potential proof for an involvement
of sodium channel dysregulation in manic states. However, other mechanisms such as the
anti-glucocorticoid mechanism appear also possible (Gallagher et al., 2006). The side effect
profile of phenytoin, especially cognitive side effects and cerebellar atrophy (De Marcos
et al., 2003), however, makes it a medication of subordinate choice in BD.
Evidence for the efficacy of oxcarbazepine in BD is not convincing; a recent review of
several small, underpowered or placebo-uncontrolled studies came to the conclusion that it
may be useful in treating manic symptoms (Popova et al., 2007), but conclusive evidence is
 Anticonvulsants in bipolar disorder 135

lacking. In addition, a randomized, controlled study in adolescent mania failed to separate

oxcarbazepine from placebo (Wagner et al., 2006); thus, the case for oxcarbazepine in acute
mania is rather weak. As far as bipolar depression and prophylactic treatment are concerned,
evidence from methodologically rigorous trials is also missing.
Due to the chemical resemblance with CBZ it is often assumed that it may be beneficial in
patients who previously responded well to CBZ but had to discontinue it for reasons of
tolerability or interaction with other medication. Oxcarbazepine may also exhibit both
interactions with other medications and tolerability issues, but to a lesser degree than CBZ
(Andreasen et al., 2007); however, the risk of hyponatremia appears to be greater with
oxcarbazepine.
Based on the GABA hypothesis of BD, expectations were quite high when gabapentin was
introduced. However, two add-on studies in acute mania failed (Pande et al., 2000; Frye
et al., 2000). For bipolar depression, open augmentation studies suggest some efficacy in the
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absence of controlled data (Wang et al., 2002; Altshuler et al., 1999). As far as long term
treatment is concerned, a recent controlled maintenance study suggests that maintenance
treatment with gabapentin can be beneficial in some patients (Vieta et al., 2006), but larger
replication studies are needed.
For levetiracetam, positive open studies in acute mania (Goldberg & Burdick, 2002;
Grunze et al., 2003; Kyomen, 2006; Kruger et al., 2008) have been reported, but controlled
evidence is again missing. More recently, a 31% remission rate was reported in patients with
BD who were in the depressed phase at baseline and who received levetiracetam as add-on
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therapy for 8 weeks in an open-label trial (Muralidharan & Bhagwagar, 2006).

Other modern antiepileptic drugs, such as tiagabine, retigabine and pregabalin, appear
not to be promising in BD (Amann et al., 2006; Carta et al., 2002; Grunze et al., 1999;
Suppes et al., 2002; Young et al., 2006a; Young et al., 2006b). Topiramate first appeared
to be a promising candidate in pilot studies, however, five double-blind, randomized
studies could not prove efficacy in acute mania (Kushner et al., 2006; Roy Chengappa
et al., 2006). A single-blind comparator study against bupropion suggests some efficacy
of topiramate in bipolar depression (McIntyre et al., 2002). Nevertheless, due to their
weight reducing effect topiramate as well as zonisamide, which showed distinct antimanic
and antidepressant properties in open trials (Anand et al., 2005; Ghaemi et al., 2006;
Kanba et al., 1994; McElroy et al., 2005; Wilson & Findling, 2007) may still be options
as add-on treatments in patients who massively gain weight with established mood
stabilizers.

Conclusions
CBZ, VPA and LTG are nowadays established treatment options in BD. They greatly
enrich our treatment portfolio, especially in mania and maintenance treatment. CBZ, VPA
and LTG share some mechanisms of action with each other, but also with lithium. However,
up to the present time it remains unclear which of their multiple site actions is more and
which one less decisive for efficacy in BD. It appears likely that these ACs will not be the last
that will enter the field of BD. There is a multitude of new ACs currently in the pipeline, but
at the moment it is unclear which of these will also be tested in BD; seletracetam which
inhibits intracellular calcium release, losigamone with activity on GABA-A receptor linked
chloride channels, ganaxolone as agonist at GABA-A receptor sites, or lacosamide, being
both a sodium channel blocker and binding intracellularly to collapsin response mediator
protein-2 (CRMP-2) might develop as further substances with potential value in the
treatment of BD.
 136 H. C. R. Grunze

Acknowledgement
Heinz Grunze received grants/research support, consulting fees and honoraria within the last
3 years from Astra Zeneca, Bial, BMS, Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen-
Cilag, Organon, Pfizer Inc, Sanofi-Aventis, Servier, UBC and UCB Belgium.

Declaration of interest: The author reports no conflict of interest. The author alone is
responsible for the content and writing of the paper.

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