Old medicine: Ketamine will bring depressive patients back to life?

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Old medicine: Ketamine will bring depressive patients back to life?

Will the old medicine that makes people linger between sleep and pleasure bring depressive patients back to life?

As a drug development strategy, ” old drugs and new uses ” can not only develop new uses beyond the existing indications, but also better understand the pharmacological mechanisms and causes of diseases.

And in the history of the development of antidepressants, there is a chemical that from the “Star anesthetic” on the battlefield in the 1960s, turned into enemies of the hallucinogenic drug everyone, but in the beginning of this century, this compound The old things are reborn again, and scientists have discovered great potential in the treatment of depression.

Ketamine , the drug previously known as “K powder” by the public, is attracting countless scientists to decipher its special anti-depressant effect.

The “black history” of Ketamine

The story of Ketamine began in the 1950s, when the medical profession discovered a new anesthetic: phencyclidine (PCP) . However, scientists soon discovered that this cyclohexylamine drug had serious adverse reactions, such as high levels of excitement and severe mental illness.

Pharmaceutical companies hope to find anesthetic drugs with less adverse effects in PCP derivatives to replace PCP. In the 1960s, a compound named Ci-581 gradually phased out PCP due to its short-acting, high safety and good anesthetic effect, and was widely used in clinical practice. This compound was later named Ketamine.

At that time, Ketamine was used as an anesthetic, and it also caused users to have a “feeling of separation.” The subjects described that they could not feel that they had arms or legs, and others described that they were dead after taking the drug and produced vivid hallucinations. As a result, scientists coined a term for Ketamine-separation anesthesia.

Such hallucinations and dissociative experiences also laid the groundwork for the subsequent abuse of Ketamine.

In the 1960s and 1970s, Ketamine became a star drug on the battlefield with its advantages of rapid sedation, pain relief, and small short-term side effects.

But soon, Ketamine was abused. Many people began to actively use Ketamine in order to experience and pursue the hallucinogenic pleasure of “soul out of the body”. The criminals made Ketamine into a white fine crystalline powder (injection in clinical practice) for transportation and sale.

This is where the name K powder comes from. Since then, Ketamine has been rapidly abused in entertainment venues all over the world, and the subsequent adverse reactions have also attacked the body and spirit of the abuser like a beast.

In addition to the hallucinogenic and dissociative experience that smokers are obsessed with, long-term abuse of Ketamine can also damage their central nervous system, kidneys, urinary system, and respiratory system, as well as damage their cognitive function, leading to memory loss and mental illness .

Countries began to quickly control the use of Ketamine and listed it as a controlled drug.

Old medicine: Ketamine will bring depressive patients back to life?

Clinically used Ketamine hydrochloride injection ,

Illegally sold “K powder”, the picture comes from public information

This vigorous “black history” ushered in a new chapter at the beginning of this century. In the process of exploring quick-acting antidepressants, scientists discovered the potential drug Ketamine.

In the conventional drug treatment of depression, the most commonly used monoamine target drugs often have a slow onset of effect, and generally take about a month to be effective, and the efficacy is sometimes not satisfactory.

In a clinical trial for patients with depression, researchers unexpectedly discovered that sub-anaesthetic doses of Ketamine can quickly relieve the symptoms of depression .

As a result, there have been numerous studies on the rapid antidepressant mechanism of Ketamine.

The “savior” for patients with refractory depression?

Globally, suicide is one of the leading causes of death, especially among young people. People with suicidal thoughts are often accompanied by severe depression , manifested as a series of physical, cognitive and emotional symptoms, psychosocial disabilities and dysfunction.

In previous studies, Ketamine has been shown to quickly reduce suicidal ideation, and its potential anti-suicide and anti-depressant effects may become a new dawn for refractory depression.

The results of clinical trials carried out in 26 patients with refractory depression showed that in addition to rapidly improving depression symptoms , Ketamine can also eliminate or relieve suicidal ideation within 24 hours of a single administration.

For patients with acute depression, Ketamine can also save lives. In a study of patients with depression in the emergency room, 14 patients with refractory depression with suicidal ideation received an intravenous bolus of low-dose Ketamine (0.2mg/kg) .

Within two minutes, their suicidal ideation was It began to fade, and 40 minutes after the administration, the antidepressant effect of Ketamine began to work, and their suicide scale scores continued to improve for more than ten days.

Old medicine: Ketamine will bring depressive patients back to life? ▷Above : 24 hours after a single subanaesthetic infusion of Ketamine, the Montgomery Depression Rating Scale score decreased significantly. The following picture shows the results of repeated infusions. Picture source: doi: 10.1016/j.biopsych.2009.04. 029

With the deepening of research, scientists have discovered that Ketamine may have an anti-suicide effect independent of its antidepressant effect .

The anti-suicide effect of Ketamine is specific, which indicates that in other mental illnesses with acute suicide risk (such as schizophrenia) , Ketamine may also be able to “do something”.

Whether Ketamine can open up a bright path for patients in the abyss, in addition to more clinical trials, it is also necessary to continuously explore its pharmacological mechanism of action and explore the internal causes of depression.

Find answers in brain areas and neural circuits

Unlike traditional antidepressants, Ketamine does not directly affect serotonin (serotonin) levels in the brain .

Serotonin is related to mood regulation. Therefore, past drug research focused on increasing the level of serotonin in the brain to improve depression.

Research on Ketamine found that it interacts with another chemical substance, glutamate .

This chemical is usually not related to emotion regulation, but to brain plasticity.

Therefore, many scientists believe that Ketamine may quickly relieve symptoms of depression by promoting the growth of new nerve connections .

