Research and Development of Antidepressant Drugs in China


Release time:

2019-09-18

Depression Overview

Depressive symptoms (Depression) is a clinical symptom of mood disorder, and depression is a kind of mood disorder [1], which is characterized by significant and lasting depression, slow thinking, cognitive impairment, decreased will activity and somatic symptoms, and belongs to central nervous system diseases.

According to the WHO, the total number of people suffering from depression in the world is 0.322 billion. The lifetime prevalence of depression varies widely in different regions of the world, ranging from 3% in Japan to 17% in the United States. According to the 2012 China Mental Health Survey data [2], male depression accounted for 3.0 percent and female depression accounted for 4.2 percent; another study showed that the lifetime prevalence rate of moderate depression in China was 3.3 percent from 2001 to 2010 [3].

Depression is different from the mood swings and brief emotional responses to challenges that are common in everyday life. Especially when depression lasts for a long time and its intensity is moderate or severe, it may pose a serious threat to human health. It can cause those affected to suffer greatly and to function poorly at work, at school and at home. In the worst cases, depression can lead to suicide. Projections indicate that by 2020, depression may be the second leading cause of death after heart disease [4].

Depression Market Size

In the field of nervous system, anxiety disorders account for 40%. The global treatment market for anxiety disorders and depression was US $15.2 billion billion in 2015. Due to the rising prevalence, the market size is expected to grow steadily and is expected to reach US $18.3 billion billion by 2025 [5]. The major depressive disorder (MDD) market, which covers all forms of depression and seasonal affective disorder, is projected to grow from $3.2 billion in 2015 to $5.8 billion by 2025, at a CAGR of 6.1 percent [6].

In 2018, the overall market for psychostimulants in China reached 33.27 billion yuan, of which antidepressants accounted for 24.43 percent, reaching 8.1 billion yuan. The antidepressant market has grown at an average annual rate of about 14.8 per cent over the past five years. Although the overall market for antidepressants is large, imported drugs account for about 45% of the antidepressants used in hospitals in China, joint venture drugs account for 45%, and domestic drugs account for only about 10%. The market competitiveness of domestic antidepressants in China is very weak.

Depression Drugs Listed in China in Recent 10 Years

At present, the main antidepressant drug treatment is antidepressant drugs, mainly in other treatment is not successful or due to the severity of the disease or lack of treatment access to psychological treatment can not choose drug treatment. According to the Chinese Guidelines for the Prevention and Treatment of Antidepressant Disorders 2015 Basic Edition, Class A recommend drugs are mainly selective serotonin reuptake inhibitors (SSRIs) drugs, such as "five golden flowers": fluoxetine, paroxetine, fluvoxamine, sertraline and citalopram.

Figure 2 Types of antidepressants

At present, there are more than 30 kinds of antidepressant drugs in the domestic market, but in the past 10 years, only 3 antidepressant drugs have been approved for marketing in China, namely milnacipran hydrochloride, agomelatine and voxetine hydrobromide (see table below).

Table 1 Antidepressant drugs approved for marketing in China in recent ten years

Data source: drug crossing database

Voltioxetine hydrobromide (Vortioxetine Hydrobromide)

Voltioxetine (Vortioxetine, trade name: Xin Da Yue®), an antidepressant drug jointly developed by Denmark's Lingbei Company and Takeda Pharmaceuticals, was approved for listing in the United States and the European Union in 2013, and was approved by NMPA in 2017. Up to now, it has been approved by regulatory agencies in more than 70 countries and regions around the world for the treatment of adult depression. Its structural formula is shown in the figure.

Figure 3 Chemical structural formula of vortioxetine hydrobromide

Data source: drug crossing database

Voltioxetine hydrobromide is a multimodal antidepressant drug with a non-classical pharmacological mechanism. It acts on six targets (5-HT1A,5-HT1B,5-HT1D,5-HT3,5-HT7 and SERT), and exerts antidepressant effects by inhibiting the reuptake of serotonin transporters and regulating the activity of 5-HT receptors.

Voltioxetine is effective in the treatment of moderate depression, with sales of $4.79 million in Q2-4 2018. There are no generic drugs on the market in China, and the compound patent will expire in October 2022. At present, only one enterprise of Yangzijiang Pharmaceutical Group in China has declared a generic drug of Voxetine Hydrobromide.

Agomelatine (Agomelatine)

Agomelatine (trade name: Dimension New®) is a new type of antidepressant developed by Shivia Company. Its mechanism of action breaks through the traditional monoamine transmitter system. By activating melatonin receptors 1A and 1B(MT1 and MT2) and antagonizing 5-HT2C receptors, it exerts antidepressant effect and regulates biological rhythm at the same time. The structure of the compound is shown in the figure below.

Figure 2 Chemical structural formula of agomelatine

Data source: drug crossing database

The drug was first approved in the European Union in 2009 and listed in China in 2010. At present, agomelatine has been recommend as a first-line treatment for patients with depression associated with sleep disorders [7] and is included in the 2019 National Health Insurance Directory.

In 2014, the first imitation drug of agomelatine produced by Jiangsu Haosen Pharmaceutical Group was approved for listing, and soon occupied the domestic market share of agomelatine. In 2018, the domestic sales of agomelatine reached 0.141 billion billion yuan, of which Jiangsu Haosen Pharmaceutical Group accounted for 99.9 of the market share. At present, a total of 27 domestic companies have declared (or jointly declared) agomelatine generic preparations; among them, only one company is currently in the production site inspection, and other companies have been approved for clinical use.

Milnacipran Hydrochloride (MilnacipranHydrochloride)

Milnacipran hydrochloride was first developed by Pierre Fabre (Pierre Fabre) and was first approved for listing in France in 1996, then approved for listing in Japan and China in 1999 and 2010 respectively for the treatment of depression, and approved for new indications of fibromyalgia syndrome in the United States in 2009. Its compound structure is shown in the figure below.

Figure 5 Chemical structural formula of milnacipran hydrochloride

Data source: drug crossing database

Milnacipran hydrochloride is a new type of antidepressant, acting on SERT and NET. It is the only SNRIs drug whose NET effect is greater than SERT. Its antidepressant effect is strong and has been included in the basic drug list and medical insurance list. At present, only Shanghai Hyundai Pharmaceuticals, a generic pharmaceutical company, produces and sells milnacipran hydrochloride in the domestic market, with domestic sales of 42.63 million yuan in 2018.

Anti-depression clinical research varieties.

At present, there are 27 clinical anti-depression varieties in China, including 12 clinical III varieties (4 of which have been terminated),8 clinical II varieties, 1 clinical I/II varieties and 5 clinical I varieties. Most of these are marketed drugs for extended depression indications. In addition, there is only one innovative target, Glycinetransporter 1, but 12 clinical varieties of this target have been discontinued. With the further elucidation of the mechanism of action of several antidepressant molecules in recent years [9,10], it is expected that new molecular targets will be gradually applied to the research and development of new antidepressant drugs.

Summary

At present, there are more than 30 kinds of antidepressants on the domestic market, and only 3 antidepressants have been listed in the past 10 years. There are fewer innovative targets in clinical research varieties. At present, although the mechanism of action of the listed drugs is diverse, the overall therapeutic effect of anti-depression is actually not very different. There are still a considerable number of patients who have partial response to drug treatment, or limit the use of drugs due to safety issues. Therefore, for the development of new antidepressant drugs in China, the treatment of complete remission and safety is still a huge challenge.