The Emerging Role of GABAergic Mechanisms in Mood Disorders by Po W. Wang, M.D., and Terence A. Ketter, M.D. Gamma-aminobutyric acid is a major inhibitory neurotransmitter widely distributed in the mammalian central nervous system. Animal models of depression have pointed toward the importance of the GABA system in the pathophysiology of mood disorders. Thus, elucidating the GABAergic effects of benzodiazepines, mood stabilizers, antidepressants, and new anticonvulsants and antipsychotics may expand our understanding of mood disorder pathophysiology and potentially generate new targets for treatment.
Sponsored by CME LLC for 2.5
Category 1 credits.
Original release date 9/05. Approved for CME credit through 8/31/06.
Upon completion of this educational activity, the reader will be familiar with:
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 GABAA and GABAB 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 GABAA 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 GABAA receptors and are metabotropic, as they decrease calcium and increase potassium channel conductances via cyclic adenosine monophosphate (AMP) effects. Some GABAB receptors are presynaptic autoreceptors, which makes interpretation of studies with GABAB findings more complex. An interesting clinical reflection of the important functional difference between GABA receptor subtypes is the observation that benzodiazepine GABAA receptor modulators such as clonazepam (Klonopin) (Chouinard et al., 1983) or lorazepam (Ativan) (Bradwejn et al., 1990) may attenuate, while the GABAB 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 GABAA 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 GABAB receptors were downregulated, and this effect was reversed by TCAs (Joly et al., 1987; Martin et al., 1989). Imipramine (Tofranil) upregulated GABAB receptors only in those animals that responded behaviorally. Thus, increased activity of GABAA receptors or inhibition of GABAB 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 increase GABAergic neurotransmission by increasing the frequency of GABAA 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).
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 GABAB but fails to alter GABAA receptors. In mice, chronic (but not acute) desipramine (Norpramin), amitriptyline and electroconvulsive therapy increased frontal GABAB 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 GABAB, but not GABAA, receptors (Lloyd et al., 1986, 1985). Another study also found no effect on GABAA 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 GABAB receptors (Pratt and Bowery, 1993). Chronic parenteral administration of some agents (desipramine and citalopram), but not all (amitriptyline and fluoxetine), also increased hippocampal GABAB (but not GABAA) 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 GABAA receptor subtypes, potentially facilitating GABAergic actions.
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 GABAB 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 GABAB receptors. In rats, chronic (but not acute) lithium, carbamazepine and valproate (but not baclofen) increased hippocampal (but not frontal, thalamic or striatal) GABAB (but not GABAA) receptors (Motohashi, 1992; Motohashi et al., 1989), suggesting that hippocampal GABAB receptor mechanisms may be an important commonality of mood stabilizers. Although an earlier study found that chronic valproate significantly increased frontal GABAB 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 GABAA receptors. However, chronic lithium had also been previously reported to reduce rat frontal (but not occipitoparietal or hippocampal) GABAA receptors as assessed by benzodiazepine binding (Hetmar et al., 1983), and decrease striatal and hypothalamic (but not cortical or hippocampal) mixed GABAA and GABAB 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 GABAB 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).
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 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 GABAA receptor modulator allopregnanolone up to fourfold (Marx et al., 2000). Also, olanzapine for one month markedly decreased hippocampal and temporal cortical GABAA 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.
A major neurotransmitter in the human brain, GABA may play a role in the pathophysiology and treatment of mood disorders. Thus, altered activity of GABAA receptors or of GABAB receptors was associated with increased depression in animal models of depression. Benzodiazepines, which modulate GABAA 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 GABAB 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.
Ahluwalia P, Grewaal DS, Singhal RL (1981), Brain gabaergic and dopaminergic systems following lithium treatment and withdrawal. Prog Neuropsychopharmacol 5(5-6):527-530.
Ambrosio AF, Soares-Da-Silva P, Carvalho CM, Carvalho AP (2002), Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res 27(1-2):121-130.
