Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial

Nägele, Peter; Duma, Andreas; Kopec, Michael; Gebara, Marie Anne; Parsoei, Alireza; Walker, Marie C.; Janski, Alvin M.; Panagopoulos, Vassilis N.; Cristancho, Pilar; Miller, J. Philip; Zorumski, Charles F.; Conway, Charles R.

doi:10.1016/j.biopsych.2014.11.016

Cited by 185 publications

(245 citation statements)

References 49 publications

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“…This NMDA receptor blocker may act at least in part by decreasing the high firing rate state of attractor networks by reducing transmission in the recurrent collateral excitatory connections between the neurons (Deco et al, 2013;Rolls, 2012;Deco, 2010, 2015;Rolls et al, 2008c). Another NMDA receptor blocker, nitrous oxide, has also been shown to have an antidepressant effect, though the therapeutic use of nitrous oxide is not recommended because it produces vitamin B12 depletion (Nagele et al, 2015). Electroconvulsive therapy (ECT), which may have antidepressant effects, may also knock the non-reward system out of its attractor state, and this may contribute to any antidepressant effect.…”

Section: Evidence Consistent With the Theorymentioning

confidence: 99%

A non-reward attractor theory of depression

Rolls

2016

Neuroscience & Biobehavioral Reviews

153

174

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Neuroscience and Biobehavioral Reviews, in press (May 2016) \papers\Emotion\depression\depression16b.docx 2 SummaryA non-reward attractor theory of depression is proposed based on the operation of the lateral orbitofrontal cortex and supracallosal cingulate cortex. The orbitofrontal cortex contains error neurons that respond to non-reward for many seconds in an attractor state that maintains a memory of the nonreward. The human lateral orbitofrontal cortex is activated by non-reward during reward reversal, and by a signal to stop a response that is now incorrect. Damage to the human orbitofrontal cortex impairs reward reversal learning. Not receiving reward can produce depression. The theory proposed is that in depression, this lateral orbitofrontal cortex non-reward system is more easily triggered, and maintains its attractor-related firing for longer. This triggers negative cognitive states, which in turn have positive feedback top-down effects on the orbitofrontal cortex non-reward system. Treatments for depression, including ketamine, may act in part by quashing this attractor. The mania of bipolar disorder is hypothesized to be associated with oversensitivity and overactivity in the reciprocally related reward system in the medial orbitofrontal cortex and pregenual cingulate cortex.

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Section: Evidence Consistent With the Theorymentioning

confidence: 99%

A non-reward attractor theory of depression

Rolls

2016

Neuroscience & Biobehavioral Reviews

153

174

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“…These results have now been replicated in numerous observational and clinical trials (see Krystal et al, 2013 for a review). Moreover, several other drugs that work as NMDA antagonists including lanicemine (Sanacora et al, 2014), memantine (Kollmar et al, 2008) and nitrous oxide (Nagele et al, 2014) have all shown antidepressant properties. Furthermore, a range of neuroimaging techniques have recently been employed to assess the effects of ketamine on brain amino acid neurotransmitter levels (Salvadore et al, 2011) with a view to stratifying patients into response groups.…”

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confidence: 99%

Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex

Shaw

Saxena

Jackson

et al. 2015

European Neuropsychopharmacology

105

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“…One recently published randomized, blind, placebocontrolled crossover pilot study compared the antidepressant effects of inhaled nitrous oxide (administered over 1 h) with placebo in patients with TRD (n = 20). 31 Nitrous oxide rapidly decreased symptoms of depression within 2 h; these effects were sustained for at least 24 h. Response to nitrous oxide was 20%, and remission was 15%. Side effects were mild to moderate in nature, with no dissociation or psychotomimetic side effects appreciated.…”

Section: Novel Therapeutics: Review Glutamatergic Modulatorsmentioning

confidence: 96%

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

Papakostas

Ionescu

2015

Mol Psychiatry

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Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments--especially for treatment-resistant depression (TRD)--are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.

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Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial

Abstract: This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.

Cited by 185 publications

References 49 publications

A non-reward attractor theory of depression

A non-reward attractor theory of depression

Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

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