Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

Zorumski, Charles F.; Nägele, Peter; Mennerick, Steven; Conway, Charles R.

doi:10.3389/fpsyt.2015.00172

Cited by 42 publications

(30 citation statements)

References 135 publications

(192 reference statements)

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“… 7 , 8 However the dose of ketamine used in the treatment of resistant major depression is similar to that shown to have psychotomimetic and cognitive effects. 9 …”

Section: Introductionmentioning

confidence: 99%

The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders

2017

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Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor. It has recently been found to have antidepressant effects and is a drug of abuse, suggesting it may have dopaminergic effects. To examine the effect of ketamine on the dopamine systems, we carried out a systematic review and meta-analysis of dopamine measures in the rodent, human and primate brain following acute and chronic ketamine administration relative to a drug-free baseline or control condition. Systematic search of PubMed and PsychInfo electronic databases yielded 40 original peer-reviewed studies. There were sufficient rodent studies of the acute effects of ketamine at sub-anaesthetic doses for meta-analysis. Acute ketamine administration in rodents is associated with significantly increased dopamine levels in the cortex (Hedge’s g= 1.33, P<0.01), striatum (Hedge’s g=0.57, P<0.05) and the nucleus accumbens (Hedge’s g=1.30, P<0.05) compared to control conditions, and 62–180% increases in dopamine neuron population activity. Sub-analysis indicated elevations were more marked in in vivo (g=1.93) than ex vivo (g=0.50) studies. There were not enough studies for meta-analysis in other brain regions studied (hippocampus, ventral pallidum and cerebellum), or of the effects of chronic ketamine administration, although consistent increases in cortical dopamine levels (from 88 to 180%) were reported in the latter studies. In contrast, no study showed an effect of anaesthetic doses (>100 mg kg−1) of ketamine on dopamine levels ex vivo, although this remains to be tested in vivo. Findings in non-human primates and in human studies using positron emission tomography were not consistent. The studies reviewed here provide evidence that acute ketamine administration leads to dopamine release in the rodent brain. We discuss the inter-species variation in the ketamine induced dopamine release as well as the implications for understanding psychiatric disorders, in particular substance abuse, schizophrenia, and the potential antidepressant properties of ketamine, and comparisons with stimulants and other NMDA antagonists. Finally we identify future research needs.

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“… 7 , 8 However the dose of ketamine used in the treatment of resistant major depression is similar to that shown to have psychotomimetic and cognitive effects. 9 …”

Section: Introductionmentioning

confidence: 99%

The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders

2017

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“…Given the volume of information obtained from research on ketamine, it appears that NMDAR antagonists have great potential as a new class of antidepressants. This is supported by studies on other NMDAR antagonists, such as nitrous oxide (Zorumski et al, 2015) and lanicemine (Sanacora et al, 2014; Downey et al, 2016), which show great promise as potential antidepressants in pre-clinical models. However, memantine does not display antidepressant properties (Zarate et al, 2006), and numerous NMDAR agonists, in particular agonists of the glycine site (e.g., GLYX-13, Moskal et al, 2014), may be potential treatments for depression.…”

Section: Nmdar Modulation As a Therapeutic Strategy: Conflicting Evidmentioning

confidence: 88%

ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression

Chan

Matthews

Burnet

2017

Front. Mol. Neurosci.

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Since the discovery that a single dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, had rapid and long-lasting antidepressant effects, there has been increased interest in using NMDAR modulators in the pharmacotherapy of depression. Ketamine’s efficacy seems to imply that depression is a disorder of NMDAR hyperfunctionality. However, studies showing that not all NMDAR antagonists are able to act as antidepressants challenge this notion. Furthermore, NMDAR co-agonists have also been gaining attention as possible treatments. Co-agonists such as D-serine and sarcosine have shown efficacy in both pre-clinical models and human trials. This raises the question of how both NMDAR antagonists and agonists are able to have converging behavioral effects. Here we critically review the evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists, and collate several theories on how both activation and inhibition of NMDARs appear to have antidepressant effects.

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“…One of the known mechanisms of induction of NO production in the CNS is the activation of nNOS by an increased influx of Ca ions due to the activation of NMDA receptors (Bredt and Snyder, 1990;Weissman et al, 2002). The NMDA receptor has been studied as a pharmacological target for psychiatric treatments (Réus et al, 2016;Zorumski et al, 2015).…”

Section: Possible Mechanismsmentioning

confidence: 99%

Global arginine bioavailability ratio is decreased in patients with major depressive disorder

et al. 2017

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IntroductionThe global arginine bioavailability ratio (GABR) is used to estimate arginine supply. Arginine is precursor to nitric oxide (NO) that has been suggested to play a role in major depressive disorder (MDD). NO also participates in neuronal, inflammatory and cardioprotective functions.ObjectivesTo compare GABR between:– D patients and non-depressed controls;– remitted and non-remitted MDD patients;– baseline and follow-up within remitted and non-remitted MDD groups.AimsTo investigate the role of NO production in MDD.MethodsThe sample comprised 99 MDD patients and 253 non-depressed controls (Beck Depression Inventory scores < 10) aged 20–71 years. Altogether, 78 patients returned for the follow-up; 33 were remitted and 45 non-remitted. GABR was calculated from serum levels of arginine, citrulline and ornithine, which were analysed using ultra-performance liquid chromatography. Differences between the study groups were examined using logistic regression adjusted for age, gender, smoking, alcohol use, physical exercise and glycated haemoglobin. The follow-up regression analyses were adjusted for age, gender and physical exercise.ResultsLowered GABR was associated with belonging to the MDD group (OR 0.13, 95% CI 0.03–0.50). Exclusion of participants using anti-depressants that were associated with measured metabolites did not change the results. Over the follow-up period, the remitted and non-remitted groups both showed an increase in GABR (Z = –.53, P < 0.001 and Z = –3.00, P = 0.003, respectively).ConclusionsDecreased GABR may characterise MDD. This could affect neuronal, immunological and cardioprotective functions of NO.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

Cited by 42 publications

References 135 publications

The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders

The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders

ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression

Global arginine bioavailability ratio is decreased in patients with major depressive disorder

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