The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders

ARTICLE IN PRESS

Neuroscience and Biobehavioral Reviews 31 (2007) 963–975 www.elsevier.com/locate/neubiorev

Review

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders Michel Bourina,, Corina Pricaa,b a

EA 3256 Neurobiologie de l’anxie´te´ et de la de´pression, Faculte´ de Me´decine 1, rue Gaston Veil BP 53508, 44035 Nantes cedex 01, France b Department of Animal Physiology and Biophysics, Faculty of Biology, 91-95, Splaiul Independentei, Bucarest 050095, Romania

Abstract It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action. r 2007 Elsevier Ltd. All rights reserved. Keywords: Mood stabilisers; Bipolar depression; Lamotrigine; Carbamazepine; Valproate; Lithium; Forced swimming test; Animal model

Contents 1. 2.

3.

4.

5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Pre-clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Pre-clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sodium valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Pre-clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Pre-clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

964 964 964 965 966 966 967 967 967 968 969 969 970 971 971

Abbreviations: 5-HT, 5-hydroxytryptamine; NA, noradrenalin; DA, dopamine; GABA, gamma-aminobutyric acid; HRSD, Hamilton rating scale for depression; MADRS, Montgomery–Asberg depression rating scale; CGIS, clinical global impression scale for severity; LOCF, last observation-carriedforward; TCAs, tricyclic drugs; NMDA, N-methyl-D-aspartate; MAOs, monoamine oxidase; MAOI-A, monoamine oxidise inhibitors A; MAOI-B, monoamine oxidise inhibitors B; FST, forced swimming test Corresponding author. Tel.: +33 240412853; fax:+33 240412856. E-mail address: [email protected] (M. Bourin). 0149-7634/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2007.03.001

ARTICLE IN PRESS 964

M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

1. Introduction Management of bipolar disorder has historically focused on the treatment of acute mania, while the treatment of bipolar depression has remained relatively neglected. However, increasing recognition of the importance of bipolar depression (Judd et al., 2002, 2003) has led to greater interest in therapeutic strategies that address both poles of the illness. Currently, there are no mood stabilisers available that have equal efficiency in both mania and bipolar depression; therefore, new nomenclature has been proposed to better describe the actions of the current therapies for bipolar disorder (Ketter and Calabrese, 2002). In this new nomenclature, bipolar disorder is viewed as an aberration of mood, behaviour and cognition from baseline (euthymia), in which mania, mixed states, hypomania and subsyndromal mood elevation are ‘above baseline’ and depression and subsyndromal depression are ‘below baseline.’ Thus, mood stabilisers can be divided into two categories: mania mood stabilisers (class A) and depression mood stabilisers (class B) (Ketter and Calabrese, 2002). Mania mood stabilisers are defined as agents that stabilise mood from ‘above baseline’ without worsening depression, while depression mood stabilisers are defined as agents that stabilise mood from ‘below baseline’ without inducing switches into mania or episode acceleration. The lifetime prevalence of bipolar disorder ranges from 3% to 6.5%, depending on the specific diagnostic definition of bipolar used (Hirschfeld et al., 2002a; Akiskal et al., 2000; Lewinsohn et al., 1995; Weissman et al., 1996). As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania (Judd et al., 2002, 2003). Although, perhaps, less overtly disruptive than the manic phase of the illness, bipolar depression is a significant cause of psychiatric morbidity and mortality, and thus a major public health concern. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity (Boerlin et al., 1998; Peet, 1994). Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. Search and debate for the ideal mood stabiliser continues. Treatment goals for bipolar disorder are to stabilise the patient’s mood while not precipitating or relapsing into a depressive or manic state. The ideal mood stabiliser for bipolar disorder effectively treats the acute mood symptoms (both mania and depression) without exacerbating them and serves in maintenance treatment as prophylaxis for manic, mixed or depressive episode. Currently, a single agent as monotherapy dose not exists, that meets this definition of an ‘‘ideal mood stabiliser.’’ The aim of this review it to collate data involving the effects of lithium, carbamazepine, valproate and lamotri-

gine in depressive aspects of bipolar disorder but as well using an animal model of depression, to understand their mechanism of action. 2. Lithium 2.1. Clinical features Lithium was proposed to act in a bimodal way, operating as stabiliser of the signalling processes fluctuations, by balancing positive and negative regulators, setting the signals within an optimal range and preventing fluctuation either above or below the best (Jope, 1999b). A large number of mechanisms related to inter-neuronal signalling have been proposed, involving different levels in neurotransmission (El-Mallakh, 1996; Manji et al., 1999b). Several pathways have been investigated, particularly serotonin and dopamine system. Serotonin (5-HT) neurotransmission was hypothesised to be involved, suggesting that lithium efficacy may be due to its enhancing of lithium on 5-HT may be presynaptic, with many secondary postsynaptic effects (El-Mallakh, 1996). Lithium administrations has shown to significantly increase the levels of cerebrospinal fluid (CFS) 5–hydroxindoleacetic acid (5-HIAA), which reflects serotonergic activity (Berrettini et al., 1985; Bowers and Heninger, 1977; Bunney and Garland-Bunney, 1987; Cowen et al., 1990; Fyro et al., 1975; Meltzer and Lowy, 1987; Mendels, 1971; Price et al., 1989, 1990; Swann et al., 1987; Wilk et al., 1972; Wood and Goodwin, 1987). Chronic lithium administration seems to enhance electro-physiological and behavioural responses mediated by post-synaptic serotonin 1A (5-HT1A) receptors (Goodwin, 1989), and it is associated to significant reduction of 5-HT1 binding sites in the hippocampus (Massot et al., 1999; Odagaki et al., 1990). Moreover, it increases the number of 5-HT transporter proteins in some cortical regions (Carli et al., 1997a; Carli and Reader, 1997). Clinical and preclinical studies have shown that the effect of lithium on serotonin (5-HT) function may occur at multilevel such as serotonin synthesis, variation on serotonin turnover and lithium has been involved in the appearance of the 5-HT syndrome (Chenu and Bourin, 2006). Lithium activity may be also mediated by dopamine receptors. In fact, lithium is affective in controlling dopamine stimulants related behaviours (Acquas and Fibiger, 1996; Barnes et al., 1986; Carli et al., 1997b; Dziedzicka-Wasyleweska et al., 1996; Goodwin and Jamison, 1990; Gottberg et al., 1988, 1989; Post and Weiss, 1995; Richelson, 1995). It should be noted that these two neurotransmitter pathways could interact: the serotonergic projections inhibit the firing of the substantia nigra dopamine cells, thus influencing dopamine function in the midbrain, while in the striatum and in the cortex they inhibit synaptic release and probably synthesis of dopamine (Kapur and

ARTICLE IN PRESS M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

Remington, 1996). As a results of these effects, partly mediated by 5-HT, hetero-receptor (Ng et al., 1999), serotonergic agonist and serotonergic precursors enhance the inhibition of the dopamine system. Conversely, lesions of the raphe nuclei, and 5-HT1A agonist binding to autoreceptors, as well as 5-HT2 antagonist, disinhibit the dopamine system (Kapur and Remington, 1996). Serotonin may also act indirectly through its modulations of gammaamino-butyric acid (GABA) and cholinergic system (Dewey et al., 1993a; Gillet et al., 1985). There are few trials comparing lithium with placebo for the treatment of patients with bipolar depression and one of them were conducted more than 20 years ago. Goodwin et al. (1969) studied 12 inpatients with bipolar depression, six with previous manic episodes, and the others with previous hypomanic episodes. Some form of response was seen in 10 patients started on lithium after a placebo run-in but only five had a complete response and the others had a partial response. The dose of lithium carbonate used was 900–1800 mg per day, with serum levels of 0.8–1.3 mEq/l. Goodwin et al. (1972) reported a further cohort of 40 acutely depressed bipolar patients. The design again involved an initial placebo period of at least 6 days followed by lithium for at least 2 weeks. An unequivocal response was seen in 12 patients, an equivocal response in 20, while eight did not respond or worsened. Mendels (1976) reported a placebo-controlled study in a group of 13 moderately to severely depressed bipolar patients. All patients had a 1–2 week period on placebo followed by 3 weeks on lithium and finally a 1–3 week period on placebo. He reported an improvement in nine patients on lithium followed by a relapse in six on placebo substitution. This trial may be the best evidence we have for lithium’s efficacy since we have data on the post response interval. Given the inadequacy of the acute treatment data, the evidence from patients randomised to receive long-term lithium is of considerable interest. This is probably appropriate because episodes of depression in bipolar patients tend to be shorter than for unipolar patients and spontaneous recovery may be more likely. Maintenance of effect is anyway more important in a highly recurrent condition. It also justifies, the assumption that patients with bipolar depression will be at a reduced risk of switching to mania when treated with lithium. In summary, the evidence reviewed above suggests that lithium is only possibly superior to placebo in the treatment of bipolar depression, evidence of superiority to an active comparator or in the presence of another agent would be equally convincing and clinically reassuring. In fact, there appears to be weak, to suggest the superiority of one treatment over another alone or in combination for bipolar depression. 2.2. Pre-clinical features It was been previously shown that, combined with lithium, sub-active doses of antidepressants (tricyclic

