Science: Breakthrough! Chinese researchers have discovered a new target drug for depression that takes effect quickly within 2 hours and has no side effects

Recently, Chinese scientists have discovered a small molecule compound ZZL-7, which acts quickly in 2 hours and produces antidepressant effects without adverse side effects. This compound, or a similar reagent, could serve as a new, fast-acting treatment for Major Depressive Disorder (MDD).

Depression is a common mental disease, its incidence is increasing year by year, prone to suicide and other serious consequences. The monoamine hypothesis is the theoretical basis for the mainstream antidepressants, but these drugs are the common disadvantages of delay effect, classic antidepressants fluoxetine needs 2-4 weeks began to emerge curative effect, seriously hindered the intensive treatment in the acute phase of depression patients, and also the low efficiency, the effect of such drugs is not stable, some patients can appear even aggravate symptoms.

Thus increasing the concentration of monoamine neurotransmitters in the synaptic cleft produces antidepressant effects. Accordingly, Sehildkraut JJ first proposed the catecholamine hypothesis of emotional disorders, and believed that the occurrence of depression was related to the lack of catecholamines in the brain, especially Norepinephrine (NE). Since then, Coppen A has found that abnormal serotonin function is associated with depressed mood and suicidal behavior, and together with subsequent findings on serotonin function in depressed patients, the serotonin hypothesis of depression has been proposed. In recent years, the research progress of monoamine transmitters and corresponding receptors in depression is of great significance for the pathogenesis of depression, especially for the development of drugs.

Recently, Qigang Zhou and other researchers from Nanjing Medical University collaborated to design fast-acting antidepressants by de-associating SERT with nNOS in the DRN. "Design of fast-onset antidepressants by dissociating SERT from nNOS in the dorsal raphe nucleus of the Brain" is published October 28 in Science in the DRN.

The researchers designed the fast-acting antidepressant to act by disrupting serotonin transporter in the dorsal raphe nucleus (DRN) SERT and neuronal nitric oxide synthase (nNOS). Enhanced SerT-NNOS interactions in DRNS cause depression-like phenotypes and explain depressive behaviors caused by CMS (Chronic Tolerant mild stress). SERT may delay onset or even aggravate depression.

The dorsal raphe nucleus (DRN) is the main source of serotonin in the brain. It projects to the cerebral cortex and limbic system and plays an important role in regulating depressive mood. Under physiological conditions, activation of somatic dendritic cells 5-HT1ARautos in the DRN inhibits neural firing of serotonergic neurons, resulting in reduced serotonin release in the cortex, HPC, and other parts of the brain. In depressive states, DRN 5-HT1ARautos are highly active, resulting in reduced firing frequency of serotonin neurons, reduced serotonin levels within the synaptic cleft, and postsynaptic inactivation of 5-HT1ARheters. SERT inhibitors activate both growing dendritic 5-HT1ARauto and postsynaptic 5-HT1ARheters. Desensitization of 5-HT1ARautos disrupts the balance between 5-HT1ARautos and 5-HT1ARheters within weeks after treatment and induces antidepressant effects via postsynaptic 5-HT1ARheters, This suggests that the enhancement of DRN5-HT/5-HT1ARauto signaling pathway is the main reason for the delayed onset of SERT inhibitors.

The discovery of this new rapid antidepressant target has a revolutionary significance on the classic hypothesis of depression, "monoamine hypothesis". The research not only sheds new light on the classic theory of depression, the monoamine hypothesis, but also develops a candidate depression drug that can act quickly. The research team synthesized a rapid acting antidepressant lead compound "ZZL-7". The study showed that ZZL-7 can exert antidepressant effect after 2 hours of injection, and does not have the toxic side effects of other rapid antidepressant drugs such as ketamine, which is suitable for widespread use. And it may overcome the defect of the third generation of antidepressant drugs that depend on the desensitization of serotonin autoreceptor, which is expected to become a candidate drug for a new generation of antidepressant drugs.

This study overcomes the deficiency that third-generation antidepressants rely on SEROTONin-autoreceptor desensitization, identifies fast-acting antidepressant targets, and updates the monoamine hypothesis. Professor Zhou Qigang said, "In the future, we will use ZZL-7 as the mother nucleus structure to synthesize a large number of compounds and conduct structure-activity relationship analysis, so as to screen out compounds with higher activity and good drug properties for preclinical pharmaceutical research."

Science highly praised the achievement and listed it as "Highlight". International peers and media also spoke highly of this study, believing that it is a major theoretical breakthrough in antidepressant research since the "monoamine hypothesis" was proposed nearly 60 years ago and the classic antidepressant fluoxetine was discovered 50 years ago.