The Emerging Role of GABAergic Mechanisms in Mood Disorders

Psychiatric Times

September 2005

Vol. XXII

Issue 10

Sponsored by CME LLC for 2.5

Category 1 credits.

Original release date 9/05. Approved for CME credit through 8/31/06.

Educational Objectives:

Upon completion of this educational activity, the reader will be familiar with:

• The basic physiology of GABA neurotransmission.
• The importance of GABA in animal models of depression.
• The diverse range of medications that have GABAergic effects and efficacy in mood disorders.
• Targets of future drug development based on commonalities of drug effects.

Who will benefit from reading this article?

Psychiatrists, primary care physicians, neurologists, nurse practitioners, psychiatric nurses and other mental health care professionals. Continuing medical education credit is available for most specialties. To determine if this article meets the CE requirements for your specialty, please contact your state licensing board.

Dr. Wang is acting assistant professor of psychiatry and behavioral sciences at the Stanford University School of Medicine Bipolar Disorders Clinic. Dr. Wang has received grant/research support and lecture honoraria from Abbott Laboratories, AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer Inc. He has also received grant/research support from Bristol-Myers Squibb Company, Elan Pharmaceuticals, Janssen Pharmaceutica, Shire Laboratories and Wyeth.

Dr. Ketter is professor of psychiatry and behavioral sciences and chief of the Bipolar Disorders Clinic at the Stanford University School of Medicine. Dr. Ketter has received grants and research support, honoraria, served as a consultant and member of the speakers' bureau for Abbott Laboratories; AstraZeneca Pharmaceuticals, L.P.; Bristol-Myers Squibb Company; Eli Lilly and Company; GlaxoSmithKline; Janssen Pharmaceutica Products, L.P.; and Wyeth. He also receives grants and research support from and serves as a consultant for Elan Pharmaceuticals and Shire US Inc. He serves as a consultant for and receives honoraria from Novartis Pharmaceuticals. He also serves as a consultant for Cephalon, Inc.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian brain (Roberts et al., 1976), and is present at nearly half of the synapses (Schon and Iversen, 1974). Primarily found in the central nervous system, GABA occurs at micromolar concentrations with higher levels in gray than in white matter. In spite of the widespread distribution of GABA receptors, evidence suggests altered GABAergic neurotransmission can have regional specificity, with particularly high concentrations in the substantia nigra, basal ganglia, hypothalamus, colliculi, periaqueductal gray and the dentate nucleus of the cerebellum (Fahn and Cote, 1968).

Gamma-aminobutyric acid is synthesized by decarboxylation of glutamate by cytosolic glutamic acid decarboxylase (GAD) and is metabolized by the mitochondrial enzyme GABA-transaminase (GABA-T) to succinic semialdehyde, which in turn can enter the Krebs cycle to ultimately regenerate glutamate. Metabolism of GABA requires substantial amounts of energy and is closely related to glucose metabolism. Clinical and basic research findings in epilepsy are consistent with the hypothesis that increased regional GABA yields decreased neuronal activity and, hence, decreased cerebral glucose metabolism.

Gamma-aminobutyric acid binds to neuronal and glial recognition sites. Receptor subtypes GABA_A and GABA_B occur both pre- and postsynaptically and are widely distributed in the CNS, with overlapping but not identical patterns, though high levels of both occur in frontal cortex (Bowery et al., 1987).

The major inhibitory receptors in the CNS are GABA_A receptors, and they mediate fast synaptic inhibition by increasing chloride conductance through a multi-subunit receptor-chloride channel complex. These receptor-chloride channel complexes are activated by GABA and modulated by anxiolytic anticonvulsants such as barbiturates and benzodiazepines. Gamma-aminobutyric acidB receptors occur at much lower concentrations than GABA_A receptors and are metabotropic, as they decrease calcium and increase potassium channel conductances via cyclic adenosine monophosphate (AMP) effects. Some GABA_B receptors are presynaptic autoreceptors, which makes interpretation of studies with GABA_B findings more complex. An interesting clinical reflection of the important functional difference between GABA receptor subtypes is the observation that benzodiazepine GABA_A receptor modulators such as clonazepam (Klonopin) (Chouinard et al., 1983) or lorazepam (Ativan) (Bradwejn et al., 1990) may attenuate, while the GABA_B receptor agonist baclofen may exacerbate (Post et al., 1991), affective symptoms in patients with bipolar disorders.