965

antidepressants, 5-HT reuptake inhibitors, atypical antidepressants) produced significant anti-immobility effects in the mouse forced swimming test (Nixon et al., 1994; Bourin et al., 1996) and mouse tail suspension test (Redrobe and Bourin, 1997). Other studies, however, was shown that lithium failed to potentiate the effects of the specific and potent 5-HT1A receptor agonist, 8-OH-DPAT, in the mouse forced swimming test (Hascoe¨t et al., 1994). Chronic administration of tricyclic antidepressants in rats produces a sensitisation of postsynaptic serotonin receptors, apparently unrelated to presynaptic uptake mechanisms (de Montigny and Aghajanian, 1978). Grahame-Smith and Green (1974) showed that enhanced hyperactivity in rats treated with lithium was mediated by the enhanced efficacy of 5-HT neurons. Short-term lithium administration was been shown to enhance 5-HT neurotransmission through its presynaptic action on 5-HT terminals (Blier and de Montigny, 1985), but also to have a sensitising effect on a sub-set of postsynaptic 5-HT1A receptors (de Montigny and Blier, 1992). Redrobe and Bourin (1999), using the mouse forced swimming test, has tested the hypothesis of the action of lithium, on some 5-HT receptor subtypes. The mouse forced swimming test was performed after single administration of lithium. Sub-active doses of lithium were administered in association with sub-active doses of the following 5-HT1 receptor agonists or antagonists: 8-hydroxy-2(di-n-propilamino)-tetralin (8-OH-DPAT, (a standard 5-HT1A receptor selective agonist), pindolol (a presynaptic and postsynaptic 5HT1A/1B receptor antagonist), NAN-190 (a 5-HT1A receptor antagonist), RU 24969 (a 5-HT1A/1B receptor agonist). Results showed that lithium significantly potentiated the antiimmobility effects of RU 24969 (Po0.01) and anpirtoline (Po0.01). Pre-treatment with lithium did not induce any significant antidepressant-like effects when tested in combination with 8-OH-DPAT, NAN-190 or (7) pindolol. The results of the study suggest that lithium may be acting through 5-HT1B receptors. In mice, lithium reportedly has few effects of its own in the FST, although it may potentiate the antidepressant-like effects of 5HT reuptake inhibitors (Nixon et al., 1994; Bourin et al., 1996) and 5HT1B receptor agonists (Redrobe and Bourin, 1999). In rats, lithium has no reported effects in the FST (Hata et al., 1995; Overstreet et al., 1995; Kitamura et al., 2002; Wegener et al., 2003). Tomasiewicz et al. (2006), designed a study, to identify the dose ranges in which short-term (acute and sub-acute) administration of lithium causes behavioural effects in rats, thereby providing a point of comparison for future studies of long-term treatment. Results: In the FST, lithium had effects opposite to those typically seen with antidepressant drugs, suggesting prodepressant-like effects (Mague et al., 2003; Carlezon et al., 2006). Lithium affected immobility behaviour (F(4, 46) ¼

ARTICLE IN PRESS 966

M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

4.06, Po0.01), causing significant increases in the occurrences of immobility at 100 mg/kg (Po0.05). Lithium also affected swimming behaviour (F(4,46) ¼ 3.04, Po0.05), although post hoc analyses revealed that this effect was due to differences in the occurrences of swimming among lithium doses, rather than differences between vehicle and lithium at any dose. Lithium did not affect occurrences of climbing at any of the doses tested. The overt side effects caused by 300 mg/kg lithium make the lack of prodepressant-like effects in the FST at this dose difficult to interpret, and the drug dramatically changed the pattern of swimming behaviour: rather than using the rear feet to paddle in an alternating pattern, the rats often kicked with both rear feet simultaneously. In conclusion, lithium increased immobility behaviour in the FST, in rats, an effect opposite to that caused by standard antidepressant drugs and similar to that caused by treatments that cause depressive symptoms in humans, such as drug withdrawal (Cryan et al., 2003) and k-opioid agonists (Pfeiffer et al., 1986; Mague et al., 2003; Carlezon et al., 2006). 3. Carbamazepine 3.1. Clinical features Carbamazepine is chemically related to the tricyclic antidepressants. First introduced in 1963, it is widely used in the treatment of partial and generalised tonico-clonic seizures (Brodie and French, 2000). Carbamazepine has been reported to stabilise the inactive form of the Na+ channel in a voltage- frequency- and time-dependent fashion, and has a greater binding rate constant, but lower affinity, for the inactivated Na+ channel. Inhibition of glutamatergic neurotransmission has also been implicated in the mechanism of carbamazepine action. Recent evidence suggests that it inhibits the rise in intracellular free Ca2+ induced by NMDA and glycine in rat cerebellar granule cells (Hough et al., 1996) and blocks veratrine induced release of endogenous glutamate (Waldmeier et al., 1995). There is no evidence that carbamazepine directly interacts with Ca2+ channels or potentate the actions of GABA. However, effects on the serotonin (Dailey et al., 1997a, b) and adenosine (Marangos et al., 1983) systems have been reported. Whether these additional actions contribute to the anticonvulsant effects of the drug is unclear. Carbamazepine primarily used for the treatment of epilepsy, has been reported to alter neurotransmitter concentrations, metabolism, receptors and second messenger systems. Indeed, the drug affects a multiplicity of neurotransmitter systems implicated in the pathophysiology of mood disorders. The primary neurotransmitters thus far shown to be altered by carbamazepine include serotonin (5-hydroxytryptamine, 5-HT), noradrenaline (NA), dopamine (DA) and gamma-aminobutyric acid (GABA) (Mac Donald et al., 1989).

Like lithium, carbamazepine’s role in the treatment of acute bipolar depression is less well delineated than its role in mania and in long-term prophylaxis of both phases. A number of open, partially controlled and double-blind studies suggest the efficacy of carbamazepine in acute depression. These data are not entirely unexpected given carbamazepine’s chemical structure, which bears some similarities to that of the tricyclic antidepressant imipramine. However, a variety of the mechanisms of action of carbamazepine are different from or opposite to those of the classic tricyclic antidepressants, perhaps accounting for its better efficacy as an antimanic than these agents and, potentially, a different spectrum of antidepressant effects as well. The double-blind study of Post et al. (1986) reported substantial antidepressant effects of carbamazepine in approximately one-third of a cohort of highly treatment refractory affectively ill patients. A variety of reasons suggested that this was not likely to be a placebo effect, including the long period on placebo prior to beginning active treatment and the previous failure to respond to numerous antidepressant agents. Nonetheless, the data were still subject to the interpretation that this was a natural course of illness event or that it was related to an increased duration of hospitalisation in a therapeutically active clinical research unit. Ketter et al. (1999) also have observed that all of the carbamazepine responsive patients were derived from the subgroup with a baseline positron emission tomography (PET) scan showing relative frontal and paralimbic hypermetabolism, a pattern of increased neural activity in association with depression that is different from the more traditional pattern of frontal hypometabolism. The relationships were particularly strong in the left insula region where higher levels of baseline activity were positively correlated with the degree of carbamazepine response. Interestingly, the inverse was the case for the dihydropyridine calcium channel blocker nimodipine where lower levels in the left insula at baseline were correlated with better treatment outcomes. Most of the data on the efficacy of carbamazepine in long-term prophylaxis have been gathered in comparative studies with lithium sequentially, in crossover trials, or in parallel group designs. In the majority of these studies in which efficacy is separated by phase of illness, the prevention rate of depressive episodes was as strong as that for carbamazepine’s prevention rate of manic episodes. In several studies, the efficacy of carbamazepine monotherapy in the prevention of mania was significantly less than that of lithium monotherapy. However, in the study of Greil and Kleindienst (1999) this trend was reversed for patients with non-classical presentations such as schizoaffective illness, comorbid substance abuse, and bipolar II presentations where in carbamazepine was more effective than lithium. The preferential effect of carbamazepine over lithium in patients with schizoaffective depression was particularly prominent. Several studies