Andersen T, Lingjaerde O (1969), Nitrazepam (Mogadon) as a sleep-inducing agent. An analysis based on a double-blind comparison with phenobarbitone. Br J Psychiatry 115(529):1393-1397.
Backonja MM (1999), Gabapentin monotherapy for the symptomatic treatment of painful neuropathy: a multicenter, double-blind, placebo-controlled trial in patients with diabetes mellitus. Epilepsia 40(suppl 6):S57-S59; discussion S73-S74.
Ballenger JC, Burrows GD, DuPont RL et al. (1988), Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 45(5):413-422.
Bartholini G, Lloyd KG, Scatton B et al. (1985), The GABA hypothesis of depression and antidepressant drug action. Psychopharmacol Bull 21(3):385-388.
Bernasconi R, Hauser K, Martin P (1984), Biochemical aspects of the mechanism of action of valproate. In: Anticonvulsants in Affective Disorders, Emrich HM, Okuma T, Muller AA, eds. New York: Elsevier Science Publishers B.V., pp14-32.
Bernasconi R, Martin P (1979), Effects of antiepiletic drugs on the GABA turnover rate [abstract 251]. Naunyn Schmiedebergs Arch Pharmacol 307:R63.
Biggs CS, Pearce BR, Fowler LJ, Whitton PS (1992), The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study. Brain Res 594(1):138-142.
Borsini F, Mancinelli A, D'Aranno V et al. (1988), On the role of endogenous GABA in the forced swimming test in rats. Pharmacol Biochem Behav 29(2):275-279.
Bowden CL (1995), Predictors of response to divalproex and lithium. J Clin Psychiatry 56(suppl 3):25-30.
Bowden CL, Brugger AM, Swann AC et al. (1994), Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. [Published erratum JAMA 271(23):1830.] JAMA 271(12):918-924 [see comment].
Bowden CL, Calabrese JR, McElroy SL et al. (2000), A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 57(5):481-489 [see comments].
Bowden CL, Calabrese JR, Sachs G et al. (2003), A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. [Published erratum Arch Gen Psychiatry 61(7):680.] Arch Gen Psychiatry 60(4):392-400.
Bowden CL, Grunze H, Mullen J et al. (2005), A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 66(1):111-121.
Bowery NG, Hudson AL, Price GW (1987), GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20(2):365-383.
Bradwejn J, Shriqui C, Koszycki D, Meterissian G (1990), Double-blind comparison of the effects of clonazepam and lorazepam in acute mania. J Clin Psychopharmacol 10(6):403-408.
Bray GA, Hollander P, Klein S et al. (2003), A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 11(6):722-733.
Calabrese JR, Bowden CL, Sachs GS et al. (1999), A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 60(2):79-88.
Calabrese JR, Bowden CL, Sachs G et al. (2003), A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 64(9):1013-1024 [see comment].
Calabrese JR, Keck PE, McElroy SL, Shelton MD (2001), A pilot study of topiramate as monotherapy in the treatment of acute mania. J Clin Psychopharmacol 21(3):340-342.
Calabrese JR, Keck PE Jr, Macfadden W et al. (2005), A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 162(7):1351-1360.
Calabrese JR, Suppes T, Bowden CL et al. (2000), A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 61(11):841-850.
Casey DE, Daniel DG, Wassef AA et al. (2003), Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 28(1):182-192.
Chouinard G (1988), The use of benzodiazepines in the treatment of manic-depressive illness. J Clin Psychiatry 49(suppl):15-20.
Chouinard G, Young SN, Annable L (1983), Antimanic effect of clonazepam. Biol Psychiatry 18(4):451-466.
Compton MT, Nemeroff CB (2000), The treatment of bipolar depression. J Clin Psychiatry 61(suppl 9):57-67.
Davis LL, Bartolucci A, Petty F (2005), Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord 85(3):259-266.
Delbello MP, Findling RL, Kushner S et al. (2005), A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 44(6):539-547.
