Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

Abstract

Major depressive disorder takes at least 3 weeks for clinical anti-depressants, such as serotonin selective reuptake inhibitors, to take effect, and only one-third of patients remit. Ketamine, a kind of anaesthetic, can alleviate symptoms of major depressive disorder patients in a short time and is reported to be effective to treatment-resistant depression patients. The rapid and strong anti-depressant-like effects of ketamine cause wide concern. In addition to ketamine, caloric restriction and sleep deprivation also elicit similar rapid anti-depressant-like effects. However, mechanisms about the rapid anti-depressant-like effects remain unclear. Elucidating the mechanisms of rapid anti-depressant effects is the key to finding new therapeutic targets and developing therapeutic patterns. Therefore, in this review we summarize potential molecular and cellular mechanisms of rapid anti-depressant-like effects based on the pre-clinical and clinical evidence, trying to provide new insight into future therapy.

Major Depression: One Brain, One Disease, One Set of Intertwined Processes

“…Possibly, because 5-HT action across discrete 5-HT receptor subtypes is thought to modulate GABAergic interneurons that influence Glu circuits involved in cognitive functions [ 285 ], the changes in 5-HT levels might result in alterations in the levels of Glu, which is essential for cognitive processing. Therapeutic agents that modulate Glu transmission, e.g., memantine and ketamine [ 286 ], have demonstrated antidepressant-like properties [ 287 ] to the point that ketamine-based drugs were “approved by the FDA for treating of treatment-resistant MDD” [ 288 ].…”

The Efficacy and Safety of Intranasal Formulations of Ketamine and Esketamine for the Treatment of Major Depressive Disorder: A Systematic Review

“…The effects of ketamine are also probably due to its action on the dopaminergic system (particularly via the D 2 receptor) by restoring dopaminergic neurotransmission in brain regions that control motivation and reward and reducing stimulation in the regions involved in anhedonia. Ketamine also acts on other types of receptors, such as serotonin receptors 5–HT 2 and 5-HT 1B , opioids receptors µ and κ, and muscarinic receptor M 1 [ 15 , 16 ]. Thus, intravenously administered ketamine at a subanesthetic dose (0.5 mg/kg) demonstrated a robust and rapid improvement in depressive symptoms in MDD patients with TRD [ 17 , 18 , 19 ].…”