ARTICLE IN PRESS M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

have suggested that carbamazepine is helpful in those with depressions presenting with a concomitant history of alcohol abuse, findings that are not unexpected in relationship to carbamazepine’s ability to block alcohol withdrawal syndromes in clinical and laboratory studies. In summary, it would appear that carbamazepine seems to share lithium’s general overall clinical profile of efficacy with better response in acute mania than in acute depression, but roughly equal efficacy in the prevention of both manic and depressive episodes. Yet, at the same time, carbamazepine appears to be useful in some of the atypical syndromes of bipolar illness that are less than adequately responsive to lithium. With regard to rapidly cycling patients, both lithium and carbamazepine appear to be less effective in rapid cycling patients compared with non-rapid cycling patients. The study of Denicoff et al. (1997) showing 50% response in rapid cycles to the combination of lithium and carbamazepine, and under 25% response to either agent in monotherapy, suggests the possible utility of using the combination of these two mood stabilisers from the outset in patients presenting with recurrent bipolar depression of the rapid-cycling variety. 3.2. Pre-clinical features Carbamazepine, primarily used for the treatment of epilepsy, has been reported to alter neurotransmitter concentrations, metabolism, receptors and second messenger systems. Indeed, the drug affects a multiplicity of neurotransmitter systems implicated in the pathophysiology of mood disorders. The primary neurotransmitters thus far shown to be altered by carbamazepine include serotonin (5-HT), NA, DA and GABA (Mac Donald et al., 1989). Redrobe and Bourin (1999), using the mouse forced swimming test, test the hypothesis of the action of carbamazepine, on some 5-HT receptor subtypes. Sub active doses of carbamazepine were administered in association with sub active doses of the following 5-HT1 receptor agonists or antagonists: 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT, a standard 5-HT1A receptor selective agonist), pindolol (a presynaptic and postsynaptic 5-HT1A/1B receptor antagonist), NAN-190 (a 5-HT1A receptor antagonist), RU 24969 (a 5-HT1A/1B receptor agonist). Results showed that pre-treatment with carbamazepine provoked anti-immobility effects when tested in combination with RU 24969 (Po0.01) and 8-OH-DPAT (Po0.01). In conclusion, the results of the study suggest that the action of carbamazepine involve 5-HT1A receptors in the mouse forced swimming test. However, considering the complexity of the actions of these compounds, it is possible that other neurotransmitter systems/receptors may be involved.

967

Based on the assumption that benzodiazepine withdrawal affects the stress response, Martijena et al. (1997) tested the influence of carbamazepine administration on behavioural strategies adopted by benzodiazepine withdrawn animals after exposure to either inescapable or escapable stressful situations. Results show the effect of carbamazepine on control rats and on those subjected to 96 h of diazepam withdrawal. Diazepam-withdrawn rats showed a reduction in the time spent immobile as compared with controls. This reduction was reversed by prior administration of carbamazepine. A two-way ANOVA based on the amount of time the animals remained motionless revealed a significant effect of the treatment (F(1, 46) ¼ 20.43, Po0.0000), a carbamazepine effect (F(1, 46) ¼ 30.67, Po0.0000), as well as a significant interaction between treatment and the carbamazepine effect (F(1, 46) ¼ 16.47, Po0.0002). Newman–Keuls post-hoc test revealed that the behaviour of the diazepam-withdrawn group without carbamazepine was significantly different from that of the other groups (Po0.01). No differences were noticed in the number of dives or in the time spent struggling. In support of earlier evidence (Martijena et al., 1996), when animals subjected to benzodiazepine withdrawal were later exposed to an uncontrollable stressful situation, such as the forced swim test, the time they remained immobile was shorter. As has been tentatively suggested, immobility in this behavioural test might be the result of an adaptive response to this particular adverse experience (Armario et al., 1991; Cancela et al., 1991). Consequently, it seems reasonable to assume that withdrawn animals are less capable of developing an adaptive response to stress. Interestingly, when carbamazepine was administered prior to the forced swim experience it normalised the reduced time spent in immobility shown by withdrawn animals; however, it failed to modify the swimming behaviour of control rats. In summary, it is evident from the present findings that carbamazepine may have potential properties to attenuate the behavioural and neurochemical disturbances in response to the stress associated with benzodiazepine withdrawal. 4. Sodium valproate 4.1. Clinical features Like carbamazepine, valproate has many effects, and the mechanisms underlying its mood-stabilizing actions are unknown. One of its actions is to reduce the turnover of dopamine, an effect thought to be beneficial in the pharmacotherapy of depression. However, there have yet been no controlled studies of valproate in the treatment of unipolar or bipolar major depression. Valproate has been reported to block voltage-dependent Na+ channels. It reduces sustained repetitive firing of mouse neurones in culture (McLean and Macdonald,

ARTICLE IN PRESS 968

M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

1986), inhibits Na+ channels in Xenopus leavis myelinated neurones (van Dongen et al., 1986), and reduces Na+ currents in neocortical neurones (Zona and Avoli, 1990). However, rat hippocampal slice studies suggest that, unlike carbamazepine, valproate has no effect on the recovery of Na+ channels from the inactivated state (Albus and Williamson, 1998). Valproate may also block T-type Ca2+ channels in a manner similar to that reported for ESM. Such an effect would explain its efficacy against generalised absence seizures. However, the reduction of T-type Ca2+ currents observed with valproate in rat primary afferent neurones is modest and requires relatively high drug concentrations (Kelly et al., 1990). In addition, valproate appears to have no effect on Ca2+ channel conductance in rat thalamic neurones (Coulter et al., 1989c). There is evidence to suggest that valproate elevates whole brain GABA levels and potentiates GABA responses, possibly by enhancing GAD activity and inhibiting GABA degradation (Lo¨scher, 1999). Anecdotal reports suggest that the drug also augments GABA release (Rowley et al., 1995) and blocks GABA uptake (Sills et al., 1996). The reproducibility of these effects has, however, been questioned (Rogawski and Porter, 1990). It is suggested that the GABAergic effects of valproate exhibit a degree of regional specificity within the brain and that inconsistent results reflect the resolution of individual studies (Lo¨scher, 1999). Single doses of valproate decrease brain levels of the excitatory amino acid aspartate, without influencing those of glutamate or GABA (Schechter et al., 1978). Decreases in aspartate concentration have been shown to correspond with the period of anticonvulsant activity in animal models (Chapman et al., 1983). The relative anticonvulsant potencies of a series of valproate analogues also correlates more closely with their ability to reduce brain aspartate levels than with their effects on GABA concentration (Chapman et al., 1984). It has been reported an open label treatment trial of valproate in unipolar major depressive disorder with positive results (Davis et al., 1996). Also, data from the double-blind study of treatment for acute mania in bipolar disorder, which compared valproate, lithium, and placebo (Bowden et al., 1994), suggests that those patient with pretreatment depressive symptoms responded preferentially to valproate compared to lithium or placebo (Swann et al., 1997). These promising results encouraged to perform a double-blind, randomised, placebo-controlled clinical trial to test the efficacy of valproate in the treatment of patients with bipolar depression. Petty and his colleagues (2005) have realized a placebocontrolled study and they obtained that the primary outcome data for the Hamilton Rating Scale for depression (HRSD) consisted of 8 weekly observations of 25 subjects receiving valproate (n ¼ 13) or placebo (n ¼ 12). Last observation was carried forward for all subjects randomised in an intent-to-treat analysis. A repeated measure

ANOVA was performed and the outcome variable percent change in HRSD and HRSA, with last observation carried forward. In this analysis, the mean percent change in HRSD for patients with bipolar depression treated with divalproex was 43.51 (S.E. ¼ 2.97), and the mean percent change in HRSD for patients treated with placebo was 27.00 (S.E. ¼ 3.16). This difference was significant at the p ¼ 0.0002 level. In a recent multisite study of valproate versus placebo for bipolar depression (types I, II, NOS; n ¼ 45), Sachs et al. (2001) found that a greater percentage of subjects treated with divalproex met response criteria compared with placebo (43% versus 27%, respectively; p ¼ 0.35) on the 26-item HRDS. Analysis of response to the depressed mood item of the HRDS improved significantly in the valproate-treated group compared to placebo at weeks 2,4, and 5 (all po0.05). In addition, the valproate-treated subjects had a greater numerical mean change from baseline compared to the placebo group (p ¼ NS) in the 26-item HRDS, reaching a statistical trend at weeks 2 and 5 (p ¼ 0.051 and 0.052), respectively; using LOCF two-way ANOVA with factors for treatment and investigator). In summary, valproate seems to be less effective in the treatment of bipolar depression comparatively with the other mood stabilisers. 4.2. Pre-clinical features Redrobe and Bourin (1999), using the mouse forced swimming test, test the hypothesis of the action of valproate on some 5-HT receptor subtypes. Sub-active doses of valproate were administered in association with sub-active doses of the following 5-HT1 receptor agonists or antagonists: 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT, a standard 5-HT1A receptor selective agonist), pindolol (a presynaptic and postsynaptic 5-HT1A/1B receptor antagonist), NAN-190 (a 5-HT1A receptor antagonist), RU 24969 (a 5-HT1A/1B receptor agonist). Results showed that administration of sodium valproate enhanced the antidepressant-like effects of (7) pindolol (Po0.01), 8-OH-DPAT (Po0.01) and RU 24969 (Po0.01). In conclusion, the results of the present study suggest sodium valproate seems to involve 5-HT1A receptors in the mouse forced swimming test. However, considering the complexity of the actions of these compounds, it is possible that other neurotransmitter systems/receptors may be involved. In mice, valproic acid also has no effects of its own in the FST in mice (Szymczyk and Zebrowska-Lupina, 2000), although it may potentiate the antidepressant-like effects of selective 5HT1A receptor ligands (Redrobe and Bourin, 1999). In rats, valproic acid reportedly decreases immobility (Rostock et al., 1989), an antidepressant-like effect. Tomasiewicz et al. (2006) designed a study, to identify the dose ranges in which short-term (acute and sub-acute) administration of valproic acid causes behavioural effects