Emrich HM, von Zerssen D, Kissling W et al. (1980), Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Arch Psychiatr Nervenkr 229(1):1-16.
Fahn S, Cote LJ (1968), Regional distribution of gamma-aminobutyric acid (GABA) in brain of the rhesus monkey. J Neurochem 15(3):209-213.
Farnbach-Pralong D, Bradbury R, Copolov D, Dean B (1998), Clozapine and olanzapine treatment decreases rat cortical and limbic GABA(A) receptors. Eur J Pharmacol 349(2-3):R7-R8.
Feighner JP, Aden GC, Fabre LF et al. (1983), Comparison of alprazolam, imipramine, and placebo in the treatment of depression. JAMA 249(22):3057-3064.
Frye MA, Ketter TA, Kimbrell TA et al. (2000), A placebo-controlled study of lamotrigine and gabapentin monotherapy in mood disorders. J Clin Psychopharmacol 20(6):607-614.
Gottesfeld Z, Ebstein BS, Samuel D (1971), Effect of lithium on concentrations of glutamate and GABA levels in amygdala and hypothalamus of rat. Nat New Biol 234(47):124-125.
Gray JA, Goodwin GM, Heal DJ, Green AR (1987), Hypothermia induced by baclofen, a possible index of GABAB receptor function in mice, is enhanced by antidepressant drugs and ECS. Br J Pharmacol 92(4):863-870.
Gray JA, Green AR (1987), Increased GABAB receptor function in mouse frontal cortex after repeated administration of antidepressant drugs or electroconvulsive shocks. Br J Pharmacol 92(2):357-362.
Greil W, Kleindienst N, Erazo N, Muller-Oerlinghausen B (1998), Differential response to lithium and carbamazepine in the prophylaxis of bipolar disorder. J Clin Psychopharmacol 18(6):455-460.
Grunze H, Erfurth A, Marcuse A et al. (1999), Tiagabine appears not to be efficacious in the treatment of acute mania. J Clin Psychiatry 60(11):759-762.
Hedges DW, Reimherr FW, Hoopes SP et al. (2003), Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 2: improvement in psychiatric measures. J Clin Psychiatry 64(12):1449-1454.
Hetmar O, Nielsen M, Braestrup C (1983), Decreased number of benzodiazepine receptors in frontal cortex of rat brain following long-term lithium treatment. J Neurochem 41(1):217-221.
Higuchi T, Yamazaki O, Takazawa A et al. (1986), Effects of carbamazepine and valproic acid on brain immunoreactive somatostatin and gamma-aminobutyric acid in amygdaloid-kindled rats. Eur J Pharmacol 125(2):169-175.
Hirschfeld RM, Keck PE Jr, Kramer M (2004), Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry 161(6):1057-1065.
Hitchcock E, Teixeira M (1982), Anticonvulsant activation of pain-suppressive systems. Appl Neurophysiol 45(6):582-593.
Hoopes SP, Reimherr FW, Hedges DW et al. (2003), Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 1: improvement in binge and purge measures. J Clin Psychiatry 64(11):1335-1341.
Jefferson JW, Greist JH, Ackerman DK, Carroll J (1987), Lithium Encyclopedia for Clinical Practice, 2nd ed. Washington, D.C.: American Psychiatric Press, Inc.
Johnson BA, Ait-Daoud N, Bowden CL et al. (2003), Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361(9370):1677-1685 [see comments].
Joly D, Lloyd KG, Pichat P, Sanger DJ (1987), Correlation between the behavioural effect of desipramine and GABA-B receptor regulation in the olfactory bulbectomized rat [abstract]. Br J Pharmacol 90:125.
Kanda T, Kurokawa M, Tamura S et al. (1996), Topiramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of spontaneously epileptic rats (SER). Life Sci 59(19):1607-1616.
Keck PE, Marcus R, Tourkodimitris S et al. (2003a), A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 160(9):1651-1658 [see comments].
