A 4-hour antidepressant "miracle drug"?

China Newsweek reporter/Niu He

Published on May 2023, 5, the 29rd issue of China Newsweek magazine

In April this year, the "esketamine hydrochloride nasal spray" (Spravato) produced by Xi'an Janssen Pharmaceutical Co., Ltd. (hereinafter referred to as Xi'an Janssen) was approved by the State Food and Drug Administration of China under the trade name of Speedairang. Xi'an Janssen is a pharmaceutical subsidiary of Johnson & Johnson, a multinational pharmaceutical company in China. Previously, Speedelon has been approved for listing in the United States, all EU countries, Canada and other countries.

Xi'an Janssen disclosed that this drug in combination with oral antidepressants can relieve the symptoms of adult depressed patients with acute suicidal ideation or behavior. Existing antidepressants usually take 4~6 weeks to exert their effect, while the use of nasal spray administration of Speedelon can quickly take effect, and the improvement of depressive symptoms can be observed 4 hours after the first dose.

Gerard Sanaco, professor of psychiatry at Yale University School of Medicine and director of the Yale Depression Research Program, said in an interview with China Newsweek that the most important feature of the drug is that it is effective for patients who are useless with standard antidepressants, giving these patients hope. Standard antidepressants are generally considered to refer primarily to monoamine oxidase inhibitors.

In Sanaco's view, this is especially important if the drug does help patients avoid hospitalization or job loss, shorten hospital stays, complete school or prevent self-harm, and "start meaningfully improving depressive states sooner." However, more data is needed in the future to prove that Speedelon does provide these benefits.

The efficacy of the drug is controversial

To this day, depression is still considered a "black box" disorder because its causes are poorly understood.

Around depression, one of the more popular hypotheses is the "serotonin hypothesis". The hypothesis suggests that low levels of the neurotransmitter serotonin in depressed patients can produce euphoric sensations similar to those in depressed patients. According to this mechanism, in 1987, the antidepressant drug "Prozac" of the American Lilly Company was launched. Since then, major pharmaceutical companies have developed the same type of drugs, namely SSRIs.

However, it has been found that the serotonin hypothesis does not fully explain depression. An article released by the official Yale University School of Medicine in the United States in 2022 pointed out that SSRIs drugs not only have limited help for more than one-third of depressed patients, but more and more studies have shown that the neurotransmitters (such as serotonin) targeted by these drugs account for less than 20% of neurotransmitters in the human brain, and the other 80% are γ-aminobutyric acid (GABA) and glutamate neurotransmitters. "The researchers believe that these two transmitters may be responsible for regulating most of the brain activity, including mood." The article reads.

"Speedalang is the first antidepressant drug approved in China with a completely new mechanism of action and mode of administration." Xi'an Janssen's official website said. The active ingredient in Speedalon is esketamine, which can be obtained from ketamine. In the United States, ketamine has only been approved as a narcotic for decades, but it is also illegally used as a party drug "K powder." Over the past few years, more and more studies have found ketamine for treatment-resistant depression, which has also contributed to the approval of Speedair.

How does the mechanism of action differ from Speedopen? SSRIs are treated by increasing levels of chemicals such as serotonin and dopamine in the body, while esketamine works by increasing glutamate levels. Research from the Yale Research Laboratory has shown that ketamine triggers the production of glutamate, prompting the brain to form new neural connections in a complex chain reaction. This makes the brain more adaptable and gives patients the opportunity to generate more positive thoughts and behaviors. The aforementioned article reads.

According to the official website of Xi'an Janssen, in adult patients with depression accompanied by acute suicidal ideation or behavior, compared with the placebo group, clinically significant and statistically significant improvement in depressive symptoms was observed in combination with standard therapy 24 hours after the first dose, and depressive symptoms were continuously improved from 4 hours to 25 days after the first dose.

Speedair's approval for marketing in China is mainly based on two key global clinical phase III studies. At the end of both trials, 41% and 43% of patients, respectively, achieved clinical remission of depression, both higher than placebo.

One phase III, double-blind, multicenter study conducted between June 2017 and December 6, enrolled 2018 adults with major depressive disorder who were suicidal and required hospitalization in a psychiatric hospital. Patients were randomized 12:226 to either tacekelon or placebo and administered twice weekly for 1 weeks.

He Rihui, the founder of Qingri Psychosomatic Doctor Group, is a former anesthesiologist who has accumulated more than ten years of clinical experience in the multidisciplinary diagnosis and treatment of depression. He Rihui told China Newsweek that speedy is not a miracle medicine, the drug itself has great limitations, let alone rely on it to truly completely cure depression.