ARTICLE IN PRESS M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

in rats, thereby providing a point of comparison for future studies of long-term treatment. He tested sodium valproate in an assay sensitive to antidepressant-like effects (forced swimming test). In conclusion, sodium valproate had no significant effect in the FST: it did not alter occurrences of immobility, swimming, or climbing behaviour in the FST at any of the doses tested. These data suggest that, at least in rats, sodium valproate has no prodepressant-like effects. 5. Lamotrigine 5.1. Clinical features Lamotrigine has been proposed as the prototype class B mood stabiliser, representing a welcome addition to the therapeutic armamentarium for bipolar disorder (Herman, 2004). Lamotrigine is an anticonvulsant drug with a broad spectrum of activity (Goa et al., 1993). In common with a number of other anticonvulsants, including sodium valproate and carbamazepine , lamotrigine exhibits moodstabilising properties and has, therefore, become a useful treatment for bipolar disorder (Bowden, 1998; Post et al., 1998). In recent years, clinical evidence indicates that lamotrigine is also effective against the depressive phase of bipolar illness (Bowden et al., 1999a, b; Calabrese et al., 1999a, b; Kotler and Matar, 1998; Suppes et al., 1999) and the difficult to treat rapid cycling form of the disorder (Bowden et al., 1999a; Calabrese et al., 2000, 2001b; Suppes et al., 1999; Walden et al., 2000) with a low potential for inducing the switch to mania thus minimising the risk of accelerated cycling that is often associated with the use of conventional antidepressants (Calabrese et al., 1999c, 2001b). Lamotrigine is a comparatively novel antiepileptic agent (Btaiche and Woster, 1995; Bazil, 2002) whose mechanism of action is considered to be a reduction in glutamate release resulting from an inhibitory effect on type IIA sodium channels (Xie et al., 2001; Remy et al., 2003) and consequent neurotransmitter exocytosis (Lees and Leach, 1993). However, the mechanism of antidepressant action of lamotrigine is still unclear. Although the blockade of neuronal voltage-dependent sodium channels elicited by lamotrigine has an important role in its anticonvulsant effect and it shares a common action with other mood stabilizing anticonvulsant drugs (e.g. sodium valproate and carbamazepine), the antiglutamatergic effect of lamotrigine has been implicated in its mood effect (Ketter et al., 2003). In addition to these effects, lamotrigine also blocks neuronal voltage-dependent calcium channels (Ketter et al., 2003). Moreover, the reduction of glutamate release induced by lamotrigine may be related to the blockade of neuronal voltage-dependent sodium and calcium channels (Ketter et al., 2003). Reduced glutamatergic neurotransmission has been related to antidepressant effect. For

969

example, functional antagonists of the N-methyl-D-aspartate (NMDA) complex (e.g. competitive and non-competitive receptor antagonists, and glycine partial agonists) exhibit an antidepressant-like effect in animal models of depression (Trullas and Skolnick, 1990; Mantovani et al., 1999; Petrie et al., 2000; Paul and Skolnick, 2003). Moreover, chronic, but not acute, treatment with several clinically effective antidepressants drugs (22 of 23 drugs tested) reduced the potency of glycine in inhibiting the [3H]-5, 7-dichlorkynurenic acid (5, 7-DCKA) binding to strychnine-insensitive glycine site (Paul et al., 1994). Clinical studies have also suggested a glutamate participation in depression. In an open-label study, riluzole, a glutamate-modulating agent, decreased the severity of depression in treatment-resistant patients (Zarate et al., 2004). Ketamine, a NMDA antagonist used in anaesthesia, administered intravenously in depressed patients, significantly reduced depressive symptoms within 3 days (Berman et al., 2000). On the other hand, lamotrigine appears to act as a nonspecific monoamine (serotonin, noradrenalin and dopamine) reuptake inhibitor in vitro and it reverses the chloroamphetamine-induced 5-HT syndrome in rats, which suggests an inhibition of 5-HT reuptake in vivo (Southam et al., 1998). Lamotrigine is the first of a new class of antiepileptic agents indicated for the use of refractory partial seizures as an adjunctive treatment. During its development, it was observed that the drug improved mood, alertness and social interactions in some patients (Smith et al., 1993). Various hypotheses have been proposed regarding the mechanism of action on mood, including serotonin inhibition and dopamine potentiation, both of which may contribute to lamotrigine’s observed antidepressant effect (Meldrum, 1996). These early reports initiated further investigations into the use of lamotrigine as an antidepressant and mood stabiliser. The treatment of depression in patients with a bipolar disorder is especially challenging. Currently available mood stabilisers, anticonvulsants and lithium, have demonstrated efficacy during manic and hypomanic phases of bipolar illness, but appear to be less effective in the treatment of bipolar depression (Calabrese et al., 1995). Traditional antidepressants are frequently utilised for bipolar depression, but this may increase the risk of inducing mania, hypomania, or cycle acceleration in bipolar patients (Post et al., 1997). In the first controlled multicenter study conducted by Calabrese et al. (1999a), 195 outpatients with bipolar I disorder experiencing a major depressive episode were randomly assigned to treatment with lamotrigine 50 mg/ day, lamotrigine 200 mg/day or placebo for 7 weeks. Scales used in this study were the 17-item Hamilton Rating Scale for depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), the MRS, and the Clinical Global Impression Scale for Severity (CGIS). Observed

ARTICLE IN PRESS 970

M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

data at each time point was analysed as well as efficacy variables using last observation-carried-forward (LOCF) scores. The results of this study demonstrated antidepressant efficacy for the 200-mg dose of lamotrigine compared with placebo as early as week 3 on measures of HAMD, MADRS and CGI-S. The rate of response to lamotrigine 50 mg/day was significantly higher on the MADRS only. More than 50% of patients in the 200 mg/day lamotrigine group responded to treatment as measured by HAMD, MADRS, and CGI-I. When looking at the switch rates to mania, hypomania, or a mixed episode as an adverse effect, there was no significant difference between lamotrigine group and placebo. Other than a higher rate of headache in the lamotrigine-treated groups, adverse rates did not differ significantly from placebo. This study concluded that lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression, while potentially limiting the risk of precipitating mania or switching. Calabrese et al. (2001a) reported on the comparison of lamotrigine versus placebo and lithium in maintenance treatment of bipolar I disorder in a double-blinded study of 173 subjects over a 76-week period. At screening, patients were bipolar with active manic episode and stabilized during an open-label 8–16 week phase using lamotrigine 100–200 mg/day in addition to other concomitant psychotropics to achieve remission. Other concomitant psychotropics were then discontinued. Stable patients were then randomised into the doubleblind stage of the study into maintenance treatment with lamotrigine (100–400 mg), lithium, or placebo. Results from this study demonstrated that the time to intervention for a mood episode was increased for patients treated with lamotrigine or lithium, with no statistically significant difference between these two treatment groups. However, lamotrigine was not statistically superior to placebo in time to intervention for a manic episode during the 76 weeks of maintenance treatment as was lithium (Pp0.05). Lamotrigine was better for maintenance treatment in decreasing depressive episode recurrence than placebo (Pp0.05), while the time to intervention for a depressive episode for the lithium-treated group did not differ significantly from the placebo group. These results suggest that lamotrigine and lithium may both be beneficial in maintenance treatment of bipolar patients but with differential effects with regards to preventing either depressive or manic exacerbations. Combining these two agents may provide a greater, synergistic protective effect during maintenance phase treatment of bipolar disorder. The largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder conducted by Calabrese et al. (2000) indicated that lamotrigine monotherapy is a useful treatment for patients with this variant of bipolar disorder. A large percentage of these study patients exhibited poor response to lithium alone

