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Novel Glutamatergic Treatments for Severe Mood Disorders.

ABSTRACT: All currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system and have varying affinities for serotonergic, norepinephrine-ergic, and/or dopaminergic receptors. Unfortunately, these drugs are only effective in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of MDD. Here, we review the putative involvement of the glutamate receptor subtypes-N-methyl-D-aspartate (NMDA), ?-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and the group I, II, and III metabotropic glutamate receptors (mGluRs)-in the development of novel and more effective treatments for MDD as well as preclinical and clinical trials of drugs targeting these receptors. The rapid and robust antidepressant effects of ketamine-an NMDA receptor antagonist-have been consistently replicated in multiple trials. Other glutamatergic drugs have been investigated with varying success. Here, we highlight some of the most interesting results, including: 1) repeated oral, intramuscular, and sublingual ketamine appears to be less robustly effective than intravenous ketamine, but also causes fewer significant adverse effects; 2) the glycine partial agonist GLYX-13 appears to be effective both as monotherapy and adjunctive treatment in the treatment of MDD. An oral analogue, NRX-1074, is currently under investigation; and 3) mGluR modulators targeting mGluR5 have demonstrated convincing preclinical results.

SUBMITTER: Park M

PROVIDER: S-EPMC4725605 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Novel Glutamatergic Treatments for Severe Mood Disorders.

Park Minkyung M Niciu Mark J MJ Zarate Carlos A CA

Current behavioral neuroscience reports 20151009 4

All currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system and have varying affinities for serotonergic, norepinephrine-ergic, and/or dopaminergic receptors. Unfortunately, these drugs are only effective in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of MDD. Her ...[more]

PMID: 26824031

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Project description:The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

Project description:BackgroundThe association between infertility treatments and mental disorders has been poorly addressed. This work aims to review current evidence on the psychopathological effects of hormonal treatments used for infertility on women and the occurrence of newly diagnosed mood and psychotic disorders.MethodsA systematic review was performed by searching PubMed and clinicaltrials.gov databases from inception until September 2019. Clinical trials on hormone treatments for infertility in patients with mood or psychotic disorders, as well as those evaluating the onset of symptoms, were included. Selected studies were published in English, Spanish, and Dutch language peer-reviewed journals. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Observational studies and case reports were excluded. Effect sizes for changes in depressive symptoms were calculated with Hedges'g and Cohen's d confidence intervals. A meta-analysis was not performed due to the heterogeneity of hormonal compounds in protocols.ResultsFrom 1,281 retrieved records, nine trials were included; all of them were conducted in non-clinical populations. Four trials compared Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists, showing a better mood profile for hormonal protocols including antagonists in one trial. Two trials compared protocols using GnRH agonists/antagonists versus natural cycle protocols (without gonadotropin stimulation), with a better mood profile (less depressive symptoms) in those protocols without gonadotropin stimulation. Other studies compared long and short protocols of GnRH agonists (no differences); two GnRH agonists, buserelin, and goserelin (no differences); and two patterns of clomiphene vs placebo administration (no differences). None of the selected studies investigated the risk of relapse in women with a previous diagnosis of depressive or psychotic disorders. When exploring pre-post changes in depressive symptoms, effect sizes suggested mild mood worsenings for most protocols (effect sizes ≤ -0.4), with the following pattern (worse to better): GnRH agonist > GnRH antagonist > no gonadotropin stimulation.ConclusionsThis is the first systematic review exploring the psychopathological effects of hormonal infertility treatments. Our study suggests that protocols without gonadotropin stimulation show a better mood profile when compared to those using GnRH antagonists or GnRH agonists. Future studies need to include patients with major mood and psychotic disorders.

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Novel Glutamatergic Treatments for Severe Mood Disorders.

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Novel Glutamatergic Treatments for Severe Mood Disorders.

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