Keck PE, Taylor VE, Tugrul KC et al. (1993), Valproate treatment of panic disorder and lactate-induced panic attacks. Biol Psychiatry 33(7):542-546.
Keck PE, Versiani M, Potkin S et al. (2003b), Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 160(4):741-748 [see comment].
Ketter TA, Post RM, Denicoff K et al. (1998), Carbamazepine. In: Mania: Clinical and Research Perspectives, Goodnick P, ed. Washington, D.C.: American Psychiatric Press, pp263-300.
Khanna S, Hirschfeld RMA, Karcher K et al. (2003), Risperidone monotherapy in acute bipolar mania. NR424. Presented at the 156th Annual Meeting of the American Psychiatric Association. San Francisco; May 20.
Kimber JR, Cross JA, Horton RW (1987), Benzodiazepine and GABAA receptors in rat brain following chronic antidepressant drug administration. Biochem Pharmacol 36(23):4173-4175.
Kishimoto A, Kamata K, Sugihara T et al. (1988), Treatment of depression with clonazepam. Acta Psychiatr Scand 77(1):81-86.
Leach MJ, Lees G, Riddall DR (1995), Lamotrigine: mechanisms of action. In: Antiepileptic Drugs, 4th ed., Levy RH, Mattson RH, Meldrum BS, eds. New York: Raven Press, pp861-869.
Lloyd KG, Pichat P (1985), Decrease in GABA-B binding in the frontal cortex of olfactory bulbectomized rats. Br J Pharmacol 87:36.
Lloyd KG, Thuret F, Pilc A (1985), Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock. J Pharmacol Exp Ther 235(1):191-199.
Lloyd KG, Thuret F, Pilc A (1986), GABA and the mechanism of action of antidepressant drugs. In: GABA and Mood Disorders: Experimental and Clinical Research. (L.E.R.S. Monograph Series, Vol. IV), Bartholini G, Lloyd KG, Morselli PL, eds. New York: Raven Press, pp33-42.
Lloyd KG, Zivkovic B, Scatton B et al. (1989), The gabaergic hypothesis of depression. Prog Neuropsychopharmacol Biol Psychiatry 13(3-4):341-351.
Loscher W (1980), Effect of inhibitors of GABA transaminase on the synthesis, binding, uptake, and metabolism of GABA. J Neurochem 34(6):1603-1608.
Loscher W (1981), Relationship between drug-induced changes in seizure thresholds and the GABA content of brain and brain nerve endings. Naunyn Schmiedebergs Arch Pharmacol 317(2):131-134.
Loscher W (1989), Valproate enhances GABA turnover in the substantia nigra. Brain Res 501(1):198-203.
Loscher W (1999), Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 58(1):31-59.
Loscher W, Horstermann D (1994), Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma. Naunyn Schmiedebergs Arch Pharmacol 349(3):270-278.
MacKinnon DF, Zandi PP, Cooper J et al. (2002), Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. Am J Psychiatry 159(1):30-35 [see comments].
Maggi A, Enna SJ (1980), Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment. J Neurochem 34(4):888-892.
Maitre L, Baltzer V et al. (1984), Pharmacological and behavioral effects of antiepileptic drugs in animals. In: Anticonvulsants in Affective Disorders, Emrich HM, Okuma T, Muller AA, eds. Princeton, N.J.: Excerpta Medica, pp3-13.
Manji HK, Potter WZ, Lenox RH (1995), Signal transduction pathways. Molecular targets for lithium's actions. Arch Gen Psychiatry 52(7):531-543.
Marcus SR, Nadiger HA, Chandrakala MV et al. (1986), Acute and short-term effects of lithium on glutamate metabolism in rat brain. Biochem Pharmacol 35(3):365-369.
Martin P, Pichat P, Massol J et al. (1989), Decreased GABA B receptors in helpless rats: reversal by tricyclic antidepressants. Neuropsychobiology 22(4):220-224.