(72–82%). This study was conducted in two phases beginning with an open label stabilisation phase, followed by a double-blind placebo-controlled randomised phase. After screening, patients with bipolar-rapid cycling who were either euthymic or experiencing a mood episode began a 6-week titration of lamotrigine to 200 mg/day. After stabilisation, the patients’ other psychotropic medications were tapered off and they were randomly assigned to lamotrigine or placebo monotherapy over 6 months. Double-blind medication dosage was flexible during the randomised phase, varying between 100 and 500 mg/day. Patients were stratified by diagnosis of bipolar II disorder or I. The primary outcome measure was time to additional pharmacotherapy for emerging mood episode. Survival in the study or time to any premature discontinuation was also analysed. The difference between the treatment groups in time to additional pharmacotherapy did not achieve statistical significance in the overall efficacy population. However, when survival was evaluated, the difference between the treatment groups was significant favouring lamotrigine (14 weeks in lamotrigine vs. 8 weeks in placebo). In the bipolar I subtype (N ¼ 125) there was no significant difference in survival analysis. This was unlike bipolar II subtype (N ¼ 52), where there was a significant difference for survival between lamotrigine and placebo group (P ¼ 0.015). The percentage of patients who completed the 6 months randomised phase and who were stable on monotherapy without relapse was significantly greater in the lamotrigine group (41% compared with placebo 26%, P ¼ 0.03). In summary lamotrigine seems to be the most effective mood stabilisers in the treatment of bipolar depression comparatively with other’s mood stabilisers. 5.2. Pre-clinical features Bourin et al. (2005), evaluate the antidepressant-like effect of lamotrigine in a mouse model of depression, namely the forced swimming test (FST). Combination studies using specific and non-specific ligands acting on serotonin (5-hydroxytryptamine; 5-HT1) receptor subtypes were undertaken to evaluate the potential role of these receptors in the anti-immobility effect of lamotrigine. The mouse FST was performed after single administration of lamotrigine. Sub-active doses of lamotrigine were administered in association with sub-active doses of the following 5-HT1 receptor agonists or antagonists: 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT, a standard 5-HT1A receptor selective agonist), pindolol (a presynaptic and postsynaptic 5-HT1A/1B receptor antagonist), NAN-190 (a 5-HT1A receptor antagonist),RU 24969 (a 5-HT1A/1B receptor agonist) and anpirtoline (5-HT1B agonist). Results: Lamotrigine impaired spontaneous locomotor activity at doses of 4 mg/kg or greater, and activity

ARTICLE IN PRESS M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

decreased by more than 50% at the 16 mg/kg dose. When administered alone, lamotrigine (8 and 16 mg/kg) decreased immobility time in the FST. Only 8-OH-DPAT (1 mg/kg), pindolol (32 mg/kg) and RU 24969 (0.5 mg/kg) enhanced the antidepressant-like effect of lamotrigine in the FST. These results suggest that postsynaptic 5-HT1A receptors might be involved in the activity of lamotrigine. Furthermore, they demonstrate that lamotrigine more closely resembles valproate and carbamazepine than lithium, with the advantage of an anti-immobility effect in the mouse FST when administered on its own. Consoni et al. (2006) evaluated the effect of lamotrigine (5–20 mg/kg, i.p.) in the modified forced swimming test in rats. The effect of lamotrigine on locomotor activity and memory was also studied in order to exclude false-positive results. The effects of lamotrigine on the modified FST; significantly decreased immobility [F(3,35) ¼ 11.97, p o0.001], increased swimming [F(3,35) ¼ 4.67, po0.01] and climbing counts [F(3,35) ¼ 11.66, po0.001]. Post hoc analysis revealed that lamotrigine produced a dosedependent decrease in immobility counts so that the doses of 10 mg/kg and 20 mg/kg significantly decreased immobility (po0.05 and o0.001, respectively), while 5 mg/kg was without effect. Lamotrigine increased swimming counts only at the highest dose of 20 mg/kg (po0.05). In addition, there was also a dose-related increase in climbing counts so that the doses of 10 and 20 mg/kg significantly increased climbing (both po0.001), while 5 mg/kg was without effect. The main finding of this study is the observation that lamotrigine produces a dose-dependent decrease in immobility behaviour, indicating an antidepressant-like effect in the modified forced swimming test. The doses used in the present study are in the anticonvulsant range and lead to plasma levels similar to the concentration range proposed for epileptic patients (Bashkatova et al., 2003; CastelBranco et al., 2003). This antidepressant effect of lamotrigine is consistent with its clinical efficacy in bipolar depression. At lower doses of lamotrigine, the reduction in immobility is due mainly to an increase in climbing behaviour, without any significant change in swimming. In conclusion, the anti-immobility effect of lamotrigine in the mouse forced swimming test was contradictory since Szymczyk and Zebrowska-Lupina (2000) and Ali et al. (2003) did not find an anti-immobility effect, whereas Bourin et al. (2005) found it. These discrepancies can be ascribed to difference in the methodology used by these authors (e.g. timing of drug administration, dose employed and cylinder diameter). The results described by Consoni et al, are in accordance with the antidepressant effect found by Bourin et al. (2005) and with the serotonergic mediation of this effect. However, our data also suggest a noradrenergic role for the anti-immobility effect of lamotrigine.

971

6. Conclusion Among the all mood stabilisers presented in this review, lamotrigine seems to be the most efficient on bipolar depression, but the other drugs are able to potentiate the antidepressant activity. References Acquas, E., Fibiger, H.C., 1996. Chronic lithium attenuates dopamine D1receptor mediated increase in acetylcholine release in rat frontal cortex. Psychopharmacology 125, 162–167. Akiskal, H.S., Bourgeois, M.L., Angst, J., Post, R., Moller, H., Hirschfeld, R., 2000. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. Journal of Affective Disorders 59, S5–S30. Albus, H., Williamson, R., 1998. Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slices. Epilepsia 39, 124–139. Ali, A., Pillai, K.K., Pal, S.N., 2003. Effects of folic acid and lamotrigine therapy in some rodent models of epilepsy and behaviour. Journal of Pharmacy and Pharmacology 55 (3), 387–391. Armario, A., Gil, M., Marti, O., Pol, O., Balasch, J., 1991. Influence of various acute stressors on the activity of adult male rats in a holeboard and in the forced swim test. Pharmacology Biochemistry and Behavior 39, 373. Barnes, J.C., Costall, B., Domeney, A.M., Naylor, R.J., 1986. Lithium and bupropion antagonise the phasic changes in locomotor activity caused by dopamine infused into the rat nucleus accumbens. Psychopharmacology 89, 311–316. Bashkatova, V., Narkevich, V., Vitskova, G., Vanin, A., 2003. The influence of anticonvulsant and antioxidant drugs on nitric oxide level and lipid peroxidation in the rat brain during pentylene-tetrazolinduced epileptiform model seizures. Progress in Neuropsychopharmacology & Biological Psychiatry 27 (3), 487–492. Bazil, C.W., 2002. New antiepileptic drugs. Neurology 8, 71–81. Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., Krystal, J.H., 2000. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47, 351–354. Berrettini, W.H., Nurnberger, J.I., Scheinin, J.M., Seppala, T., Linnoila, M., Narrow, W., 1985. Cerebrospinal fluid and plasma monoamines and their metabolites in euthymic bipolar patients. Biological Psychiatry 20, 257–269. Blier, P., de Montigny, C., 1985. Short-term lithium administration enhances serotonergic neurotransmission: electrophysiological evidence in the rat CNS. European Journal of Pharmacology 113, 69–77. Boerlin, H.L., Gitlin, M.J., Zoellner, L.A., Hammen, C.L., 1998. Bipolar depression and antidepressant-induced mania: a naturalistic study. Journal of Clinical Psychiatry 59, 374–379. Bourin, M., Hascoet, M., Colombel, M.C., Redrobe, J.P., Baker, G., 1996. Differential effects of clonidine, lithium and quinine in the forced swimming test in mice for antidepressants: possible roles of serotonergic system. European Neuropsychopharmacology 6, 231–236. Bourin, M., Hascoe¨t, M., Masse, F., 2005. Evidence for the activity of lamotrigine at 5-HT1A receptors in the mouse forced swimming test. Journal of Psychiatry & Neuroscience 30, 275–282. Bowden, C.L., 1998. New concepts in mood stabilization: evidence for the effectiveness of valproate and lamotrigine. Neuropsychopharmacology 19, 194–199. Bowden, C.L., Brugger, A.M., Swann, A.C., Calabrese, J.R., Janicak, P., Petty, F., Dilsaver, S., Davis, J., Rush, A.J., Small, J., Garza-Trevino, E., Risch, S.C., Goodnick, P.J., Morris, D.D., 1994. Efficacy of divalproex sodium vs. lithium and placebo in the treatment of mania. Journal of American Medical Association 271, 918–924. Bowden, C.L., Calabrese, J.R., McElroy, S.L., Rhodes, L.J., Keck, Jr., P.E., Cookson, J., Anderson, J., Boldon-Watson, C., Ascher, J., Monaghan, E.,