In fact, there has been controversy surrounding this drug. On February 2019, 2, STAT, a medical media affiliated with the Boston Globe, reported that Johnson & Johnson submitted five phase III studies of the drug to the FDA, including three short-term studies, one effect maintenance study and one long-term safety study. In June of the same year, The Guardian reported that the US Food and Drug Administration (FDA) needed to complete two successful phase III short-term trials before approving antidepressants. In both of the three short-term trials of Speedel, the results showed that the experimental group was no better than placebo. The FDA accepted only the results of the third short-term trial and added a different type of trial.

According to STAT above, two of the five phase III studies had positive results. One was a randomised trial in adults under 65 years of age with treatment-resistant depression. After one month of receiving the drug, depression was reduced in about 70% of patients, compared with slightly lower but more than 50% in the placebo group; The other was an effect maintenance study, in which participants who responded to Speedican in a short-term study were randomly assigned to continue taking or switch to placebo.

In 2019, the FDA voted "14:2" to quickly approve the drug for use in adults with treatment-resistant depression on March 3 of that year. A press release issued by Johnson & Johnson states that "taking Speedalang reduces the likelihood of relapse in patients with treatment-resistant depression by 5% compared to those who maintain a placebo and oral antidepressant regimen." In August of the following year, the indications for the drug were expanded to include a full course of twice-weekly treatment for 51 weeks in patients with major depressive disorder at risk of self-harm or suicide, after which treatment benefit was assessed to determine the need for continued treatment.

In December 2019, the European Commission authorized Speedairon to combine with other depression drugs to treat adult patients with refractory major depressive disorder. On February 12, 2021, the indications for this drug were expanded in combination with oral antidepressants for major depressive episodes in adults for rapid reduction of depressive symptoms.

On November 2022, 11, Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, announced a phase III trial data comparing Speedelon with the extended-release quetiapine of the British pharmaceutical company AstraZeneca, which had better remission than the latter. The quetiapine extended-release dosage form was approved by the FDA in 23 for the combination treatment of major depressive disorder.

Even if approved, the debate about speediness did not dissipate. On May 2019, 5, an assistant professor in the Department of Psychiatry at Yale University and two Harvard Medical School experts published a fiery commentary on the media platform. "Eketamine doesn't represent a revolution in mental health treatment as touted, but it's not a breakthrough at all." The article reads.

More than 4 years have passed since the rapid approval of the US for the listing of Speedelang. Sanako said he didn't see any data during this time that explicitly stated that the introduction of Speedelon reduced suicide rates in the United States. In addition, in clinical trial studies, there is currently no large enough research data to determine that Tacholon is effective in reducing suicide. "Hopefully, in the near future, we will see some research on this important issue." He emphasized.

The side effects and abuse of Speedy are worth being wary of. The FDA noted in 2019 that speedy cheerfulness may impair attention, judgment, thinking, reaction speed, and motor skills. In clinical trials, the most common side effects in patients include schizophrenia, nausea, and increased blood pressure. Patients with hypertension or previous aneurysmal vascular disease may be at increased risk of cardiovascular and cerebrovascular adverse reactions with this drug. In addition, it can cause harm to the fetus.

In a warning document issued by the FDA in February 2022, it was mentioned that Speedalon was strictly controlled in dispensing and administering drugs because of the potential risks of multiple medications. For example, patients must use the drug in an officially certified medical facility, and after the medical facility administers the drug, the patient must be monitored for at least two hours until the patient is safely gone.

Luca Pani, former director general of the Italian Medicines Agency (AIFA) and professor of clinical psychiatry at the University of Miami, said in an interview with China Newsweek that in some cases, patients may also experience hallucinations or other changes in perception after using Speedopen. Patients should not drive a car or operate heavy machinery on the day of treatment and should discuss their complete medical history, including any drug abuse, with their doctor.

"Speedy can't be sprayed with you like a normal nasal spray. Now that Sukailang has entered the country, I believe that it will also follow a strict use process, and domestic supervision will be stricter. He Rihui said.

He Rihui said that in foreign countries, in clinical anesthesia, the dosage of ketamine is generally 2~3 mg/kg; For antidepressant therapy, the dosage is generally only 0.5 mg/kg. In the United States, some patients with depression go to medical institutions once a week to receive a small dose of ketamine injection, which has become an ongoing antidepressant therapy.

In a warning document issued in 2022, the FDA mentioned that in recent years, some pharmacies in the United States have used ketamine nasal sprays in combination with other ingredients, and there have been alarming reports of adverse events. The frequency of nasal spray complex ketamine was reported to range from 3 to 8 times per day, with an unknown amount of each spray. In most adverse event case reports, patients used the product at home and it was not known whether it was monitored by professionals.