Animal Models of Depression

Activation of GABAA receptors may yield antidepressant effects in animal models of depression (Table 1). Levels of GABA are reduced in the cortex, nucleus accumbens and brain stem in the forced swim model of depression (Borsini et al., 1988). Injected into the frontal cortex, GABA prevented learned helplessness (Sherman and Petty, 1980), while GABA_A receptor antagonist injections into the hippocampus induced learned helplessness (Petty and Sherman, 1981). In rats exposed to the learned helplessness model of depression compared to controls, hippocampal slices had decreased depolarization-induced GABA release (Petty and Sherman, 1981), and chronic tricyclic antidepressant administration normalized both depression-like behavior and hippocampal GABA release (Sherman and Petty, 1982). In both the learned helplessness (Martin et al., 1989) and olfactory bulbectomy (Lloyd and Pichat, 1985) models, frontal cortical GABA_B receptors were downregulated, and this effect was reversed by TCAs (Joly et al., 1987; Martin et al., 1989). Imipramine (Tofranil) upregulated GABA_B receptors only in those animals that responded behaviorally. Thus, increased activity of GABA_A receptors or inhibition of GABA_B receptors may be targets for antidepressant drug development.

GABAergic Drugs in Mood Disorders

Several lines of converging preclinical and clinical evidence developed over the last two decades suggest that GABAergic mechanisms may be relevant to the treatment of mood disorders (Bartholini et al., 1985; Emrich et al., 1980; Lloyd et al., 1989; Motohashi et al., 1989; Petty, 1995). Gamma-aminobutyric acid modulates monoamines and, thus, such mechanisms are not inconsistent with more familiar putative monoaminergic mechanisms of affective disorders. Medications with GABAergic effects appear to have utility in mood (and particularly bipolar) disorders. We review the role of GABAergic actions of benzodiazepines, antidepressants, mood stabilizers, new anticonvulsants and antipsychotics (Table 2).

Benzodiazepines

Benzodiazepines increase GABAergic neurotransmission by increasing the frequency of GABA_A receptor-activated chloride channel opening (Twyman et al., 1989). These agents have prominent hypnotic (Andersen and Lingjaerde, 1969) and anxiolytic activity (Ballenger et al., 1988), but only modest antimanic (Bradwejn et al., 1990) and antidepressant activity (Rickels et al., 1987).

Alprazolam (Xanax) has been reported effective in the treatment of unipolar (Feighner et al., 1983; Rickels et al., 1985) and bipolar (Rush et al., 1984) depression and may have more robust antidepressant properties than other benzodiazepines. Meta-analyses of intent-to-treat and adequate treatment exposure samples for alprazolam, diazepam (Valium) and chlordiazepoxide (Librium) in acute-phase, randomized, controlled trials in major depression noted overall efficacy of 47% to 63% and a drug-placebo difference of 0% to 27% (Petty et al., 1995). For alprazolam, efficacy was 27.1% greater than placebo, which is comparable to standard antidepressants. Another meta-analysis of 11 randomized, controlled studies found alprazolam had similar efficacy to low doses of TCAs (Srisurapanont and Boonyanaruthee, 1997). Of interest, emergence of hypomania has been reported with alprazolam even in patients who tolerated diazepam (Reddy et al., 1996). Thus, alprazolam should be considered with caution in adjunctive treatment of mania. One open study suggested that clonazepam may have antidepressant effects (Kishimoto et al., 1988).

Benzodiazepines may also offer modest benefits in acute mania (Chouinard, 1988). In a two-week, double-blind, controlled study of 24 acutely manic patients, clonazepam only yielded 18.2% response and 0% remission, whereas lorazepam yielded 61% response and 38.5% remission (Bradwejn et al., 1990). Therefore, benzodiazepines are commonly used in the initial phases of controlled trials of other agents in acute mania, without systematically interfering with the ability to separate active treatments from placebo. However, up to 20% of patients with bipolar disorder (BD) have comorbid panic disorder (MacKinnon et al., 2002). Thus, benzodiazepines are common adjuncts in BD treatment, targeting comorbid anxiety disorders.