ARTICLE IN PRESS 972

M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

Zhou, J., 1999a. The efficacy of lamotrigine in rapid cycling and nonrapid cycling patients with bipolar disorder. Biological Psychiatry 45, 953–958. Bowden, C.L., Mitchell, P., Suppes, T., 1999b. Lamotrigine in the treatment of bipolar depression. European Neuropsychopharmacology 9, S113–S117. Bowers, M.B., Heninger, G.R., 1977. Clinical effects and cerebrospinal fluid acid monoamine metabolites. Communications in Psychopharmacology 1, 135–145. Brodie, M.J., French, J.A., 2000. Management of epilepsy in adolescents and adults. The Lancet 356, 323–329. Btaiche, I.F., Woster, P.S., 1995. Gabapentine and lamotrigine: novel antiepileptic drugs. American Journal of Health-System Pharmacy 52, 61–69. Bunney, W.E., Garland-Bunney, B.L., 1987. Mechanism of action of lithium in affective illness: basic and clinical implications. In: Meltzer (Ed.), Psychopharmacology: The Third Generation of Progress. Raven Press, New York, pp. 553–565. Calabrese, J.R., Bowden, C.L., Woyshville, M.J., 1995. Lithium and the anticonvulsants in the treatment of bipolar disorder. In: Bloom, F.E., Kupfer, D.J. (Eds.), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, pp. 1099–1111. Calabrese, J.R., Bowden, C.L., Sachs, G.S., Ascher, J.A., Monaghan, E., Rudd, G.D., 1999a. A double-blind placebo controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Journal of Clinical Psychiatry 60, 79–88. Calabrese, J.R., Bowden, C.L., McElroy, S.L., Cookson, J., Anderson, J., Keck, Jr., P.E., Rhodes, L.J., Boldon-Watson, C., Zhou, J., Ascher, J., 1999b. Spectrum of activity of lamotrigine in treatmentrefractory bipolar disorder. American Journal of Psychiatry 156, 1019–1023. Calabrese, J.R., Rapport, D.J., Kimmel, S.E., Shelton, M.D., 1999c. Controlled trials in bipolar depression: focus on switch rates and efficacy. European Neuropsychopharmacology 9, S109–S112. Calabrese, J.R., Suppes, T., Bowden, C.L., Sachs, G.S., Swann, A.C., McElroy, S.L., Kusumaker, V., Ascher, J., Earl, N.L., Greene, P.L., Monaghan, E.T., 2000. A double-blind, placebo controlled prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 study group. Journal of Clinical Psychiatry 61, 841–850. Calabrese, J.R., Bowden, C.L., DeVeaugh-Geiss, A., Early, N., Gyulai, L., Sachs, G., Montgomery, P., 2001a. Lamotrigine Demonstrates Longterm Mood Stabilization in Recently Manic Patients. American Psychiatric Association meeting, New Orleans. Calabrese, J.R., Shelton, M.D., Bowden, C.L., Rapport, D.J., Suppes, T., Shirley, E.R., Kimmel, S.E., Caban, S.J., 2001b. Bipolar rapid cycling: focus on depression as its hallmark. Journal of Clinical Psychiatry 62, 34–41. Carlezon Jr., W.A., Beguin, C., DiNieri, J., Baumann, M.H., Richards, M., Todtenkopf, M.S., Rothman, R.B., Ma, Z., Lee, D.Y.-L., Cohen, B.M., 2006. Depressive-like effects of the k-opioid receptor agonist Salvinorin A on behavior and neurochemistry in rats. Journal of Pharmacology and Experimental Therapeutics 314, 440–447. Carli, M., Reader, T.A., 1997. Regulation of central serotonin transporters by chronic lithium: an autoradiographic study. Synapse 27, 83–89. Carli, M., Afkhami-Dastjerdian, S., Reader, T., 1997a. Effects of a chronic lithium treatment on cortical serotonin uptake sites and 5HT1A receptors. Neurochemical Research 22, 427–435. Carli, M., Morissete, M., Hebert, C., Di Paolo, T., Reader, T.A., 1997b. Effects of the chronic lithium treatment on central dopamine neurotransporters. Biochemical Pharmacology 54, 2391–2397. Cancela, L.M., Rossi, S., Molina, V.A., 1991. Effect of different restraint schedules on the immobility in the forced swim test: modulation by an opiate mechanism. Brain Research Bulletin 26, 671. Castel-Branco, M., Lebre, V., Falcao, A., Figueiredo, I., Caramona, M., 2003. Relationship between plasma and brain levels and the anticonvulsant effect of lamotrigine in rats. European Journal of Pharmacology 482, 163–168.

Chapman, A.G., Meldrum, B.S., Mendes, E., 1983. Acute anticonvulsant activity of structural analogues of valproic acid and changes in brain GABA and aspartate content. Life Science 32, 2023–2031. Chapman, A.G., Croucher, M.J., Meldrum, B.S., 1984. Anticonvulsant activity of intracerebroventricularly administered valproate and valproate analogues. A dose-dependent correlation with changes in brain aspartate and GABA levels in DBA/2 mice. Biochemical Pharmacology 33, 1459–1463. Chenu, F., Bourin, M., 2006. Potentiation of the antidepressants-like activity with lithium: mechanism involved. Current Drug Targets 7, 159–163. Consoni, F., Vital, M.A.B.F., Andreatini, R., 2006. Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test. European Neuropsychopharmacology 16 (6), 451–458. Coulter, D.A., Huguenard, J.R., Prince, D.A., 1989c. Characterization of ethosuximide reduction of low-threshold calcium currents in thalamic neurons. Annals of Neurology 25, 582–593. Cowen, P.J., Cohen, P.R., McCance, S.L., Friston, K.J., 1990. 5-HT neuroendocrine response during psychotropic drug treatment: an investigation of the effects of lithium. Journal of Neuroscience Methods 34, 201–205. Cryan, J.F., Hoyer, D., Markou, A., 2003. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biological Psychiatry 54, 49–58. Dailey, J.W., Reith, M.E., Yan, Q.S., Li, M.Y., Jobe, P.C., 1997a. Anticonvulsant doses of carbamazepine increase hippocampal extracellular serotonin in genetically epilepsy-prone rats: dose response relationships. Neuroscience Letters 227, 13–16. Dailey, J.W., Reith, M.E., Yan, Q.S., Li, M.Y., Jobe, P.C., 1997b. Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+. European Journal of Pharmacology 328, 153–162. Davis, L.L., Kabel, D., Patel, D., Choate, A.D., Foslien-Nash, C., Gurguis, G., Kramer, G., Petty, F., 1996. Valproic acid as an antidepressant in major depressive disorder. Psychopharmacological Bulletin 32, 647–652. de Montigny, C., Aghajanian, G.K., 1978. Tricyclic antidepressants: longterm treatment increases responsivity of the rat forebrain neurons to serotonin. Science 202, 1303–1306. de Montigny, C., Blier, P., 1992. Potentiation of 5-HT neurotransmission by short-term lithium: in vivo electrophysiological studies. Clinical Neuropharmacology 15, 610A–611A. Denicoff, K.D., Smith-Jackson, E.E., Disney, E.R., Ali, S.O., Leverich, G.S., Post, R.M., 1997. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Journal of Clinical Psychiatry 58, 470–478. Dewey, S.L., Smith, G.S., Logan, J., Brodie, J.D., 1993a. Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-bentropine in primates. Neuropsychopharmacology 8, 371–376. Dziedzicka-Wasyleweska, M., Mackowiak, M., Fijat, K., Wedzony, K., 1996. Adaptative changes in the rat dopamine transmission following repeated lithium administration. Journal of Neural Transmission 103, 765–776. El-Mallakh, S., 1996. Lithium: action and mechanism. In: Spiegel, D. (Ed.), Progress in Psychiatry. American Psychiatric Press, Washington, DC, pp. 49–86. Fyro, B., Patterson, V., Sedvall, G., 1975. The effect of lithium treatment on manic symptoms and levels of monoamine metabolites in cerebrospinal fluid of manic depressive patients. Psychopharmacologia 44, 99–103. Gillet, G., Ammor, S., Fillon, G., 1985. Serotonin inhibits acetylcholine release from rat striatum slices: evidence for a presynaptic receptormediated effect. Journal of Neurochemistry 45, 1687–1691. Goa, K.L., Ross, S.R., Chrisp, P., 1993. Lamotrigine, a review of its pharmacological properties and efficacy in epilepsy. Drugs 46, 152–176. Goodwin, F., Jamison, K., 1990. Manic-depressive Illness, pp. 891–898. Goodwin, F.K., Murphy, D.L., Bunney Jr., W.E., 1969. Lithiumcarbonate treatment in depression and mania. A longitudinal double-blind study. Archives of General Psychiatry 21, 486–496.

