‘Dopamine storm’, a cure for schizophrenia, was originally a cold medicine

22-10-17

[The Hankyoreh S] Shin Chan-young's mind poison, mind medicine - Chlorpromazine

If Vincent Van Gogh, who suffered from schizophrenia, had not committed a tragic suicide, would we have seen more <Sunflower>, <Almond Tree> and <Starry Night>?

A violent storm rages through the brain and mind of the schizophrenic patient. Hallucinations and hallucinations appear, and delusions of persecution and grandiosity are common, sometimes leading to jumbled cognitive functions, irrational speech and behavior, emotional outbursts, and violent behavior. In the brain and mind of a patient with schizophrenia, the suffocating, windless silence of midsummer sometimes continues. Like a dry tree, he becomes a person without any emotions, and shows an expressionless and insensitive appearance without reacting to the surroundings.

Those of us who have seen the remarkable development of modern science do not know that there was no drug that could treat mental illness such as schizophrenia until just 70 to 80 years ago. Even in the early 1950s, patients with severe symptoms of schizophrenia were forcibly admitted to mental hospitals and tied up using straitjackets, or parts of the patient's prefrontal cortex were damaged with a drill to alleviate symptoms such as hallucinations, delusions, and rage. He also developed frontal lobotomy. Although it is now considered a horrific and inhumane operation, Portuguese doctor Antonio Egas Monis was awarded the Nobel Prize in Physiology or Medicine for developing the technique. It is known that the sister of former US President John F. Kennedy also received this surgery and lived in a state of mind as if only an empty shell remained for the rest of her life.

Amazing effects of cold medicine

The history of many medicines that have changed human lives, such as penicillin, has been developed through serendipitous discovery (not an 'invention') and further research using it. In the days when there were only brain drills and shock therapy using insulin in mental hospitals, chlorpromazine was the first commercially available treatment for schizophrenia in a practical sense.

Chlorpromazine was not originally designed to treat schizophrenia. French surgeon Henri Laborie discovered that the antihistamine promethazine, which was developed by the French pharmaceutical company Ronpoulenc in the late 1940s to treat rhinitis, allergies, and a runny nose, suppresses excessive excitement and shock in surgical patients and provides mental stability and sedation. After confirming that it worked (which is also why taking cold medicine makes you sleepy), he proposed to Ronpoulenc to develop a better anesthetic adjuvant (an anesthetic cocktail). Accordingly, Paul Charpentier synthesized a similar compound, chlorpromazine, in 1950, and Ronpoulenc commercialized it in 1952 as an anesthetic adjuvant. Focusing on the fact that chlorpromazine exhibits excellent arousal suppression without a direct sleep-inducing action, the effect was tested on psychotic patients, and as a result, an excellent effect that had not been seen before was confirmed and used as a treatment for schizophrenia.

Since the advent of chlorpromazine, the number of patients with schizophrenia who have to be admitted to psychiatric hospitals has decreased significantly, making deinstitutionalization a reality. Chlorpromazine has been evaluated as a drug that has completely changed the way psychiatric treatment is done three years after its release.

However, the true importance of chlorpromazine does not stop at its excellent therapeutic effect on patients. Chlorpromazine is a drug that has revolutionized the study of the cause and mechanism of schizophrenia and the development of follow-up treatments. Although it cannot be said to be a perfect drug, for a while, chlorpromazine was used as a standard product to evaluate the treatment effect of schizophrenia, and the treatment effect of subsequently developed treatments was expressed as the chlorpromazine comparative equivalent rate (CPZE).

Originally, it was a substance synthesized in the process of developing an antihistamine, but through studies such as animal behavior analysis showing schizophrenia symptoms, it soon became clear that the treatment effect of schizophrenia was not directly related to the histamine suppression effect. Nobel laureate Dr. Arvid Carlsson of Sweden and others applied research methods such as spectroscopic quantification of neurotransmitters and reported the possibility that the therapeutic effect of chlorpromazine would appear by blocking excessive dopamine activity, and was actually developed after chlorpromazine. It has been confirmed that the therapeutic effect of numerous follow-up treatments that have been tested is exactly the same as the effect of blocking D2 dopamine receptors, which are some of the dopamine receptors that transmit the action of dopamine. In other words, strong blocking of the dopamine D2 receptor results in a therapeutic effect at a low dose, and a treatment that blocks less strongly requires a larger dose to achieve the same therapeutic effect.

Interestingly, the action on the D1 dopamine receptor, which has a similar structure, was not related to the treatment effect of schizophrenia. Rather, inhibition of D1 dopamine receptors can cause motor ataxia with symptoms similar to those of Parkinson's disease, which is one of the common side effects of many anti-schizophrenia drugs, including chlorpromazine. In addition to dopamine, chlorpromazine also blocks acetylcholine, histamine, norepinephrine, and serotonin neurotransmission to some extent, and studies on the neurological side effects caused by these blockages have been actively conducted. It will indeed make a great contribution to pioneering and developing the new field of science and neuropsychopharmacology. Dopamine is a neurotransmitter involved in the regulation of various brain functions, such as the regulation of high-level cognitive functions based on emotion, the regulation of happiness and euphoria, the induction of motivation and concentration, and the regulation of motor function.

The starting point for controlling brain diseases

Excessive activation of dopamine neurotransmission causes addiction and dependence by various causes such as drugs, games, and gambling, and in severe cases, it can cause schizophrenia-like symptoms such as hallucinations. To make an oversimplified analogy, in the brain of a schizophrenic patient, a surge of dopamine is rushing wildly over the embankment and into the field. Of course, recent treatments for schizophrenia emphasize the effect on serotonergic neurotransmission regulation, but through neuropharmacological studies initiated with chlorpromazine, we can learn how the delicate and beautiful flow of the human brain is maintained and/or prevent brain diseases. The reason why it occurs and the artificial control method are being realized one by one.

Do you like fluorescent pumpkins and water droplets? The infinitely repeating mirror room? Despite suffering from schizophrenia, Yayoi Kusama is one of Japan's leading painters, creating a global buzz. In her long struggle since the 1950s, I believe that Chlor Pro Mazin and her descendants have become a breeze to take a break from the storm that blows the mind.

Professor Shin Chan-yeong, Konkuk University