An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression

Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, Maryland, USA.
Biological Psychiatry (Impact Factor: 10.26). 03/2005; 57(4):430-2. DOI: 10.1016/j.biopsych.2004.11.023
Source: PubMed


Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression.
This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of >/=20 received riluzole (50-200 mg/day) for 8 weeks.
Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated.
Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.

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    • "By acting on sodium and calcium ion channels, lamotrigine inhibits presynaptic release of glutamate (Lees and Leach, 1993), and thus prevents excessive stimulation of serotonin, which secondarily would impede the shutdown of dorsal raphe serotonin neuron firing. Two other glutamate modulating agents have been successfully used in TRD as monotherapy: (1) riluzole, an FDA approved for amyotrophic lateral sclerosis, with a complex mechanism of action including glutamate release inhibition and reuptake enhancement (Zarate et al., 2004, 2005; Sanacora et al., 2007), and (2) sub-anesthetic doses of ketamine infusion, a dissociative anesthetic agent that possesses NMDA antagonist effects (Berman et al., 2000; Zarate et al., 2006; Valentine et al., 2011). Relevance of the antiglutamatergic effects of lamotrigine is suggested by the rapid onset of ketamine, also an antiglutamatergic through inhibition of NMDA receptors. "
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    ABSTRACT: First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are less than 50%. The authors examine the putative biological substrates underlying “Treatment Refractory Depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin (5-HT) system becomes impervious to the desired enhancement of 5-HT neurotransmission by SSRI’s. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple 5-HT deficit state but rather an excess of midbrain peri-raphe 5-HT and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in 5-HT-mediated neuroplasticity. Glutamate, 5-HT, noradrenaline and histamine are activated by stress and exert an inhibitory effect on 5-HT outflow, in part by “flooding” 5-HT1A autoreceptors by 5-HT itself. Certain factors putatively exacerbate this scenario- presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder- each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing 5-HT neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on 5-HT neurons. Future studies are recommended to test this biologically based approach for TRD.
    Frontiers in Behavioral Neuroscience 05/2014; 8:189. DOI:10.3389/fnbeh.2014.00189 · 3.27 Impact Factor
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    • "Another open-label study of riluzole in BPD reported changes in glutamate metabolites and significant improvements in depressive symptoms.41 An 8-week augmentation trial of riluzole (50–200 mg/day) with lithium in bipolar depression reported significant improvements in depression ratings at weeks 5–8, without evidence of hypomania or mania.42 Another open-label trial of riluzole augmentation of ongoing medications in TRD demonstrated significant decreases in depression and anxiety severity that reached significance by the end of the first riluzole treatment week and persisted for the 12-week duration of the study.43 "
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    ABSTRACT: Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.
    Neuropsychiatric Disease and Treatment 08/2013; 9:1101-12. DOI:10.2147/NDT.S36689 · 1.74 Impact Factor
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    • "Finally, an increasing interest on glutamatergic neurotransmission in depression stemmed from trials reporting antidepressant effects of the NMDA antagonists ketamine122 and the glutamatergic modulator riluzole.123 "
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    ABSTRACT: Chronotherapeutics refers to treatments based on the principles of circadian rhythm organization and sleep physiology, which control the exposure to environmental stimuli that act on biological rhythms, in order to achieve therapeutic effects in the treatment of psychiatric conditions. It includes manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance, and controlled exposure to light and dark. The antidepressant effects of chronotherapeutics are evident in difficult-to-treat conditions such as bipolar depression, which has been associated with extremely low success rates of antidepressant drugs in naturalistic settings and with stable antidepressant response to chronotherapeutics in more than half of the patients. Recent advances in the study of the effects of chronotherapeutics on neurotransmitter systems, and on the biological clock machinery, allow us to pinpoint its mechanism of action and to transform it from a neglected or "orphan" treatment to a powerful clinical instrument in everyday psychiatric practice.
    12/2012; 14(4):401-11.
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