Overview of the development of global antidepressant medications

On June 4th, the medical network reported depression as the fourth largest disease in the world, and 350 million patients suffered from the disease. According to IQIVA, the market for antidepressants in the US and Europe in 2017 reached $5.62 billion and $3 billion, respectively. China's antidepressant market is in the ascendant. Relevant data show that from 2015 to 2017, China's antidepressant market increased at a compound annual growth rate of 12.9%. In 2017, the market size reached 4.64 billion yuan.

At present, there are at least 68 antidepressant drugs listed worldwide, of which the best-selling 8 are: fluoxetine, paroxetine, sertraline, fluvoxamine, venlafaxine, mirtazapine, duloxetine. And amitriptyline, total sales exceed 80% of the global antidepressant market.

New drug research and development progress is slow

At present, due to the expiration of patents for heavy antidepressant drugs, the global antidepressant drug market has shrunk severely, resulting in slower development of new drugs. There are two main reasons for this: First, it is subject to human understanding of the nervous system and emotional regulation system, and there is no breakthrough innovation in the mechanism of newly listed drugs. Second, existing drugs are ineffective for refractory depression. Long-term use has large side effects, which raises the threshold for approval of new drugs, and increases the investment and risk of new drug research and development in this field.

At this stage, the direction of antidepressant drug research and development is based on the development of new indications and the development of new targets. Among them, the existing indications for the increase of antidepressant drugs include: obsessive-compulsive disorder and obsessive-compulsive disorder, panic disorder and other neurosis and psychogenic disorders, as well as anorexia nervosa and bulimia nervosa; New antidepressants require less adverse reactions and stronger therapeutic effects. The most ideal antidepressant is able to act on NE, 5-HT and DA at different specific sites, inhibiting their reuptake and exerting antidepressant effects. However, it does not act on the site of action that causes adverse reactions.

6 new drugs listed in recent years

Although there are many difficulties in developing antidepressant drugs, there are still many pharmaceutical companies that are constantly striving to have new products approved for listing.

Pregnenolone was approved by the US FDA on March 19 this year under the trade name Zulleso, and the dosage form was intravenous injection. The drug, a gamma-aminobutyric acid type A receptor modulator for the treatment of epilepsy and depression, was originally developed by Ligand and was licensed to Sage Therapeutics in 2011 for the treatment of postpartum depression. Pregnenolone is the first FDA-approved drug for postpartum depression.

As a non-competitive and subtype non-selective activity-dependent N-methyl-D-aspartate receptor antagonist, ketamine has a completely new unique mechanism of action, and its principle of action and other currently available on the market. The drugs used to treat depression are different. On March 5 this year, ketamine was approved by the FDA for sale under the trade name Spravato, and the dosage form was nasal spray. The approval is based on the results of a phase III clinical trial involving more than 1,700 adult patients with refractory depression, making Spravato the first antidepressant drug with a new mechanism of action in the past 30 years. However, since the drug is an isomer of ketamine, it was approved in the controversy. Some people are against it and worry about whether acetaminophen will be abused and whether there will be unexpected side effects.

Brayiprazole was approved by the FDA in July 2015 and is a dopamine D2 (DRD2) receptor/5-HT1A receptor agonist and 5-HT2A receptor antagonist, jointly developed by Otsuka Pharmaceutical and Lingbei Pharmaceutical. Developed for the treatment of adult schizophrenia and combined with antidepressants to treat major depression in adults. It is reported that major depression is a recurrent disease and is fatal. About 15% of patients choose to suicide to end their lives. According to statistics, there are currently about 16 million patients with major depression in the United States, and more than 41,000 suicides occur each year, many of which are caused by untreated or poorly treated depression.

Wortixetine was approved by the FDA in September 2013 and was developed by Takeda and Lingbei Pharmaceutical in Japan for the treatment of adult patients with major depression. The drug is a serotonin reuptake inhibitor and is also a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, and a 5-HT3, 5-HT1D, 5-HT7 receptor antagonist. Votilizine is considered to be the first and only compound that combines pharmacodynamic activity. This drug is suitable for the treatment of major depression and is the fastest growing new antidepressant drug in the US market.

L-Minilapron was approved by the FDA in July 2013. It is a potent and selective serotonin and norepinephrine reuptake inhibitor developed by Forest, and its dosage form is oral. Release capsules for the treatment of major depression.