Marx CE, Duncan GE, Gilmore JH et al. (2000), Olanzapine increases allopregnanolone in the rat cerebral cortex. Biol Psychiatry 47(11):1000-1004.
Mattson RH, Cramer JA, Collins JF (1992), A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med 327(11):765-771 [see comments].
Mayo CC, Marco E et al. (1978), Antipsychotics and GABA turnover in mammalian brain nuclei. In: Interactions Between Putative Neurotransmitters in the Brain, Garattini S, Pujol JF, Samanin R, eds. New York: Raven Press, pp151-160.
McElroy SL, Arnold LM, Shapira NA et al. (2003), Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. [Published erratum Am J Psychiatry 160(3):612.] Am J Psychiatry 160(2):255-261.
McIntyre RS, Mancini DA, McCann S et al. (2002), Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 4(3):207-213.
Meldrum BS, Chapman AG (1999), Basic mechanisms of gabitril (tiagabine) and future potential developments. Epilepsia 40(suppl 9):S2-S6.
Mendels J (1976), Lithium in the treatment of depression. Am J Psychiatry 133(4):373-378.
Mitsushio H, Takashima M, Mataga N, Toru M (1988), Effects of chronic treatment with trihexyphenidyl and carbamazepine alone or in combination with haloperidol on substance P content in rat brain: a possible implication of substance P in affective disorders. J Pharmacol Exp Ther 245(3):982-989.
Motohashi N (1992), GABA receptor alterations after chronic lithium administration. Comparison with carbamazepine and sodium valproate. Prog Neuropsychopharmacol Biol Psychiatry 16(4):571-579.
Motohashi N, Ikawa K, Kariya T (1989), GABAB receptors are up-regulated by chronic treatment with lithium or carbamazepine. GABA hypothesis of affective disorders? Eur J Pharmacol 166(1):95-99.
Nagaki S, Kato N, Minatogawa Y, Higuchi T (1990), Effects of anticonvulsants and gamma-aminobutyric acid (GABA)-mimetic drugs on immunoreactive somatostatin and GABA contents in the rat brain. Life Sci 46(22):1587-1595.
Nau H, Loscher W (1982), Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse. J Pharmacol Exp Ther 220(3):654-659.
Otero Losada ME, Rubio MC (1986), Acute and chronic effects of lithium chloride on GABA-ergic function in the rat corpus striatum and frontal cerebral cortex. Naunyn Schmiedebergs Arch Pharmacol 332(2):169-172.
Pande AC, Crockatt JG, Janney CA et al. (2000a), Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2(3 pt 2):249-255.
Pande AC, Davidson JR, Jefferson JW et al. (1999), Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 19(4):341-348.
Pande AC, Pollack MH, Crockatt J et al. (2000b), Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 20(4):467-471.
Patsalos PN, Lascelles PT (1981), Changes in regional brain levels of amino acid putative neurotransmitters after prolonged treatment with the anticonvulsant drugs diphenylhydantoin, phenobarbitone, sodium valproate, ethosuximide, and sulthiame in the rat. J Neurochem 36(2):688-695.
Petroff OA, Hyder F, Mattson RH, Rothman DL (1999), Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy. Neurology 52(3):473-478.
Petroff OA, Rothman DL, Behar KL et al. (1996), The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 39(1):95-99.
Petty F (1995), GABA and mood disorders: a brief review and hypothesis. J Affect Disord 34(4):275-281.
Petty F, Sherman AD (1981), GABAergic modulation of learned helplessness. Pharmacol Biochem Behav 15(4):567-570.
Petty F, Trivedi MH, Fulton M, Rush AJ (1995), Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry 38(9):578-591.
Pope HG, McElroy SL, Keck PE, Hudson JI (1991), Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry 48(1):62-68.
Post RM (1988), Time course of clinical effects of carbamazepine: implications for mechanisms of action. J Clin Psychiatry 49(4 suppl):35-48.
