Strategy for development of fast-onset antidepressive agents: Candidate hypothesis of monoamine (5-HT)-nonmonoamine (Glu/GABA) long-feedback neural circuit / 中国药理学与毒理学杂志

ABSTRACT

Depression has become a serious global public health concern. Almost all the current first-line antidepressants developed are based on the classical "monoamine hypothesis (strategy)". These drugs commonly possess a series of defects, including slow-onset, lower response, cognitive injury and suicidal tendencies. So, by breaking through the classical monoamine strategy framework, developing new antidepressants with fast-onset, cognitive-enhancement and less adverse reactions is a major global demand. In 2019, fast-onset antidepressants S-ketamine(S-Ket) and brexanolone were approved by the FDA of USA, which opened up a new field for the non-monoamine strategy mainly based on the N-methyl-D-aspartic acid (NMDA) and y-aminobutyric acid A (GABAA) receptors. There are currently two main trends in the research and development of rapid onset antidepressants the optimized multi-target monoamine strategy (modem monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance regulation. According to the research of our laboratory and foreign colleagues, we propose a candidate hypothesis of the "monoamine (5-HT)-nonmonoamine (Glu/ GABA) long feedback neural circuit". It is believed that both monoamine regulatory mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoamine regulatory mechanisms (Glu/GABA neurons located in the prefrontal cortex and other brain regions) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long-feedback neural loop mediating the fast synaptogenesis of the brain regions including the prefrontal cortex and hippocampus. Based on this hypothesis, we propose five candidate strategies for rapid onset of antidepressant development. (1) By relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating glutamatergic pyramidal neurons, the rapid excitation/inhibition (E/l) balance can be achieved; (2) simultaneous regulation of 5-HT neuronal activity and E/l balance by 5-HT transporter and 5-HT receptors such as 5-HT1A (that means simultaneous enhancement of monoamine and nonmonoamine links); (3) direct activation of mammalian sirolimus (rapamycin) target protein complex 1 (mTORCI) and rapid enhance ment of the brain- derived neurotrophic factor (BDNF)- mTOR signaling; (4) stimulation of the fast release of BDNF in the brain; (5) positive allosteric modulator of GABAA receptor. We hope that these ideas and strategies will bring about a breakthrough for the development of a new generation of antidepressants in China in the future, and provide useful reference for further discovery of candidate targets for rapid antidepressant therapy.