ARTICLE IN PRESS M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975 Goodwin, F.K., Murphy, D.L., Dunner, D.L., Bunney Jr., W.E., 1972. Lithium response in unipolar versus bipolar depression. American Journal of Psychiatry 129, 44–47. Goodwin, G.M., 1989. The effects of antidepressants treatments and lithium upon 5-HT1A receptor function. Progress in Neuro-Psychopharmacology & Biological Psychiatry 13, 445–451. Gottberg, E., Montreuil, B., Reader, T.A., 1988. Acute effects of lithium on dopaminergic responses: iontophoretic studies in the rat visual cortex. Synapse 2, 442–449. Gottberg, E., Grondin, L.B., Reade, T.A., 1989. Acute effects of lithium on catecholamines, serotonin, and their major metabolites in discrete brain regions. Journal of Neuroscience Research 22, 245–338. Grahame-Smith, D.G., Green, A.R., 1974. The role of brain 5hydroxytryptamine in the hyperactivity produced by lithium and monoamine oxidase inhibition. British Journal of Pharmacology 52, 19–26. Greil, W., Kleindienst, N., 1999. The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder. International Clinical Psychopharmacology 14, 277–281. Hata, T., Itoh, E., Nishikawa, H., 1995. Behavioral characteristics of SART-stressed mice in the forced swim test and drug action. Pharmacology Biochemistry and Behaviour 51, 849–853. Hascoe¨t, M., Bourin, M., Khimake, S., 1994. Additive effect of lithium and clonidine with 5-HT1A agonists in the forced swimming test. Progress in Neuropsychopharmacology & Biological Psychiatry 18, 381–396. Herman, E., 2004. Lamotrigine: a depression mood stabiliser. European Neuropsychopharmacology 14S2, S89–S93. Hirschfeld, R., Calabrese, J.R., Weissman, M., Frye, M., Keck, P., McElroy, S., Wagner, K., Reed, M., 2002a. Prevalence of bipolar spectrum in US adults [abstract]. European Neuropsychopharmacology 12, S218. Hough, C.J., Irwin, R.P., Gao, X.M., Rogawski, M.A., Chuang, D.M., 1996. Carbamazepine inhibition of N-methyl-D-aspartate-evoked calcium influx in rat cerebellar granule cells. Journal of Pharmacology and Experimental Therapeutics 276, 143–149. Jope, R.S., 1999b. A biomodal model of the mechanism of action of lithium. Molecular Psychiatry 4, 21–25. Judd, L.L., Akiskal, H.S., Schettler, P.J., Endicott, J., Maser, J., Solomon, D.A., Leon, A.C., Rice, J.A., Keller, M.B., 2002. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of General Psychiatry 59, 530–537. Judd, L.L., Akiskal, H.S., Schettler, P.J., Coryell, W., Endicott, J., Maser, J.D., Solomon, D.A., Leon, A.C., Keller, M.B., 2003. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Archives of General Psychiatry 60, 261–269. Kapur, S., Remington, G., 1996. Serotonin–dopamine interaction and its relevance to schizophrenia. American Journal of Psychiatry 153, 466–476. Kelly, K.M., Gross, R.A., Macdonald, R.L., 1990. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neuroscience Letters 116, 233–238. Ketter, T., Kimbrell, T., George, M., 1999. Baseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders. Biological Psychiatry 46, 1364–1374. Ketter, T.A., Calabrese, J.R., 2002. Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature. Journal of Clinical Psychiatry 63, 146–151. Ketter, T.A., Manji, H.K., Post, R.M., 2003. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. Journal of Clinical Psychopharmacology 23, 484–495. Kotler, M., Matar, M.A., 1998. Lamotrigine in the treatment of resistant bipolar disorder. Clinical Neuropharmacology 21, 65–67. Kitamura, Y., Araki, H., Gomita, Y., 2002. Influence of ACTH on the effects of imipramine, desipramine, and lithium on duration of

973

immobility of rats in the forced swim test. Pharmacology Biochemistry and Behaviour 71, 63–69. Lees, G., Leach, M.J., 1993. Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neurological cultures from rat cortex. Brain Research 612, 190–199. Lewinsohn, P.M., Klein, D.N., Seeley, J.R., 1995. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. Journal of American Academy of Child and Adolescent Psychiatry 34, 446–454. Lo¨scher, W., 1999. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Progress in Neurobiology 58, 31–59. Mac Donald, R.L., Rogers, C.J., Twyman, R.E., 1989. Barbiturate regulation of kinetic properties of the GABA receptor channel of mouse spinal neurones in culture. Journal of Physiology 417, 483–500. Manji, H.K., Chen, G., Hsiao, J.K., Masana, M.I., Moore, G.J., Potter, W.Z., 1999b. Regulation oh signal transduction pathways by mood-stabilizing agents. Implication for the pathophysiology and treatment of bipolar disorder. In: Manji, H.K., Bowden, C.L., Belmaker, R.H. (Eds.), Bipolar Medications. Mechanism of Action. American Psychiatric Press, Washington, DC, pp. 129–177. Mantovani, M.M., Mateussi, A.S., Rodrigues, A.L., 1999. Antidepressant-like effect of lead in adult mice. Brazilian Journal of Medical and Biological Research 32, 1555–1560. Marangos, P.J., Post, R.M., Patel, J., Zander, A., Parma, K., Weiss, S., 1983. Specific and potent interactions of carbamazepine with brain adenosine receptors. European Journal of Pharmacology 93, 175–182. Martijena, I.D., Tapia, M., Molina, V.A., 1996. Altered behavioural and neurochemical response to stress in benzodiazepine-withdrawn rats. Brain Research 712, 239. Martijena, I.D., Lacerra, C., Molina, V.A., 1997. Carbamazepine normalizes the altered behavioural and neurochemical response to stress in benzodiazepine-withdrawn rats. European Journal of Pharmacology 330, 101–108. Massot, O., Rousselle, J.C., Fillion, M.P., Januel, D., Plantefol, M., Fillion, G., 1999. 5-HT receptors: a novel target for lithium. Possible involvement in mood disorders. Neuropsychopharmacology 21, 530–541. Mague, S.M., Pliakas, A.M., Todtenkopf, M.S., Tomasiewicz, H.C., Zhang, Y., Stevens, W.C., Jones, R.M., Portoghese, P.S., Carlezon Jr., W.A., 2003. Antidepressant-like effects of a-opioid receptor antagonists in the forced swim test in rats. Journal of Pharmacology and Experimental Therapeutics 305, 1–8. McLean, M.J., Macdonald, R.L., 1986. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. Journal of Pharmacology and Experimental Therapeutics 237, 1001–1011. Meldrum, B.D., 1996. Update on the mechanism of action of antiepileptic drugs. Epilepsia 37, 1–4. Meltzer, H.Y., Lowy, M.T., 1987. The serotonin hypothesis of the depression. In: Meltz, HY. (Ed.), Psychopharmacology: The Third Generation of Progress. Raven Press, New York, pp. 513–526. Mendels, J., 1976. Lithium in the treatment of depression. American Journal of Psychiatry 133, 373–378. Mendels, J., 1971. Relationship between depression and mania. The Lancet i, 242. Nixon, M., Bourin, M.K., Hascoet, M., Colombel, M.C., 1994. Additive effects of the lithium and antidepressants in the forced swimming test: further evidence for involvement of the serotonergic system. Psychopharmacology 115, 59–64. Ng, N.K., Lee, H.S., Wong, P.T., 1999. Regulation of striatal dopamine release through 5-HT1 and 5-HT2 receptors. Journal of Neuroscience Research 55, 600–607. Odagaki, Y., Koyama, T., Matsubara, S., Matsubara, R., Yamashita, I., 1990. Effects of chronic lithium treatment on serotonin binding sites in rat brain. Journal of Psychiatric Research 24, 271–277.