Patient accessibility is not high

The price of Speedy is not cheap. In April 2021, the "Pharmacoeconomics Report" released by the Canadian Health Drug and Technology Agency showed that a dose of esketamine intranasal spray 4 mg is priced at 28 US dollars, about 273 yuan, and the average annual cost in the first year is 1900 US dollars ~ 18564 US dollars, and the average annual cost is 45591 US dollars ~ 14196 US dollars in the second year and thereafter.

According to the "Technical Appraisal Guidance for the Treatment of Refractory Depression" issued by the National Institute of Health and Care Excellence in the UK on December 2022, 12, one dose of Speedalon 14 mg is sprayed in 28 divided doses, and each nostril is sprayed once 2 mg. The price of a 14 mg dose is 28 pounds, about 163 yuan.

At the beginning of the listing, Johnson & Johnson once had high hopes for Speedy and Cheerful, and regarded it as a growth driver for subsequent revenue. According to the US Consumer News and Business Channel in April 2019, the company said at the time that as many as 4 medical centers had been approved to use Speedelon and patients were already taking medication. Michelle Kramer, vice president of U.S. Neuroscience Medical Affairs at Johnson & Johnson, said that since it was approved for the treatment of treatment-resistant depression in March 800, Speedelang has been used by about 2020,8 people to treat treatment-resistant depression, according to Bloomberg in August 2019.

However, Speedairang's sales did not meet expectations. Sanako said that in the United States, speedican treatment is limited by many barriers, some of which can make treatment more expensive, which discourages patients. Pani said the cost of Speedalon is significantly higher than most other antidepressants, and insurance companies are less willing to insure Speedalang when other, cheaper treatments are available.

"This medicine is very expensive, and only wealthy patients can afford it." Eric Turner, an associate professor of psychiatry at Oregon Health and Science University in the United States, told China Newsweek that many people seem to think it is a miracle drug. However, based on its performance in clinical trials, the actual effect seems to be comparable to antidepressants that existed decades ago.

An August 2022 article published by Harvard Health Press mentioned that independent ketamine clinics are widely available in the United States, and it is expected that there are hundreds or thousands of such clinics today. Almost all of these clinics were established in 8 when Speedelon was approved for treatment-resistant depression. The article explains that because insurance rarely covers this type of treatment, patients need to pay for it themselves.

WHO estimated in 2018 that around 2 million people worldwide suffer from depression. The incidence of depression is about 8% higher in women than in men. Worldwide, more than 50% of pregnant women and women who have recently given birth experience depression.

In 2019, Huang Yueqin, director of the Social Psychiatry and Behavioral Medicine Research Office at Peking University Sixth Hospital, published a study in The Lancet Psychiatry that the 12-month prevalence of depression patients in China was 3.6%, while the lifetime prevalence was 6.9%.

"The approval of Speedelon in China may fill an important unmet need in the treatment of depression in China, especially for patients who are resistant to other treatments." However, differences in culture, society, and health care systems may affect its use in China. Pani said.

In Pani's view, adding esketamine to oral antidepressant treatment is not a cure for major depressive disorder. It can be considered as an additional tool in the treatment of this complex disease. Depression usually requires long-term treatment, and patients should undergo a relatively comprehensive treatment plan, including psychotherapy and lifestyle changes.

Following Speedi, in August 2022, the FDA approved the marketing of a new depression drug, Auvelity, for the treatment of major depressive disorder in adults. This drug was inspired by clinical trials of ketamine. The drug has two active ingredients, dextromethorphan and bupropion, the former directly acts on NMDA receptors, and the latter mainly prevents the degradation of dextromethorphan in the body. It is known that NMDA receptors modulate the neurotransmitter glutamate.

Sanako believes that depression is not a single disorder and that it is unlikely that a cure will be developed that will work for all. For example, to treat cough, drugs like dextromethorphan can be developed to help reduce the intensity of coughing, but it does not really stop the progression of the disease. To cure a disease, you need to understand the specific pathogenesis, such as knowing whether the patient's cough is caused by bacterial pneumonia, or by viruses, tumors and other factors, in order to prescribe the right medicine during treatment.

In Sanaco's view, for depression, when more understanding of the different pathophysiological mechanisms associated with it, new treatments can gradually be developed.

According to Pani, depression is thought to be caused by a combination of biological, genetic, environmental and psychological factors. Due to the complexity of depression, developing drugs to treat depression is challenging. Treatment of depression may continue to evolve in the future, and more personalized therapies, such as biomarker recognition, may emerge.

China Newsweek, Issue 2023, 19

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