glyx-13-peptide and Depressive-Disorder--Major

Major depressive disorder (MDD) is a debilitating disorder with increasing prevalence globally. Despite the development of novel treatments for MDD, many patients present with treatment resistant depression (TRD), identified by treatment non-response following one or more adequate trials of an antidepressant. Rapastinel may prove to be a viable treatment for TRD; it has the potential to produce a rapid antidepressant response without serious adverse events and improve functional symptoms. Areas covered: We review the efficacy of rapastinel via completed and on-going clinical trials. The online databases Pubmed, clinicaltrials.gov and clinicaltrialsregister.eu were searched for rapastinel (GLYX-13) treatment in subjects with MDD. Nine clinical trials were identified. Expert opinion: Rapastinel is a novel and potentially transformative treatment for individuals with TRD. There is a limited number of clinical studies so far, but this compound has the potential to provide rapid, reliable and robust antidepressant effects without psychotomimetic and other unwanted side effects. Alternative formulations such as the oral formulation, provide the opportunity for rapastinel to be administered less frequently, i.e. once weekly. Furthermore, the beneficial effects on measures of cognition and suicidality so far, represent a tremendous advantage.

Topics: Administration, Oral; Animals; Antidepressive Agents; Depressive Disorder, Major; Drug Administration Schedule; Humans; Oligopeptides; Receptors, N-Methyl-D-Aspartate; Time Factors

Mammalian brains contain at least 7 primal emotional systems--Seeking, Rage, Fear, Lust, Care, Panic and Play (capitalization reflects a proposed primary-process terminology, to minimize semantic confusions and mereological fallacies). These systems help organisms feel affectively balanced (e.g. euthymic) and unbalanced (e.g. depressive, irritable, manic), providing novel insights for understanding human psychopathologies. Three systems are especially important for understanding depression: The separation distress (Panic) system mediates the psychic pain of separation distress (i.e. excessive sadness and grief), which can be counteracted by minimizing Panic arousals (as with low-dose opioids). Depressive dysphoria also arises from reduced brain reward-seeking and related play urges (namely diminished enthusiasm (Seeking) and joyful exuberance (Play) which promote sustained amotivational states). We describe how an understanding of these fundamental emotional circuits can promote the development of novel antidepressive therapeutics--(i) low-dose buprenorphine to counteract depression and suicidal ideation emanating from too much psychic pain (Panic overarousal), (ii) direct stimulation of the Seeking system to counteract amotivational dysphoria, and (iii) the discovery and initial clinical testing of social-joy-promoting molecules derived from the analysis of the Play system.

Topics: Analgesics, Opioid; Animals; Antidepressive Agents; Bipolar Disorder; Brain; Buprenorphine; Deep Brain Stimulation; Depression; Depressive Disorder, Major; Emotions; Humans; Oligopeptides; Panic; Play and Playthings; Reward; Suicidal Ideation

Approximately 45% of patients with major depressive disorder (MDD) do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents with different mechanisms of action. Early proof of concept (POC) studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate (NMDA) receptor blockers (eg, ketamine) can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist.. In this double-blind, randomized, placebo-controlled study, a single intravenous (IV) dose of GLYX-13 (1, 5, 10, or 30 mg/kg) or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 (Ham-D17), which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration.. GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects.. In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Discovery; Excitatory Amino Acid Agonists; Female; Glycine; Humans; Male; Middle Aged; Oligopeptides; Receptors, N-Methyl-D-Aspartate; Treatment Outcome; Young Adult

GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.

Topics: Animals; Antidepressive Agents; Chemistry Techniques, Synthetic; Depressive Disorder, Major; Mice; Models, Molecular; Molecular Structure; Neurons; Oligopeptides; Receptors, N-Methyl-D-Aspartate; Spectrum Analysis; Structure-Activity Relationship