Benzodiazepines are generally well tolerated but can cause sedation and ataxia, especially when combined with other agents with the same effects. Additionally, the utility of these agents may be limited by their abuse potential (particularly in patients with histories of substance abuse) and the risk of disinhibition (particularly in children and adolescents and patients with Cluster B personality disorders).

Antidepressants

In contrast to benzodiazepines, which have robust anxiolytic, but modest antidepressant, effects, some antidepressants have robust effects for both anxiety and depression. Data suggest that chronic, but not acute, antidepressant exposure upregulates GABA_B but fails to alter GABA_A receptors. In mice, chronic (but not acute) desipramine (Norpramin), amitriptyline and electroconvulsive therapy increased frontal GABA_B receptor function (Gray and Green, 1987; Gray et al., 1987). In rats not previously exposed to a model of depression, chronic administration of antidepressants (desipramine, amitriptyline, maprotiline [Ludiomil], fluoxetine [Prozac], citalopram [Celexa], trazodone [Desyrel] or a series of ECT treatments) increased frontal GABA_B, but not GABA_A, receptors (Lloyd et al., 1986, 1985). Another study also found no effect on GABA_A receptors, with chronic desipramine or tranylcypromine (Parnate) failing to alter benzodiazepine receptor binding (Kimber et al., 1987). There have been some discordant findings regarding specific antidepressants, however. Chronic desipramine, but not paroxetine (Paxil) or amitriptyline, increased frontal GABA_B receptors (Pratt and Bowery, 1993). Chronic parenteral administration of some agents (desipramine and citalopram), but not all (amitriptyline and fluoxetine), also increased hippocampal GABA_B (but not GABA_A) receptors.

Selective serotonin reuptake inhibitors are used in the treatment of depression and anxiety in mood disorders (combined with mood stabilizers in patients with bipolar disorders). While the SSRIs are not directly GABAergic, they may indirectly enhance GABAergic neurotransmission. For example, in patients with (unipolar) major depressive disorder, SSRIs (fluoxetine and citalopram) increased occipital GABA concentrations (Sanacora et al., 2002), normalizing a baseline cerebral GABA deficiency (Sanacora et al., 1999). This effect could be related to SSRI-induced increases in brain allopregnanolone, as these medicines can increase cerebrospinal fluid allopregnanolone concentrations in depressed patients (Uzunova et al., 1998). Allopregnanolone is a GABAergic neurosteriod that binds with high affinity to various GABA_A receptor subtypes, potentially facilitating GABAergic actions.

Mood Stabilizers

The classic mood stabilizers--lithium (Eskalith, Lithobid), carbamazepine (Equetro, Tegretol) and divalproex (Depakote)--have few mechanistic commonalities (Figure). A decrease in GABA turnover in preclinical studies is one shared mechanism, and with chronic administration, these agents all tend to increase limbic GABA_B receptors. All three agents also decrease dopamine turnover.

Lithium, carbamazepine and valproate have all been reported to decrease GABA turnover in animals (Bernasconi and Martin, 1979; Bernasconi et al., 1984; Schwark and Loscher, 1985). However, valproate has also been reported to increase (Loscher, 1989) or not alter (Loscher, 1980) GABA turnover. Lithium, carbamazepine and valproate have also all been reported to decrease dopamine turnover (Maitre et al., 1984; Waldmeier, 1987), perhaps by GABAergic modulation of dopaminergic neurotransmission. Gamma-aminobutyric acid-ergic projections from the basal forebrain and the large numbers of GABAergic neurons in the substantia nigra and ventral tegmental area (Walaas and Fonnum, 1980) may mediate these effects.

Mood stabilizers may upregulate brain GABA_B receptors. In rats, chronic (but not acute) lithium, carbamazepine and valproate (but not baclofen) increased hippocampal (but not frontal, thalamic or striatal) GABA_B (but not GABA_A) receptors (Motohashi, 1992; Motohashi et al., 1989), suggesting that hippocampal GABA_B receptor mechanisms may be an important commonality of mood stabilizers. Although an earlier study found that chronic valproate significantly increased frontal GABA_B receptors (Lloyd et al., 1985), this change was only evident at trend level in a later report (Motohashi, 1992). Other groups had previously reported that chronic valproate (Slevin and Ferrara, 1985) and lithium (Maggi and Enna, 1980) failed to alter frontal and hippocampal GABA_A receptors. However, chronic lithium had also been previously reported to reduce rat frontal (but not occipitoparietal or hippocampal) GABA_A receptors as assessed by benzodiazepine binding (Hetmar et al., 1983), and decrease striatal and hypothalamic (but not cortical or hippocampal) mixed GABA_A and GABA_B receptors (Maggi and Enna, 1980).

