The interactive effects of ketamine and magnesium upon depressive-like pathology

Abstract

Approximately one-third of patients with major depressive disorders (MDDs) are resistant to current treatment methods, and the majority of cases relapse at some point during therapy. This has resulted in novel treatments being adopted, including subanesthetic doses of ketamine, which affects aberrant neuroplastic circuits, glutamatergic signaling, and the production of brain-derived neurotrophic factor. Ketamine rapidly relieves depressive symptoms in treatment-resistant major depressive disorder patients with effects that last for up to 2 weeks even after a single administration. However, it is also a drug with an abusive potential and can have marked side effects. Hence, this study aimed at enhancing the antidepressant-like effects of ketamine (allowing for lower dosing regimens) by coadministering magnesium hydroaspartate (Mg2+ normally affects the same receptors as ketamine) and also assessed whether an Mg2+-deficient diet would modify the impact of ketamine. It was found that a single 15 mg/kg dose of ketamine did indeed induce rapid antidepressant-like effects in the forced swim test but did not affect brain levels of the brain-derived neurotrophic factor. Contrary to our hypothesis, magnesium administration or deficiency did not influence the impact of ketamine on these outcomes. Thus, these data do not support the use of magnesium as an adjunct agent and instead suggest that further research involving other antidepressant and animal models is required to confirm the present findings.

Magnesium in Ketamine Administration in Treatment-Resistant Depression

“…In preclinical studies, magnesium administered together with a low dose NMDA antagonist caused a reduction in depressive-like behaviors during the animal depression model test-FST (forced swim test) in mice [17,19]. One animal study hypothesized about magnesium potentially being a co-factor that would increase the effect of ketamine but not confirm the usefulness of magnesium as a supportive treatment for ketamine in depression in mice [7]. Other studies suggested magnesium supplementation to antidepressants-such as imipramine, fluoxetine, citalopram, tianeptine, and bupropion-resulted in a synergistic antidepressant effect in FST paradigm [20,21].…”

“…Current antidepressant treatment (ADT) includes drugs exhibiting a homogeneous mechanism of action mainly related to the regulation of the monoaminergic systems, with unmet needs in non-monoaminergic mechanisms of action [2,4]. Pathophysiology of depression is complex and it also incorporates glutamatergic system and magnesium ions imbalance [5][6][7].…”