Glutamate is the main excitatory neurotransmitter in the brain, and abnormal glutamatergic neuromodulation may be one of the key factors that induce symptoms of depression.

Such abnormalities include changes in glutamate levels and mutations in glutamate receptors. In the brain, there are two main types of glutamate receptors: NMDA receptors and AMPA receptors.

These receptors mediate the rapid excitatory synaptic transmission of glutamate. Ketamine is a non-competitive channel blocker of NMDA receptors.

The function of NMDA receptors is closely related to AMPA receptors.

When AMPA receptors are activated, the postsynaptic membrane is depolarized and the NMDAR channel pores are opened. This is a necessary prerequisite for Ketamine to block NMDAR channels.

Although most hypotheses about the antidepressant efficacy of Ketamine rely on its inhibitory effect on NMDA receptors, research has begun to focus on AMPA receptor activity .

Ketamine allows AMPAR to transmit excitatory signals, which subsequently leads to the activation of neuroplasticity-related pathways, such as those regulated by brain-derived neurotrophic factor (BDNF) .

Inhibition of NMDAR may affect the production of BDNF, leading to the up-regulation of AMPAR.

These mechanisms may collectively lead to excitatory synapses in brain circuits associated with depression.

Scientists are currently actively exploring the areas of the brain that mediate the rapid antidepressant effects of Ketamine.

Previous studies have preliminarily proved that a small amount of Ketamine injected into the submarginal prefrontal cortex (IL-PFC) can produce rapid and sustained antidepressant effects.

The results of morphological studies found that a single dose of Ketamine can increase the number of dendritic spines of layer V pyramidal neurons in the medial prefrontal cortex .

Old medicine: Ketamine will bring depressive patients back to life? ▷The blue part is the prefrontal cortex of the brain , image source: Wikimedia Commons

In addition, studies have shown that the lateral habenular nucleus mediates the rapid antidepressant effect of Ketamine .

In our brain, the lateral habenula mediates most of the negative emotions of people: fear, tension, anxiety, etc.

The researchers discovered that Ketamine can block the cluster-like discharge of neurons in the lateral habenula by inhibiting NMDAR.

The use of Ketamine to control the lateral habenular nucleus neurons and reduce their cluster discharges can directly alleviate the symptoms of depression.

From the research of neurobiology, pharmacology and structural imaging, we are getting closer and closer to dissociating the mechanism of Ketamine to quickly alleviate the symptoms of depression.

Researchers are also developing fast, efficient, low-side-effect antidepressants based on these breakthrough knowledge.

The “race” between benefits and risks

The title of “A quick effect in one hour, regaining the meaning of life in two minutes” is certainly eye-catching, but like the birth of other “magic drugs”, before the perfect derivative is developed, Ketamine is effective in patients with refractory depression.

Use requires careful evaluation of benefits and risks . In 2019, the US FDA officially approved the use of esKetamine nasal spray as a standard treatment for refractory depression.

Escamine is an enantiomer of Ketamine. Regarding this currently the only Ketamine-derived drug that has come out, various parties in the medical community have also expressed different concerns and worries.

Some researchers believe that there are limitations in the treatment data of Ketamine. Existing studies focus on short-term efficacy evaluation and lack data on long-term effects and potential risks .

In addition, the “appearance” of the quick-acting antidepressant makes it easy for patients to ignore its long-term side effects. The first thing to bear is the sense of dissociation.

More and more clinicians are concerned about this. For patients with depression, the sense of dissociation may have a long-term effect on them, and this is also a blank area in current research.

In addition, clinicians have observed symptoms such as shortness of breath and chest pain in some patients. Dr. Carolyn Rodriguez of Stanford University pointed out: “ For drugs like Ketamine that affect heart rate and blood pressure, the patient’s heart disease history, laboratory screening evaluations, and monitoring during infusions should be recorded in detail. Especially important .”

People’s curiosity about hallucinogenic sensations made Ketamine attract attention as a new antidepressant drug at the beginning of its research and development.

Although the new use of old drugs is nothing new, from the “K fan” everyone shouted to the “savior” of refractory depression, the “rebirth” of Ketamine has also set sail again for the long-stale depression research.

The huge number of patients and the heavy burden of disease make the world look forward to the arrival of the “magic drug”, and for scientists, studying Ketamine is a journey of neuropharmacology that needs to be treated with caution.

The clinical application of hallucinogenic drugs requires caution and strict control, just like standing in front of a labyrinth like a brain. You don’t know whether the next step is an oasis or an abyss.

Reference:

1. Rozet, Irene. “Ketamine in depression and electroconvulsive therapy.” Current Opinion in Anesthesiology 34.5 (2021): 556-562.

2. Fuchikami, Manabu, et al. “Optogenetic stimulation of infralimbic PFC reproduces Ketamine’s rapid and sustained antidepressant actions.” Proceedings of the National Academy of Sciences 112.26 (2015): 8106-8111.

3. Postorivo, Danielle, and Susannah J. Tye. “Novel Antidepressant Approaches for Refractory Depression.” Current Treatment Options in Psychiatry 8.3 (2021): 141-157.

4. Price, Rebecca B., et al. “Effects of intravenous Ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.” Biological psychiatry 66.5 (2009): 522-526.

5. Larkin, Gregory Luke, and Annette L. Beautrais. “A preliminary naturalistic study of low-dose Ketamine for depression and suicide ideation in the emergency department.” International journal of neuropsychopharmacology 14.8 (2011): 1127-1131.

6. The Ketamine Cure-The New York Times, By DAVID DODGE

Old medicine: Ketamine will bring depressive patients back to life?

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