Ketamine: a fail-safe first responder, or dangerous drug of abuse

By Lauren Wheeler

Suicide is the leading cause of death in the UK among adults aged 20-35, with 5,691 cases reported in 2019. Many of these were people with pre-existing mental health conditions and it is estimated that of those who had previously accessed NHS services, roughly half were in contact with mental health professionals in the week before their death. With the pressure on these services increasing, not least as a result of the recent pandemic, it is clear that more needs to be done to prevent these crises. One approach could be to identify an effective, fast-acting solution for patients who present with acute mental distress, mitigating the risk of harm to themselves or others. That is where ketamine comes in.

Ketamine is a phencyclidine derivative which acts primarily as an antagonist of N-Methyl-D-aspartic acid (NMDA) receptors in the central nervous system. Ketamine molecules block calcium channels on gamma-Aminobutyric acid (GABA) interneurons, inhibiting the entry of ions and therefore preventing depolarisation (Pai & Heining, 2007). Since the interneuron acts as an inhibitor of glutamate-release, ketamine has a disinhibitory effect, causing a surge in the levels of the excitatory neurotransmitter in the pre-frontal cortex (Abdallah et al., 2018). The drug was originally intended solely as an anaesthetic but its use in clinical settings has diminished due to the psychological effects associated with administration of the drug, such as distortion of sights, sounds and even the self, alongside the availability of other agents. However, ketamine’s ability to produce dissociative effects in the brain has led to its resurgence as a neuropsychiatric drug, with recent studies suggesting its efficacy as a rapidly-acting antidepressant, chronic pain and tool for psychedelic-assisted psychotherapy (Pribish et al., 2020).

Interestingly, ketamine has also been implicated in reducing suicidality. This has been observed both in patients with long-term, treatment-resistant depression and in acute psychiatric conditions (Dadiomov & Lee, 2019), with studies suggesting that reductions in suicidal ideations are related to, but independent of decreases in anxious and depressive symptoms (Ballard et al., 2014). It is thought that this effect is at least partly mediated through an increase in neuronal plasticity, brought about by a molecular cascade initiated by a rise in glutamate (Collo & Merlo., 2018). This increase in plasticity may facilitate neural rewiring, leading to clearer thinking, and opening the patient up to new, more rational patterns of thought and behaviour, at least in the short term. Another benefit of ketamine in emergency psychiatric care is its rapid speed of onset. Currently, the typical treatment for patients experiencing suicidal ideations is a course of antidepressants, however, these have limited efficacy and can take several weeks to produce an effect. Ketamine, on the other hand, takes hold almost instantaneously, producing effects within seconds to minutes when administered intravenously.

Unfortunately, the drug, like many other exogenous molecules, is not without its risks.  Although ketamine does not depress the airways or circulatory system when taken at a moderate dose, as is the often the case with anaesthetics, it can be highly addictive, introducing the potential for abuse. Whilst the drug is not associated with any physical withdrawal symptoms, a person who is addicted to ketamine can develop a ‘psychological dependence’ on the drug. The dream-like state induced can help people to feel relaxed but can also leave them confused and disorientated. If the user then develops a tolerance to the drug, the dose needed to produce its tranquillising effect increases, and further increases their risk of harm. Large doses of the drug cause rapid rises in heart rate and blood pressure, nausea or vomiting, and can also produce highly destabilising ‘out-of-body’ hallucinogenic experiences. In the very worst case, the dose taken can be so high that a person becomes unconscious or goes into a comatose state.

Nevertheless, when used in a clinically supervised setting, especially at low doses, ketamine appears to be a safe and efficacious agent in the treatment of a variety of psychiatric conditions and the majority of patients who take it never go on to develop a dependency. When weighing up the benefits against the risks of administering the drug to patients at high risk of suicide, it is important to remember that we are quite literally dealing with a matter of life or death. It may seem like a quick-fix and is unlikely to be a long-term solution, but seconds, minutes and hours count to avoid paying the ultimate cost.

References:

Abdallah, C.G., De Feyter, H.M., Averill, L.A., Jiang, L., et al. (2018) The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 43(10), 2154–2160. Available from: doi:10.1038/s41386-018-0136-3.

Ballard, E.D., Ionescu, D.F., Vande Voort, J.L., Niciu, M.J., et al. (2014) Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. Journal of Psychiatric Research. 58, 161–166. Available from: doi:10.1016/j.jpsychires.2014.07.027.

Collo, G. & Merlo Pich, E. (2018) Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression. Neural Regeneration Research. 13(4), 645–646. Available from: doi:10.4103/1673-5374.230288.

Dadiomov, D. & Lee, K. (2019) The effects of ketamine on suicidality across various formulations and study settings. The Mental Health Clinician. 9(1), 48–60. Available from: doi:10.9740/mhc.2019.01.048.

Pai, A. & Heining, M. (2007) Ketamine. Continuing Education in Anaesthesia Critical Care & Pain. [Online] 7 (2), 59–63. Available from: doi:10.1093/bjaceaccp/mkm008.

Pribish, A., Wood, N. & Kalava, A. (2020) A Review of Nonanaesthetic Uses of Ketamine. Anaesthesiology Research and Practice. 2020, 1–15. Available from: doi:10.1155/2020/5798285.

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