The Facts about Ketamine – Special K 

 Ketamine, or “Special K,” is back in the news primarily because a coroner in Colorado changed the cause of death for Elijah McClain to Ketamine, administered by paramedics called to the scene. One of the old drugs in the anesthetic class, Ketamine, was first introduced in 1962. Ketamine is an analog of Phencyclidine, first produced by the Parke Davis Company in 1956. It has been used primarily as an anesthetic drug, but over the last twenty years, it has emerged as a helpful agent in the battle against major depressive disorders. Major depressive disorder is the second primary reason for worldwide disability. It was also used as a recreational drug in powder and liquid form in the early days of its production and was named “Special K “because it produces hallucinations. It is currently classified as a Schedule-III substance by the Drug Enforcement Administration (DEA).

Ketamine was an interesting option for intravenous anesthesia, but when it showed a significant role in Psychiatry, it became more critical to the medical community. It has been used as an anti-depressant and anti-suicidal treatment. However, its primary effect on depression is due to its rapid onset of action.

Its bioavailability is subject to its route of administration. For example, 100% of the drug is available if we administer it through an intravenous route. On the other hand, 93%, 45%, 30%, and 20% through Intramuscular, intranasal, sublingual, and oral routes, respectively, in the body. In the IV route, its onset of action is within seconds, and through IM and subcutaneous route, it may take 1-5 and 15-30 min, respectively. Its half-life is usually 2-3 hours and is primarily excreted through urine.

Neurotransmitter which acts mainly on NMDA receptors as an excitatory antagonist is glutamate. When glutamate is released in the synaptic cleft, it triggers AMPA receptors which are co-localized with NMDA receptors. Subsequently, the release of sodium ions activates the NMDA receptors, and thus sodium and calcium ions are released. Hence its antagonism effect to NMDA receptors causes inhibition of excitation.

Ketamine has opened the gateway for removing the challenges with treatment-resistant depressive disorders like depression and suicidal tendencies. Furthermore, due to its advanced mechanism of action and strong effects, it is one of the best choices for major anxiety and depression issues.

Its clinical uses are:

• Its primary use is as a rapid-acting general anesthetic drug with reflexes, enhanced skeletal muscle tone, and respiratory and cardiovascular stimulation. Anesthesia by Ketamine is also called dissociative anesthesia because it selectively interrupts associative pathways.
• Single-dose administration usually causes immediate anti-depressant effects.
• It affects brain oscillations with four different types theta, gamma, alpha, and delta. As theta is associated with learning, gamma controls sensory and cognitive abilities, alpha is linked to sleep cycles, and beta is associated with emotional behaviors.
• Ketamine has also been found to regulate glucose metabolism in different parts of the brain, which are linked with anxiety and depression, which is very effective in managing resistant depression.
• Pathologies of depression have evidence of alteration in brain energy metabolism and Ketamine while its effects stabilize homeostasis of that part of the brain.
• While acute administration, plasticity and synaptic connectivity of the brain are triggered. Ketamine has a significant effect in controlling fear memory management which may be a part of depression.
• Due to its unique behavior, it is observed pharmacologically that Ketamine reaches that molecular mechanism that is not matched by standard anti-depressant drugs. That’s why it is called a golden anti-depressant.
• It may also sometimes be used in the limited treatment of Epileptic conditions.
• It may show some effects on bipolar depression as a mood stabilizer.
• It can be a promising drug for patients with social cut-off, suicidal tendencies, and fears of being alone.
• It reduces pain and relieves patients after surgeries.

It is available in nasal sprays, IV injections, and infusions for greater results. Its anti-depressant effect usually lasts for seven days and diminishes. In some patients, relapse occurs at ten days.

Besides all these benefits and unique purposeful properties of Ketamine, there are also some limitations with this drug:

• First, its cellular mechanisms are not yet fully understood in research studies.
• Long-term treatments with Ketamine may result in alteration in brain functions, dependency, and changes in the topology of the brain.
• It should be used cautiously at subanesthetic doses, with is very critical.

Ketamine has some dose-dependent drawbacks too, which are listed below:

• Nausea and vomiting
• Dizziness
• Hypersalivation
• Psychological dissociation
• Altered feelings and perceptions
• High blood pressure should be used in cardiac patients with great care.
• Upon regular use, liver and kidney toxicities are usual.

Ketamine has served the great interest of researchers in recent years, but it has to be handled with extra care and precautions until there are more clinical studies and proven results. All the data available is subject to further investigation.

References:

1. Persson J, Hasselstr€om J, Wiklund B, et al. The analgesic effect of racemic Ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans. Acta Anaesthesiol Scand 1998;42: 750e758.
2. Ferrari, AJ, Charlson, FJ, Norman, RE, et al. Burden of depressive disorders by country, sex, age, and year: findings from the Global Burden of disease study 2010. PLoS Med 2013; 10: e1001547.
3. Patten SB, Williams JV, Lavorato DH, et al. Descriptive epidemiology of major depressive disorder in Canada in 2012. Can J Psychiatry 2015; 60: 23–30.
4. Ther Adv Psychopharmacol 2020, Vol. 10: 1–21 DOI: 10.1177/ 2045125320916657
5. Brenner GJ, Ji RR, Shaffer S, Woolf CJ. Peripheral noxious stimulation induces the NMDA receptor NR1 subunit phosphorylation at the PKC-dependent site, serine-896, in spinal cord dorsal hornneurons. Eur J Neurosci 2004; 20:375-384.