Ketamine for treating of depression

Medical use of psychedelics have been an increasingly popular topic in recent years. However in many cases these procedures are not only talked about but officially applied in particular circumstances. As in most of the regulatory systems the use of these substances are illegal outside medical context, the surrounding division charged with political and economic interests is significant.

Psychedelics like LSD and psilocybin have raised interest in scientific communities since the 1950s for their therapeutic potentials. From the ‘60s on ketamine got included into these researches. Although experiments got hindered due to the roaring ‘70s’ “War on Drugs” initiated by the Reagan-administration, there has been a revival of psychedelic research in the last three decades. Today there is no doubt in their substantial effect: more and more scientific trials are set to experiment on developing the psychiatric use of these substances. Furthermore ketamine is already in use as an antidepressant, especially for depression.

What is ketamine exactly?

Ketamine was first synthesised in 1962 by US chemist Calvin Lee Stevens. Two years later trials executed on people started and besides the rapid anesthetic effects they observed the substance’s psychedelic impact on human consciousness. Because of the former, its large-scale use first spread during the Vietnam War, and it is still a general anesthetic used in human and animal medicine today.

Although ketamine is not considered as a classic psychedelic due to its different mechanism of action, it is often classified as such due to its dissociative properties. This dissociative effect is manifested in a sense of detachment from one’s surroundings, perceptions, and loss of control over one’s body. Esketamine, a derivative of ketamine, has shown promise in the treatment of treatment-resistant depression in particular. Treatment-resistant depression is moderate to severe depression that does not respond to conventional antidepressants and affects approximately 30% of those diagnosed. Following successful trials in treating these cases, various forms of ketamine have been used as an approved therapeutic protocol in the United States and the European Union since 2019. The drug can only be prescribed by a healthcare professional in an accredited medical institution and can only be used in prescribed doses.

How does ketamine work?

The exact mechanism of action of ketamine is still not fully understood. Ketamine exerts its effects mainly on NMDA receptors. These receptors are found at nerve connections, called synapses, and play a role in the communication between nerve cells. NMDA is a glutamate receptor, which is the number one excitatory neurotransmitter in our brain. According to our current knowledge, it is responsible for the formation of memory. Ketamine in high doses (2 mg/kg, which is 0.12 grams for a 70 kg person) inhibits the release of glutamate, which turns off certain parts of our brain, resulting in a general anesthetic state. In lower doses (about 0.5 mg/kg, 0.03 grams for a 70 kg person) it increases the release of glutamate typically causing an out-of-body feeling, unusual sensations, and a dissociative state. Meanwhile, being in this temporary condition, neural connections in the brain that have been altered due to depression are regenerated through ketamine’s effect on NMDA receptors.

In the medical use of ketamine, and psychedelics in general (experimental or established), there are important differences that distinguish between two processes: psychedelic-assisted therapy and treatment. The former basically means that the client participates in a therapeutic process under the influence of the substance, the length of which depends on the effect of the substance. Since there is no universally developed procedure for this method yet, in the case of ketamine it is applied rather in private care, and in the case of other psychedelics it is used in formal scientific trials. Treatment, in the case of ketamine, means the supervised application of the substance by medical personnel and the monitoring of the client, without psychotherapy.

Ketamine treatment in Hungary

Ketamine was first used in Hungary in 2016 on a therapy-resistant patient, at the Kenézi Gyula University Hospital of the University of Debrecen. The treatment consisted of two infusions, administered 15 days apart. The rapid effect, safe and supervised procedure, and the lack of long-term side effects had a positive outcome regarding the patient’s condition. In 2019, the European Medicines Agency approved the esketamine-containing nasal spray extracted from ketamine under the name Spravato, making it available in Hungary. In practice, it is not yet that widespread; in most cases, other, longer-established procedures are used (such as electroconvulsive therapy, where an epileptic seizure is triggered by an electrical impulse to change the biochemistry of the brain). In the case of Hungary, the use of esketamine is more typical in larger hospitals and clinics.

According to psychiatric resident Dr. Bernadett Karsai, ketamine treatment is carried out in an outpatient setting: the client is placed in a comfortable position, then self-administers the nasal spray. The effects last for about four hours. After that, the treatment is repeated twice a week for the first four weeks. If the client’s condition improves and there are no factors that prevent it from continuing, the number of treatments is reduced to once a week for the next four weeks. From the ninth week, the intervention is repeated every two weeks, and then monthly, depending on the review of clinical improvement. While clients are generally optimistic about the treatment, there are those for whom the experience becomes unpleasant at the beginning, or are afraid of it due to temporary dissociative side effects, and therefore do not agree to start or continue the treatment.

Currently most of the Hungarian clinics do not combine the use of ketamine with a psychotherapy process. This is due, on the one hand, to the fact that the antidepressant effect occurs without psychotherapy, and on the other hand, there is no unified, official protocol for the KAP (ketamine-assisted psychotherapy) method. If the psychotherapy framework becomes available in the future, it will require the training of special professionals, and the therapeutic process itself will become much more time-consuming, and therefore more expensive.

Another example: Poland

The treatment is available in many European countries, either as an antidepressant or as a therapeutic tool, in public health services and in private clinics. In Poland, for example, ketamine therapy, applied as a nasal spray, is structured similarly to the procedure in Hungarian state clinics. These treatments are financed by the state through social health insurance, but are relatively inaccessible due to strict entry criteria: those who suffer from recurrent moderate or severe depression and have tried at least two antidepressants without any improvement can participate in the treatment. Nevertheless, treatment may still be refused if the client has already tried more than five types of antidepressants, as the medical staff considers esketamine to be unlikely to help.

Private clinics have a generally lower entry threshold, and other types of procedures – such as intravenous treatment or combined use with psychotherapy – are available as well. However, these are not supported by public health insurance, and the price of a single treatment session ranges from at least PLN 1,500 to PLN 2,100 (350 to 500 EUR). Since it has often not proven to be more effective than other available therapies and its price is exceptionally high, several media platforms have criticized the intervention, stating that its high price has made it accessible only to a certain social class.

From the borderlands to clinical method

The psychiatric use of ketamine is currently one of the most striking examples of the change in attitude towards psychedelics. Although its mechanism of action differs from that of classical psychedelics, its proven antidepressant effect and its appearance in therapeutic practice have opened up new possibilities for patients who have been less responsive to previously available treatments. At the same time, the framework for its application – be it therapeutic protocol, accessibility or psychotherapeutic integration – is still in the process of being developed. The key to the future therefore lies not only in the continuation of clinical trials, but also in the embedding of treatments in an ethical, accessible and complex manner. The example of ketamine clearly shows how procedures operating on the borderlands of psychiatry can become an accepted part of modern medicine – if social, scientific and health policy aspects are coordinated.

Ráhel Vermes

This content was published as part of PERSPECTIVES – the new label for independent, constructive and multi-perspective journalism. PERSPECTIVES is co-financed by the EU and implemented by a transnational editorial network from Central-Eastern Europe under the leadership of Goethe-Institut. Find out more about PERSPECTIVES: goethe.de/perspectives_eu.
Co-funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the granting authority can be held responsible.

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