Verazosone hydrochloride was approved by the FDA in January 2011 and was developed by Trovis Pharmaceuticals LLC of the United States for the treatment of major depression in adults under the trade name Viibryd. This drug is the first steroidal antidepressant drug with a dual role of a selective serotonin reuptake inhibitor and a 5-HT1A receptor agonist.

Products in the new drug application/ clinical trial phase

In addition to the above-mentioned anti-depressant drugs approved by the FDA in recent years, some products are in the stage of new drug application and clinical trials. This article mainly introduces two products in the new drug application and six in the clinical trial phase.

Lumateperone (ITI-007) is a dopamine D2 receptor modulator and a 5-HT2A receptor antagonist for the treatment of schizophrenia, bipolar depression and behavioral disorders. Lumateperone has a novel mechanism of action that has a 60-fold affinity for the 5-HT2A receptor to reach the dopamine D2 receptor, a figure that is much higher than almost all atypical antipsychotics on the market today. There is a view that this mechanism can effectively reduce side effects. Currently, Lumateperone has filed a new drug application in the United States for the treatment of schizophrenia. In addition, Lumateperone is undergoing Phase III clinical trials for the treatment of schizophrenia and bipolar depression and Phase II clinical trials for the treatment of Alzheimer's disease.

Samidorphan/Buprenorphine is a novel opioid modulator that combines mu-opioid receptor antagonists and opioid receptor partial agonists to balance brain function in patients with refractory depression. In 2017, Alkermes filed a new drug application in the United States. In April 2018, the FDA accepted its new drug application to aid in the treatment of major depression.

According to statistics, a total of 33 anti-depression related projects are in Phase III clinical trials, of which only 6 are under research, 5 are no progress, and 22 have been terminated.

Lurasidone/cycloserine: a compound preparation consisting of cycloserine (treatment of tuberculosis) and lurasidone (anti-schizophrenia) developed by NeuroRx, and lurasidone hydrochloride is central dopamine D2 (DRD2) and 5- HT2A receptor antagonist. A phase III clinical trial for the treatment of bipolar depression is currently underway.

Rapastinel (GLYX-13): a partial agonist of NMDA receptors, intended for the treatment of major depression, was granted fast track status in the United States in 2014. In 2015, GLYX-13 completed Phase II clinical trials and obtained some positive experimental results, and obtained FDA breakthrough new drug certification. Currently, GLYX-13 is conducting a phase III clinical trial as an adjunct to refractory major depression. However, the results of three key phase III clinical trials published in March this year showed no difference between the GLYX-13 treatment group and the placebo group in terms of primary endpoint and key secondary endpoint.

Olanzapine/Samidorphan: a combination of a μ-opioid receptor antagonist and a dopamine receptor/5-hydroxytryptamine receptor antagonist (olanzapine), developed by Alkermes, in Phase III clinical trials for the treatment of double Mental illness such as phase depression and schizophrenia. The compound is undergoing clinical trials in the United States and Europe, and Alkermes plans to submit a new drug application to the FDA by the middle of this year.

SAGE-217: Developed by Sage Therapeutics, is currently in Phase III clinical trials for the treatment of postpartum depression and major depression, for Phase II clinical trials for bipolar depression, insomnia, idiopathic tremors and Parkinson's disease. clinical trials and pre-clinical trials for the treatment of a movement disorder treatment of epileptic seizures. In February 2018, Sage Therapeutics announced that the FDA has awarded the drug a breakthrough therapy certification for the treatment of major depression.

Anshufacine hydrochloride: a potential serotonin-norepinephrine reuptake inhibitor for the treatment of depression, Luye Pharmaceutical Group Co., Ltd.. In 2015, it was approved for clinical practice; in June 2018, Luye Pharmaceutical initiated a phase III clinical trial of ashufaxine hydrochloride.

Bupropion/dextromethorphan: currently in Phase III clinical trials for the treatment of depression, Phase II/III clinical trials for the treatment of Alzheimer's disease, and Phase II clinical trials for smoking cessation treatment. In 2017, the FDA placed a bid for the use of bupropion/dextromethorphan in the treatment of depression and Alzheimer's disease in the rapid approval list.

In summary, there is great potential in the field of depression treatment, but in recent years there has been a lack of breakthrough innovation in the development of antidepressant drugs. [Author: Huanuotong (Beijing) Pharmaceutical Technology Co., Ltd.]