Mood stabilizers also increase brain GABA. In rats, chronic lithium (Ahluwalia et al., 1981; Gottesfeld et al., 1971; Marcus et al., 1986; Rubio and Otero Losada, 1986), carbamazepine (Higuchi et al., 1986; Mitsushio et al., 1988; Nagaki et al., 1990) or valproate (Higuchi et al., 1986; Nagaki et al., 1990; Patsalos and Lascelles, 1981) have been noted to increase regional cerebral GABA levels. In mice, valproate increased brain (Loscher, 1981; Nau and Loscher, 1982; Simler et al., 1976) and nerve ending (synaptosomal, i.e., directly related to neurotransmission) (Loscher, 1981) GABA levels. However, discordant results have also been reported (Bernasconi and Martin, 1979; Biggs et al., 1992; Hitchcock and Teixeira, 1982; Loscher and Horstermann, 1994; Otero Losada and Rubio, 1986; Rubio and Otero Losada, 1986), possibly due to methodological limitations. Indeed, not all GABAergic medications are mood stabilizers.

Lithium. Lithium is an ion with multiple biochemical effects. Although intracellular signaling actions are the most active area of current exploration of lithium mechanisms (Manji et al., 1995), this agent also has effects on GABA. Lithium has impressive efficacy in classic BD (euphoric manias, not rapid cycling) (Jefferson et al., 1987), but appears less effective in patients with mixed mood states (dysphoric mania); rapid cycling; comorbid substance abuse; and severe, psychotic or secondary manias. It is also less effective in adolescents and patients who have had three or more prior episodes (Bowden, 1995). However, lithium does have well-established, though modest, antidepressant effects. Thus, five of seven placebo-controlled trials suggested that lithium was more efficacious than placebo for treatment of bipolar depression, with 79% of participants in a pooled analysis of these studies receiving mild-to-moderate relief of depression (Compton and Nemeroff, 2000; Mendels, 1976). However, only 36% of patients from these pooled data met more stringent responder criteria. In addition, lithium's utility is limited by adverse effects (sedation, renal, thyroid and weight gain), which can undermine compliance.

Valproate. Valproate is a branched chain fatty acid with structural similarity to GABA and prominent GABAergic effects. However, valproate has a panoply of other effects, which could be related to its psychotropic profile, and direct mechanistic relationships remain to be established. Nevertheless, valproate has multiple GABAergic effects, which include not only upregulating limbic GABA_B receptors and decreasing GABA turnover, but also increasing cerebral GABA synthesis, release and concentrations, and attenuating GABA degradation (Loscher, 1999). Occipital and medial prefrontal GABA in patients with BD, primarily euthymic and on primarily GABAergic medications (valproate plus/minus gabapentin [Neurontin]), measured by magnetic resonance spectroscopy (MRS) were higher (54% and 31% greater, compared to controls, respectively) (Wang et al., 2002a). This GABAergic agent has sedative, antimanic (Bowden et al., 1994; Pope et al., 1991) and weight gain effects (Mattson et al., 1992), and more modest anxiolytic (Keck et al., 1993) and antidepressant effects (Winsberg et al., 2001).

The limited available data suggest that, like lithium and carbamazepine, divalproex has less robust acute antidepressant than acute antimanic effects. However, our group found that in mood stabilizer naive, depressed patients with bipolar II disorder (BD-II), open divalproex monotherapy (mean serum concentration=80.7 µg/mL) yielded a 63% overall response rate (Winsberg et al., 2001). In a double-blind, multicenter, parallel-group, placebo-controlled pilot study designed to provide preliminary data regarding the efficacy of divalproex during depressive episodes in patients with bipolar I disorder (BD-I) or BD II, divalproex-treated patients had a nonsignificantly higher rate of antidepressant response compared with the placebo group (43% versus 27%, respectively; p

Despite clear utility in acute mania and widespread general use for the treatment of BD, long-term efficacy data for divalproex have limitations. Apparently due in part to methodological limitations, the primary efficacy measure in a one-year maintenance study failed to separate divalproex, lithium and placebo (Bowden et al., 2000). However, secondary efficacy measures suggested utility, and divalproex is commonly used in maintenance treatment of BD (Work Group on Bipolar Disorder, 2002).