Post RM, Ketter TA, Joffe RT, Kramlinger KL (1991), Lack of beneficial effects of l-baclofen in affective disorder. Int Clin Psychopharmacol 6(4):197-207.
Post RM, Uhde TW, Roy-Byrne PP, Joffe RT (1986), Antidepressant effects of carbamazepine. Am J Psychiatry 143(1):29-34.
Powers P, Sachs GS, Kushner SF et al. (2004), Topiramate in adults with acute bipolar I mania: pooled results. NR365. Presented at the 157th Annual Meeting of the American Psychiatric Association. New York; May 4.
Pratt GD, Bowery NG (1993), Repeated administration of desipramine and a GABAB receptor antagonist, CGP 36742, discretely up-regulates GABAB receptor binding sites in rat frontal cortex. Br J Pharmacol 110(2):724-735.
Rattya J, Vainionpaa L, Knip M et al. (1999), The effects of valproate, carbamazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy. Pediatrics 103(3):588-593.
Reddy J, Khanna S, Anand U, Banerjee A (1996), Alprazolam-induced hypomania. Aust N Z J Psychiatry 30(4):550-552.
Rhee DJ, Goldberg MJ, Parrish RK (2001), Bilateral angle-closure glaucoma and ciliary body swelling from topiramate. Arch Ophthalmol 119(11):1721-1723 [see comment].
Rickels K, Chung HR, Csanalosi IB et al. (1987), Alprazolam, diazepam, imipramine, and placebo in outpatients with major depression. Arch Gen Psychiatry 44(10):862-866.
Rickels K, Feighner JP, Smith WT (1985), Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42(2):134-141.
Roberts E, Chase TN, Tower DB (1976), GABA in Nervous System Function. New York: Raven Press.
Rosenthal M (2003), Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry 64(10):1245-1249.
Roth T, Walsh JK (2004), Sleep-consolidating effects of tiagabine in patients with primary insomnia. NR839. Presented at the 157th Annual Meeting of the American Psychiatric Association. New York; May 6.
Rowbotham M, Harden N, Stacey B et al. (1998), Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 280(21):1837-1842 [see comments].
Rubio MC, Otero Losada ME (1986), GABAergic responses to lithium chloride: dependence on dose, treatment length and experimental condition. Adv Biochem Psychopharmacol 42:69-77.
Rush AJ, Schlesser MA, Erman M, Fairchild C (1984), Alprazolam in bipolar-I depressions. Pharmacotherapy 4(1):40-42.
Sachs GS, Altshuler L, Ketter TA et al. (2001), Divalproex versus placebo for the treatment of bipolar depression. Presented at the 40th Annual Meeting of the American College of Neuropsychopharmacology. San Juan, Puerto Rico; Dec. 9-13.
Sakai K, Gao XM, Hashimoto T, Tamminga CA (2001), Traditional and new antipsychotic drugs differentially alter neurotransmission markers in basal ganglia-thalamocortical neural pathways. Synapse 39(2):152-160.
Sanacora G, Mason GF, Rothman DL, Krystal JH (1999), Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56(11):1043-1047.
Sanacora G, Mason GF, Rothman DL et al. (2002), Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159(4):663-665.
Schon FE, Iversen LL (1974), GABA synapses in the central nervous system. Life Sci 15:157-166.
Schwark WS, Loscher W (1985), Comparison of the anticonvulsant effects of two novel GABA uptake inhibitors and diazepam in amygdaloid kindled rats. Naunyn Schmiedebergs Arch Pharmacol 329(4):367-371.
Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE (2000), An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41(suppl 1):S3-S9.
Sherman AD, Petty F (1980), Neurochemical basis of the action of antidepressants on learned helplessness. Behav Neural Biol 30(2):119-134.
Sherman AD, Petty F (1982), Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 35(4):344-353.
Silberstein SD, Neto W, Schmitt J, Jacobs D (2004), Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 61(4):490-495.
