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.

Keywords: depression; ketamine; neural circuit; rapid anti-depressant; synaptic plasticity.

FIGURE 1

The neural circuits of depression affected by ketamine. ACC, anterior cingulate gyrus; BLA, basolateral amygdala; Dorsal PFC, dorsal pre‐frontal cortex; DRN, dorsal raphe nucleus; HP, hippocampus; mPFC, medial pre‐frontal cortex

FIGURE 2

Proposed mechanisms of ketamine act on synaptic plasticity. AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor; BDNF, brain‐derived neurotrophic factor; eEF2, eukaryotic elongation factor 2; GSK‐3β, glycogen synthase kinase‐3β; mTORC1, mechanistic target of rapamycin complex 1; NMDAR, N‐methyl‐d‐aspartate receptor; P70S6K, P70S6 kinase; PSD‐95, post‐synaptic density‐95; TrkB, tropomyosin receptor kinase B

FIGURE 3

Proposed mechanisms of CR act on synaptic plasticity. AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor; BDNF, brain‐derived neurotrophic factor; ERK, extracellular signal‐regulated kinase; GHS‐R1a, growth hormone secretagogue receptor 1a; PI3K, phosphatidylinositol 3‐kinase; PKA, protein kinase A

FIGURE 4

Proposed mechanisms of SD act on synaptic plasticity. A1R, A1 receptors; AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor; mGlu5, metabotropic glutamate receptor 5; mTOR, mechanistic target of rapamycin; SD, sleep deprivation