An Open-Label Trial of Riluzole in Patients With Treatment-Resistant Major Depression

Zarate, Carlos A.; Payne, Jennifer L.; Quiróz, Jorge A.; Sporn, Jonathan; Denicoff, Kirk K.; Luckenbaugh, David A.; Charney, Dennis S.; Manji, Husseini K.

doi:10.1176/appi.ajp.161.1.171

Cited by 297 publications

(194 citation statements)

References 13 publications

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“…14 A recent series of openlabelled studies and case reports demonstrated its efficacy. [15][16][17][18][19] Although the glutamatergic system may influence directly or indirectly the serotonergic and noradrenergic neurotransmission, there are only few data in the literature dealing with this interaction. NMDA receptor antagonists increase the serotonin levels in the brain.…”

Section: Glutamate In Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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Section: Glutamate In Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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“…[215][216][217] Supporting this idea, there is now preliminary evidence that riluzole, another drug that inhibits the release of glutamate, also has antidepressant properties both in MDD and BD. 218,219 Riluzole, approved by the FDA for the treatment of amyotrophic lateral sclerosis, exhibits neuroprotective properties in animal models of Parkinson's disease, NMDA receptor hypofunction neurotoxicity, ischemia and traumatic CNS injury. 212,213 NMDA receptor antagonism.…”

Section: Glutamatergic Strategiesmentioning

confidence: 99%

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Carlson¹,

Singh²,

Zarate³

et al. 2006

NeuroRX

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135

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Summary:Major depressive disorder and bipolar disorder are severe mood disorders that affect the lives and functioning of millions each year. The majority of previous neurobiological research and standard pharmacotherapy regimens have approached these illnesses as purely neurochemical disorders, with particular focus on the monoaminergic neurotransmitter systems. Not altogether surprisingly, these treatments are inadequate for many individuals afflicted with these devastating illnesses. Recent advances in functional brain imaging have identified critical neural circuits involving the amygdala and other limbic structures, prefrontal cortical regions, thalamus, and basal ganglia that modulate emotional behavior and are disturbed in primary and secondary mood disorders. Growing evidence suggests that mechanisms of neural plasticity and cellular resilience, including impairments of neurotrophic signaling cascades as well as altered glutamatergic and glucocorticoid signaling, underlie the dysregulation in these circuits. The increasing ability to monitor and modulate activity in these circuits is beginning to yield greater insight into the neurobiological basis of mood disorders. Modulation of dysregulated activity in these affective circuits via pharmacological agents that enhance neuronal resilience and plasticity, and possibly via emerging nonpharmacologic, circuitry-based modalities (for example, deep brain stimulation, magnetic stimulation, or vagus nerve stimulation) offers promising targets for novel experimental therapeutics in the treatment of mood disorders.

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“…Charney's group 127,128 reported open-label efficacy for riluzole in patients with refractory depression and those with bipolar depression. Gorman's group 129 presented similar uncontrolled data for riluzole in patients with GAD.…”

Section: Drugs With Effects On Glutamatergic Neurotransmissionmentioning

confidence: 99%

Advances in the treatment of anxiety: Targeting glutamate

Simon

Gorman

2006

NeuroRX

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Our current psychopharmacological treatments for anxiety disorders evince a number of shortcomings, including troublesome side effects and lack of primary effects. Whereas many new drugs have been developed in the past few decades, most are based on outmoded theories of the pathogenesis of these disorders (i.e., monoamine hypotheses), thus frustrating our ability to create more specific and effective interventions. Recently, however, the neurobiological literature has shown a convergence of findings focusing on the glutamatergic system in anxiety disorders, and the growth of pharmacological tools targeting these receptors has led to the development of novel treatments having anxiolytic effects in humans and animals alike. Additionally, as this system is showing promise as a final common pathway in the pathogenesis of anxiety disorders, we may be able to employ glutamate-specific neuroimaging techniques (e.g., N-acetyl-aspartate, GLX) to both guide treatment decisions and present reliable objective biomarkers for treatment efficacy.

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An Open-Label Trial of Riluzole in Patients With Treatment-Resistant Major Depression

Abstract: Although preliminary, these results indicate that riluzole may have antidepressant properties in some patients.

Cited by 297 publications

References 13 publications

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Advances in the treatment of anxiety: Targeting glutamate

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