ARTICLE IN PRESS 974

M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975

Overstreet, D.H., Pucilowski, O., Rezvani, A.H., Janowsky, D.S., 1995. Administration of antidepressants, diazepam, a psychomotor stimulant further confirms the utility of Flinders sensitive rats as an animal model of depression. Psychopharmacology 121, 27–37. Paul, I.A., Skolnick, P., 2003. Glutamate and depression: clinical and preclinical studies. Annals of the New York Academy of Sciences 1003, 250–272. Peet, M., 1994. Induction of mania with selective serotonin reuptake inhibitors and tricyclic antidepressants. British Journal of Psychiatry 164, 549–550. Paul, I.A., Nowak, G., Layer, R.T., Popik, P., Skolnick, P., 1994. Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. Journal of Pharmacology and Experimental Therapeutics 269, 95–102. Petrie, R.X.A., Reid, I.C., Stewart, C.A., 2000. The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder: a critical review. Pharmacology & Therapeutics 87, 11–25. Petty, F., Bartolucci, A., Davis, L., 2005. Divalproex in the treatment of bipolar depression: a placebo-controlled study. Journal of Affective Disorders 85, 259–266. Pfeiffer, A., Brantl, V., Herz, A., Emrich, H.M., 1986. Psychotomimesis mediated by kappa opiate receptors. Science 233, 774–776. Post, R.M., Weiss, S.R., 1995. The neurobiology of the treatment-resistant mood disorders. In: Bloom, F.E., Kupfer, D.J. (Eds.), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, pp. 1155–1170. Post, R.M., Uhde, T.W., Roy-Byrne, P.P., Joffe, R.T., 1986. Antidepressant effects of carbamazepine. American Journal of Psychiatry 143, 29–34. Post, R.M., Denicoff, K.D., Leverich, G., 1997. Drug-induced switching in bipolar disorder: epidemiology and therapeutic implications. CNS Drugs 8, 352–365. Post, R.M., Frye, M.A., Denicoff, K., Leverich, G.S., Kimbrell, T.A., Dunn, R.T., 1998. Beyond lithium in the treatment of bipolar illness. Neuropsychopharmacology 19, 206–219. Price, L.H., Charney, D.S., Delago, P.L., Herninger, G.R., 1989. Lithium treatment and serotoninergic function. Neuroendocrine and behavioral responses to intravenous tryptophan in affective disorder. Archives of General Psychiatry 46, 13–19. Price, L.H., Charney, D.S., Delago, P.L., Heninger, G.R., 1990. Lithium an serotonin function: implication for the serotonin hypothesis. American Journal of Human Genetics 65, 220–228. Redrobe, J.P., Bourin, M., 1997. Effects of pretreatment with clonidine, lithium and quinine on the activities of antidepressant drugs in the mouse tail suspension test. Fundamental & Clinical Pharmacology 11, 381–386. Redrobe, J.P., Bourin, M., 1999. Evidence of the activity of lithium on the 5-HT1B receptors in the mouse forced swimming test: comparision with carbamazepine and sodium valproate. Psychopharmacology 141, 370–377. Remy, S., Urban, B.W., Elger, C.E., Beck, H., 2003. Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats. European Journal of Neuroscience 17, 2648–2658. Richelson, E., 1995. Cholinergic transduction. In: Bloom, F.E., Kupfer, D.J. (Eds.), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, pp. 125–134. Rogawski, M.A., Porter, R.J., 1990. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacological Reviews 42, 223–286. Rostock, A., Hoffman, W., Siegemund, C., Bartsch, R., 1989. Effects of carbamazepine, valproate calcium, clonazepam and piracetam on behavioral test methods for evaluation of memory-enhancing drugs. Methods and Findings in Experimental and Clinical Pharmacology 11, 547–553. Rowley, H.L., Marsden, C.A., Martin, K.F., 1995. Differential effects of phenytoin and sodium valproate on seizure-induced changes in

gaminobutyric acid and glutamate release in vivo. European Journal of Pharmacology 294, 541–546. Sachs, G.S., Collins, M.A., Altshuler, L.L., Ketter, T.A., Suppes, T., Rasgon, N.L., Frye, M.A., Wozniak, P., 2001. Divalproex sodium versus placebo for the treatment of bipolar depression. In: Proceedings of the 40th Annual Meeting of the American College of Neuropsychopharacology, 8 December 2001, San Juan, Puerto Rico. Schechter, P.J., Tranier, Y., Grove, J., 1978. Effect of n-dipropylacetate on amino acid concentrations in mouse brain: correlation with anticonvulsant activity. Journal of Neurochemistry 31, 1325–1327. Sills, G.J., Leach, J.P., Butler, E., Carswell, A., Thompson, G.G., Brodie, M.J., 1996. Antiepileptic drug action in primary cultures of rat cortical astrocytes. Epilepsia 37, 116. Smith, D., Chadwick, D., Baker, G., 1993. Seizure severity and the quality of life. Epilepsia 34, 31–35. Southam, E., Kirkby, D., Higgins, G.A., Hagan, R.M., 1998. Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats. European Journal of Pharmacology 358, 19–24. Suppes, T., Brown, E.S., McElroy, S.L., Keck Jr., P.E., Nolen, W., Kupka, R., Frye, M., Denicoff, K.D., Altshuler, L., Leverich, G.S., Post, R.M., 1999. Lamotrigine for the treatment of bipolar disorder: a clinical case series. Journal of Affective Disorders 53, 95–98. Swann, A.C., Koslow, S.H., Katz, M.M., Maas, J.W., Secunda, S., 1987. Lithium carbonate treatment of mania: cerebrospinal fluid and urinary monoamone metabolites and treatment outcome. Archives of General Psychiatry 44, 345–354. Swann, A.C., Bowden, C.L., Morris, D., Calabrese, J.R., Petty, F., Small, J., Dilsaver, S.C., Davis, J.M., 1997. Depression during mania: treatment response to lithium or divalproex. Archives of General Psychiatry 54, 37–42. Szymczyk, G., Zebrowska-Lupina, I., 2000. Influence of antiepileptics on efficacy of antidepressant drugs in forced swimming test. Polish Journal of Pharmacology 52, 337–344. Trullas, R., Skolnick, P., 1990. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. European Journal of Pharmacology 185, 1–10. Tomasiewicz, H.C., Mague, S.D., Cohen, B.C., Carlezon Jr., W.A., 2006. Behavioral effects of short-term administration of lithium and valproic acid in rats. Brain Research 1093 (1), 83–94. van Dongen, A.M.J., van Erp, M.G., Voskuyl, R.A., 1986. Valproate reduces excitability by blockage of sodium and potassium conductance. Epilepsia 27, 177–182. Walden, J., Schaerer, L., Schloesser, S., Grunze, H., 2000. An open longitudinal study of patients with bipolar rapid cycling treated with lithium or lamotrigine for mood stabilisation. Bipolar Disorders 2, 336–339. Waldmeier, P.C., Baumann, P.A., Wicki, P., Feldtrauer, J.J., Stierlin, C., Schmutz, M., 1995. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45, 1907–1913. Wegener, G., Bandpey, Z., Heiberg, I., Mork, A., Rosenberg, R., 2003. Increased extracellular serotonin level in rat hippocampus induced by chronic citalopram is augmented by subchronic lithium: neurochemical and behavioral studies in the rat. Psychopharmacology 166, 188–194. Weissman, M.M., Bland, R.C., Canino, G.J., Faravelli, C., Greenwald, S., Hwu, H.G., Joyce, P.R., Karam, E.G., Lee, C.K., Lellouch, J., Lepine, J.P., Newman, S.C., Rubio-Stipec, M., Wells, J.E., Wickramaratne, P.J., Wittchen, H., Yeh, E.K., 1996. Cross-national epidemiology of major depression and bipolar disorder. JAMA 276, 293–299. Wilk, S., Shopsin, B., Gershon, S., Suhl, M., 1972. Cerebrospinal fluid levels of MHPG in the affective disorders. Nature 235, 440–441. Wood, A.J., Goodwin, G.M., 1987. A review of biochemical and neuropharmacological action of lithium. Psychological Medicine 17, 579–600.

ARTICLE IN PRESS M. Bourin, C. Prica / Neuroscience and Biobehavioral Reviews 31 (2007) 963–975 Xie, X., Dale, T.J., John, V.H., Cater, H.L., Peakman, T.C., Clare, J.J., 2001. Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. Pflugers Archiv 441, 425–433. Zarate, C.A., Payne, J.L., Quiroz, J., Sporn, J., Denicoff, K.K., Luckenbaugh, D., Charney, D.S., Manji, H.K., 2004. An open label

975

trial of riluzole in patients with treatment-resistant major depression. American Journal of Psychiatry 161, 171–174. Zona, C., Avoli, M., 1990. Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture. Experimental Brain Research 81, 313–317.