Carbamazepine. Carbamazepine has a tricyclic structure, with some GABAergic (Motohashi, 1992; Motohashi et al., 1989) effects that may not be as marked as some of its other multiple cellular and intracellular actions (Ambrosio et al., 2002; Post, 1988). Carbamazepine has antimanic (Ketter et al., 1998) and more modest antidepressant effects (Post et al., 1986), but not anxiolytic effects (Uhde et al., 1988). Carbamazepine, which has less prominent GABAergic actions than valproate, has less weight gain (Mattson et al., 1992; Rattya et al., 1999).

However, carbamazepine may be an important treatment option in BD, particularly in patients with "nonclassical" BD (BD-II, BD not otherwise specified, or BD with mood-incongruent delusions or comorbidity) (Greil et al., 1998).

Newer Anticonvulsants

Several newer anticonvulsants, like some older ones, increase GABAergic inhibitory neurotransmission and have been investigated for their clinical efficacy in mood disorders.

Gabapentin. Gabapentin is structurally similar to GABA. Although gabapentin lacks direct GABAergic actions such as binding to GABA receptors or affecting GABA uptake or catabolism, it appears to have more subtle GABAergic effects such as increasing glial GABA release and acting on GABA transporters. In an MRS study of patients with epilepsy, gabapentin at 1800 mg/day and 3600 mg/day yielded 20% and 40% increases in cerebral GABA, respectively (Petroff et al., 1996). Like other anticonvulsants, gabapentin has multiple actions in addition to effects on amino acids (Taylor et al., 1998). This GABAergic agent has sedative, anxiolytic (Pande et al., 2000b, 1999) and perhaps some weight gain effects (Frye et al., 2000). It also may have antidepressant (Wang et al., 2002b), but not antimanic, effects (Pande et al., 2000a).

Despite early encouraging open reports of gabapentin in BD, in two controlled studies of specific applications as a primary treatment for BD, gabapentin was ineffective. In a double-blind, placebo-controlled study of patients with BD suffering from mania or hypomania while taking lithium or valproate, adjunctive placebo tended to lower mania scores more than adjunctive gabapentin (Pande et al., 2000a). Thus, gabapentin has been shown to be ineffective in acute mania. Also, in treatment-resistant (primarily rapid-cycling BD) mood disorders, gabapentin was no more effective than placebo (Frye et al., 2000). During this six-week trial, patients on gabapentin gained 1.83 kg (3.7 lb). In contrast, lamotrigine (Lamictal) was more effective than both gabapentin and placebo and yielded a 0.96 kg (2.1 lb) weight loss.

However, our group found that adding open gabapentin to mood stabilizers yielded antidepressant effects in mild-to-moderate (but not severe) bipolar depression (Wang et al., 2002b). In the earlier study, the few treatment-resistant patients who experienced antidepressant effects with gabapentin also had mild-to-moderate (but not severe) depression (Frye et al., 2000). Thus, gabapentin, like benzodiazepines (Rickels et al., 1987), may have modest antidepressant effects.

In contrast, gabapentin appears effective in anxiety disorders, with double-blind, placebo-controlled trials demonstrating efficacy in social phobia (Pande et al., 1999) and, in a post hoc analysis, in moderate-to-severe panic disorder (Pande et al., 2000b). Double-blind, placebo-controlled trials also noted gabapentin effective in diabetic neuropathy (Backonja, 1999) and postherpetic neuralgia (Rowbotham et al., 1998).

Taken together, the above considerations suggest that the GABAergic agent gabapentin may, like benzodiazepines, be a useful adjunct for comorbid problems, but not a primary treatment for BD.

