The molecular pathophysiology of depression and the new therapeutics

Abstract

Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long-lasting antidepressant effects in treatment-resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects.

Keywords: (R)‐ketamine; (S)‐ketamine; ketamine; major depressive disorder (MDD).

FIGURE 1

The potential underlying mechanisms of depression

FIGURE 2

Timeline of the key events history of ketamine and its metabolic formation of hydroxynorketamines from ketamine. (A) The key events of the ketamine findings and development for MDD. (B) The ADME parameters, pharmacokinetic properties, drug‐like nature, and medicinal chemistry friendliness of ketamine metabolites predicted by SwissADME. The radar plot reflects the physicochemical properties in regard to six aspects: SIZE (molecular weight), INSOLU (solubility), LIPO (lipophilicity), POLAR (polarity), FLEX (flexibility), and INSATU (insaturation). The structure formula of Figure 2B was drawn by ChemDraw20.0.

FIGURE 3

Ketamine pharmacological profile and its underlying mechanisms for rapid‐acting antidepressant action. (A) The neurocircuits implicated in the ketamine rapid antidepressant action. (B) Four potential mechanisms underlying the rapid and sustained antidepressant action of ketamine in the PFC and hippocampus: (1) Disinhibition of glutamate release from GABAergic interneurons by blocking the presynaptic NMDARs in the mPFC and hippocampus. (2) Inhibition of the extra‐synaptic NMDARs subunit (NR2B) of the pyramidal neurons in the cortex. (3) Inhibition of the spontaneous NMDARs‐mediated miniature excitatory postsynaptic current (mEPSCs) at rest in the PFC and hippocampus. (4) Direct AMPARs triggering. (C) Inhibition of NMDAR‐dependent neuron burst firing in the LHb.

FIGURE 4

The construction and analysis of the Compound‐Target‐Pathway. The candidate ketamine metabolites (yellow diamond mesh node) are divided into the following groups based on the metabolic processes: (R,S)‐KET, (R,S)‐norKET, (R,S)‐DHNK, (2,6)‐HKs, and (2,6; 2,5; 2,4)‐HNKs. The figure was drawn by Cytoscape.

FIGURE 5

The protein–protein interaction (PPI) networks of ketamine metabolites. The figure was drawn by Cytoscape.