Simler S, Gensburger C, Ciesielski L, Mandel P (1976), [Effects of sodium n-dipropylacetate on the GABA level in various areas of the mouse brain.] C R Seances Soc Biol Fil 170(6):1285-1288.
Slevin JT, Ferrara LP (1985), Chronic valproic acid therapy and synaptic markers of amino acid neurotransmission. Neurology 35(5):728-731.
Srisurapanont M, Boonyanaruthee V (1997), Alprazolam and standard antidepressants in the treatment of depression: a meta-analysis of the antidepressant effect. J Med Assoc Thai 80(3):183-188.
Suppes T, Chisholm KA, Dhavale D et al. (2002), Tiagabine in treatment refractory bipolar disorder: a clinical case series. Bipolar Disord 4(5):283-289.
Suppes T, Webb A, Paul B et al. (1999), Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry 156(8):1164-1169.
Taylor CP, Gee NS, Su TZ et al. (1998), A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 29(3):233-249.
Tohen M, Jacobs TG, Grundy SL et al. (2000), Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzapine HGGW Study Group. [Published erratum Arch Gen Psychiatry 59(1):91.] Arch Gen Psychiatry 57(9):841-849.
Tohen M, Sanger TM, McElroy SL et al. (1999), Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 156(5):702-709.
Tohen M, Vieta E, Calabrese J et al. (2003), Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60(11):1079-1088.
Twyman RE, Rogers CJ, Macdonald RL (1989), Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol 25(3):213-220.
Uhde TW, Stein MB, Post RM (1988), Lack of efficacy of carbamazepine in the treatment of panic disorder. Am J Psychiatry 145(9):1104-1109.
Uzunova V, Sheline Y, Davis JM et al. (1998), Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A 95(6):3239-3244.
Walaas I, Fonnum F (1980), Biochemical evidence for gamma-aminobutyrate containing fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat. Neuroscience 5(1):63-72.
Waldmeier PC (1987), Is there a common denominator for the antimanic effect of lithium and anticonvulsants? Pharmacopsychiatry 20(2):37-47.
Waldmeier PC, Baumann PA, Wicki P et al. (1995), Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45(10):1907-1913.
Wang PW, Dieckmann N, Sailasuta N et al. (2002a), 3 Tesla 1H-magnetic resonance spectroscopic measurements of prefrontal cortical gamma-aminobutyric acid (GABA) levels in bipolar disorder patients and healthy volunteers. Abstract 571. Presented at the 57th Annual Convention and Scientific Program of the Society of Biological Psychiatry. Philadelphia; May 16-18. Biol Psychiatry 51(8S):197S.
Wang PW, Santosa C, Schumacher M et al. (2002b), Gabapentin augmentation therapy in bipolar depression. Bipolar Disord 4(5):296-301.
Wassef AA, Dott SG, Harris A et al. (1999), Critical review of GABA-ergic drugs in the treatment of schizophrenia. J Clin Psychopharmacol 19(3):222-232.
White HS, Brown SD, Woodhead JH et al. (1997), Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 28(3):167-179.
Winsberg ME, DeGolia SG, Strong CM, Ketter TA (2001), Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression. J Affect Disord 67(1-3):207-212.
Work Group on Bipolar Disorder (2002), Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 159(4 suppl):1-50.
If you are a first-time user, you must update your profile.
If you are not on the Lifelong Learning site, click here.
You must keep your own records of this activity. Copy this information and include it in your continuing education file for reporting purposes.
CME LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME LLC designates this educational activity for a maximum of 1.5 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits actually spent on the educational activity.
CME LLC is an approved provider of continuing medical education for physicians, nurses and physician assistants in the State of Florida and is registered with CE Broker.
CME LLC is approved by the California Board of Registered Nursing, Provider No. CEP12748, and designates this educational activity for 1.5 contact hours for nurses. The American Nurses Credentialing Center (ANCC) accepts AMA category 1 credit toward recertification requirements.