Topiramate. Topiramate (Topamax) is a fructopyranose sulfamate anticonvulsant with diverse mechanisms of action, including both GABAergic and antiglutamatergic effects (Shank et al., 2000). Topiramate appears to have robust preclinical GABAergic effects (White et al., 1997) and clinically robustly increases brain GABA (Petroff et al., 1999). In addition, topiramate has antiglutamatergic actions (Kanda et al., 1996), including blocking a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors. Topiramate's novel "mixed" psychotropic profile, which includes both sedation and weight loss, could be related to GABAergic and antiglutamatergic effects, respectively.

Initial open data suggested topiramate might have psychotropic (in addition to weight loss) effects in BD (Calabrese et al., 2001); though in four double-blind, placebo-controlled studies, topiramate was no better than placebo in acute mania (Powers et al., 2004). On the other hand, in a four-week, multicenter, randomized, double-blind, placebo-controlled trial with adolescents in acute mania, 29 adolescents on topiramate (mean dose=278 mg/day) compared to 27 on placebo had a significantly greater mean Young Mania Rating Scale (YMRS) rate of decrease (Delbello et al., 2005). However, this trial was terminated early when the adult acute mania trials failed to show efficacy. Additional evaluation of topiramate in acute mania in adolescents may be warranted. Also, a small eight-week, single-blind bipolar depression study suggested that topiramate (mean dose=176 mg/day) and bupropion (Wellbutrin) (mean dose=250 mg/day) added to mood stabilizers had similar antidepressant efficacy, but topiramate was somewhat more poorly tolerated (McIntyre et al., 2002). Patients on topiramate had greater weight loss (5.8 kg [12.8 lb]) than those on bupropion (1.2 kg [2.6 lb]). Additional double-blind, placebo-controlled trials suggest topiramate is effective in migraine headaches (Silberstein et al., 2004), alcohol dependence (Johnson et al., 2003), binge-eating disorder (McElroy et al., 2003), bulimia (Hedges et al., 2003; Hoopes et al., 2003) and obesity (Bray et al., 2003).

Topiramate's adverse effects include cognitive impairment, paresthesias, renal calculi, metabolic acidosis and acute secondary angle closure glaucoma (Rhee et al., 2001). Further controlled studies are needed to better understand the potential role of topiramate in BD.

Tiagabine. Tiagabine (Gabitril) is a derivative nipecotic acid, a GABA reuptake inhibitor with structural similarity to GABA (Meldrum and Chapman, 1999).

There are no controlled studies of tiagabine in BD. However, rapid loading of open primarily adjunctive tiagabine, starting at 20 mg/day (five times the recommended starting dose according to the PDR), in eight patients with mania not only was ineffective, but also yielded unacceptable adverse effects (Grunze et al., 1999). Furthermore, an open case series of patients with treatment-refractory BD followed in the Stanley Foundation Bipolar Network found limited efficacy for tiagabine added to treatment, with the majority of patients showing no change or worsening of clinical symptoms (Suppes et al., 2002). Common adverse effects include sedation, fatigue, dizziness, tremor, weakness and gastrointestinal disturbance. Seizures were reported in two case series with patients with BD (Grunze et al., 1999; Suppes et al., 2002). In contrast, small controlled trials have reported that low-dose (≤16 mg/day) tiagabine was generally well tolerated and yielded benefit in generalized anxiety disorder (Rosenthal, 2003) and primary insomnia (Roth and Walsh, 2004). Taken together, the above suggest that, like gabapentin and topiramate, tiagabine does not appear to be effective as a primary treatment for bipolar disorders, but may yield benefit in common comorbid problems (such as generalized anxiety disorders and insomnia). However, reports of tolerability problems suggest that considerable caution ought to be exercised with this agent in patients with bipolar disorders (Grunze et al., 1999; Suppes et al., 2002).

Lamotrigine. Lamotrigine has a phenyltriazine structure and is a sodium channel and weak 5-HT₃ receptor blocker, and decreases glutamate release (Leach et al., 1995). Lamotrigine also appears to modestly inhibit reuptake of serotonin. Lamotrigine was approved by the U.S. Food and Drug Administration for maintenance treatment in BD-I (particularly for preventing depressive episodes) based on two 18-month, double-blind, placebo-controlled studies (Bowden et al., 2003; Calabrese et al., 2003). Controlled trials also suggest lamotrigine is effective in acute bipolar depression (Calabrese et al., 1999), rapid-cycling BD (Calabrese et al., 2000) and in treatment-resistant (primarily rapid-cycling BD) mood disorders (Frye et al., 2000). Of note, lamotrigine does not appear to have substantive GABAergic activity. On the other hand, decreasing glutamate release is also observed with carbamazepine and oxcarbazepine (Trileptal) (Waldmeier et al., 1995), suggesting a different mechanistic commonality with other agents.

