Ketamine: party drug or life saving antidepressant?

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Depression affects more than 264 million people and is the leading cause of disability worldwide, according to WHO.[1] With the percentages of people suffering from depression increasing in studies around millennials, new treatments have been sought out, one of them being ketamine.

Ketamine, commonly known as Ket or Special K, is a drug often used recreationally (in its crystal/powdery form) due to its hallucinogenic and dissociative effects. With recurrent use of the drug being reported to lead to neurocognitive impairment as well as addiction, it would be a shock to some that it contains properties that could be vital to treating severe depression and suicidal ideation.

To the medical world, ketamine is known as a NDMA receptor antagonist, forming a class of drugs that work to inhibit (antagonize) the action of the NMDA-receptor – a glutamate receptor/channel protein found in nerve cells. In doing so, Ketamine can induce a dissociative anaesthetic state and has been used as an anaesthetic agent often in otherwise painful emergency operations. [2]

First experimented with in 2000, the antidepressant effects of ketamine were explored through the use of a low sub-anaesthetic dose given via intravenous infusion (sending the medication directly into your vein using a needle or tube), or nasal mist, it was found that ketamine could produce antidepressant effects within four hours, lasting up to several weeks, showing much faster results than commonly used antidepressants, SSRIs (selective serotonin reuptake inhibitor) and TCAs (tricyclic antidepressants), which usually need to be taken for several weeks in order for the medicines to build up in your system enough to have an effect.

The possible theory behind Ketamine’s profound effect lies in the brain. Within a normal brain lies a circuit of neurons with neurotransmitters at the end of each neuron to allow for neuronal communication, allowing for us to respond to stimuli around us, such as taking our hand away from a hot stove. Within the brains of those suffering from depression, however, there are abnormalities in the neuronal plasticity and transmission, which can lead to altered levels of glutamate in the brain. Glutamate is an excitatory neurotransmitter released by nerve cells in the brain and holds a vital role in synaptic transmission, sending signals between nerve cells and has been shown to play a role in memory. As a result, receptors for glutamate (such as the NDMA-receptor, which Ketamine inhibits) also play a role in memory as well as other neuronal functions. Excessive glutamate acting on the receptors have been linked to neurodegeneration due to high concentrations of the ion, Ca2+ being transported to neighbouring neurons and can lead to cell death. This could be why within cases of severe depression catatonia and psychomotor retardation -due to the slowing of cognitive functions within the brain- occur.

Fig. 1. NDMA Glutamate receptors. The receptors are located in the post-synaptic membrane and form channels composed of NR1 and NR2 subunits. Anti-glutamate receptor (type NMDA) antibodies are directed against a main epitope located in the extracellular domain of the NR1 subunit. [3]

Such neurodegeneration can lead to a decrease in neuroplasticity which can affect how serotonin, the happiness hormone, is transmitted from one neurone to another, leading to low levels of this chemical that is deeply intertwined with depression. By inhibiting the NDMA receptor, Ketamine allows for excessive glutamate levels in the brains of those suffering from depression to lower, allowing for neuroplasticity to continue, which may allow for serotonin levels to increase. [4]

Despite the many benefits of ketamine, it is not known yet as to whether it will be licensed for use in depression in England, as regular users can develop ‘ketamine bladder’- symptoms of this being, incontinence, severe pain when passing urine as well as blood in the urine. Moreover, the addictive nature of Ketamine and its danger of overdose makes ketamine an unlikely drug to be prescribed the same way as antidepressants are and are usually only considered to be a viable option for those with treatment-resistant depression, limiting the types of people it would be used for. However, as research into the effects of Ketamine continue, hopefully it will shine light on more ways that the debilitating and seemingly “invisible” illness of depression can be treated. [5]


References

  1. World Health Organization (2020), Depression, Available from: https://www.who.int/news-room/fact-sheets/detail/depression [Last Accessed 06/09/2020]
  2. DrugBank, Ketamine (2020), Available from: https://www.drugbank.ca/drugs/DB01221 [Last Accessed 06/09/2020]
  3. Anti-NMDA-receptor encephalitis: A severe, multistage, treatable disorder presenting with psychosis – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Glutamate-receptors-type-NMDA-The-receptors-are-located-in-the-post-synaptic-membrane_fig1_47448748 [Last Accessed 06/092020]
  4. Corriger, A., & Pickering, G. (2019). Ketamine and depression: a narrative review. Drug design, development and therapy, 13, 3051–3067.  Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717708/ [Last Accessed 06/09/2020]
  5. NHS (2014), Ketamine tested as severe depression treatment, Behind the headlines. Available from: https://www.nhs.uk/news/mental-health/ketamine-tested-as-severe-depression-treatment/ [Last Accessed 06/09/2020]

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