Antipsychotics

Antipsychotics are commonly used in severe, psychotic and treatment-resistant mood disorders. Older (typical) antipsychotics offered prominent dopamine D₂ receptor blockade and antimanic effects. Newer (atypical) antipsychotics block not only dopamine D₂, but also serotonin 5-HT₂ receptors, which could contribute to antimanic and antidepressant effects, respectively. Controlled clinical trials suggest acute antimanic efficacy for olanzapine (Zyprexa) (Tohen et al., 2000, 1999), risperidone (Risperdal) (Hirschfeld et al., 2004; Khanna et al., 2003), quetiapine (Seroquel) (Bowden et al., 2005), ziprasidone (Geodon) (Keck et al., 2003b) and aripiprazole (Abilify) (Keck et al., 2003a). Studies have also suggested a role for adjunctive clozapine (Clozaril) in the long-term management of treatment-resistant BD (Suppes et al., 1999). Additionally, recent studies have found that olanzapine-fluoxetine combination therapy (Symbyax) (Tohen et al., 2003) and quetiapine monotherapy (Calabrese et al., 2005) robustly and olanzapine monotherapy modestly yielded more relief of bipolar depression than placebo.

Olanzapine has multiple cellular actions, which could differentially contribute to its varying clinical effects. These actions may even include GABAergic effects. In rats, acute olanzapine increased cerebral cortical levels of the potent GABA_A receptor modulator allopregnanolone up to fourfold (Marx et al., 2000). Also, olanzapine for one month markedly decreased hippocampal and temporal cortical GABA_A receptor density (Farnbach-Pralong et al., 1998), and for six months increased GAD expression in the reticular nucleus of thalamus (Sakai et al., 2001).

Thus, although atypical antipsychotics have been considered primarily as dopamine D₂ and serotonin 5-HT₂ receptor antagonists, their multiple mechanisms of action may include GABAergic actions, which could contribute to their clinical effects. Also, as GABA negatively modulates dopamine, GABAergic agents may have adjunctive roles in psychotic disorders (Wassef et al., 1999). Of interest, acute traditional antipsychotics increased GABA turnover proportional to their ability to block D₂ receptors (Mayo et al., 1978). Thus, the GABAergic medication divalproex, added to atypical antipsychotics (olanzapine or risperidone), resulted in earlier improvement compared to monotherapy with atypical antipsychotics (Casey et al., 2003).

Taken together, the above considerations are consistent with at least some antipsychotics having some GABAergic actions, and some GABAergic medications having utility as adjuncts in psychosis.

Conclusion

A major neurotransmitter in the human brain, GABA may play a role in the pathophysiology and treatment of mood disorders. Thus, altered activity of GABA_A receptors or of GABA_B receptors was associated with increased depression in animal models of depression. Benzodiazepines, which modulate GABA_A receptors, have robust anxiolytic effects, are common adjuncts in acute mania, and may have modest antidepressant efficacy. Mood stabilizers have multiple effects, though commonalities include GABAergic actions. These agents have robust antimanic, and more modest antidepressant, effects. Antidepressants have robust antidepressant and in many instances anxiolytic effects; they have primary actions that are not GABAergic but chronic use upregulates GABA_B receptors. Other medications with efficacy in mood disorders also have effects in GABA function. On the other hand, lamotrigine has robust efficacy for maintenance BD treatment (Bowden et al., 2003; Calabrese et al., 1999) and bipolar depression (Calabrese et al., 1999), but lacks substantive GABAergic effects. Some medications with prominent GABAergic activity (such as gabapentin) do not have robust antimanic efficacy. Thus, GABAergic mechanisms may complement other hypotheses, including monoamine mechanisms, to expand our overall understanding of mood disorders; and medications with effects on specific GABA receptors may be targets for future treatment in mood disorders.

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