Ketamine was once used mainly as an anaesthetic on battlefields and for horses. Later it became a party drug, the notorious ‘Special K’. Now it’s being used for depression and even to prevent suicide. Drugs have taken on new roles before, but ketamine’s career change is one of the most surprising.

Ketamine research
How does ketamine work?

How does it work?

Chemically, ketamine is an arylcyclohexylamine derivative that acts as a non-competitive antagonist at glutamate N-methyl-D-aspartate (NMDA) receptors. A non-competitive antagonist does not compete for the receptor’s binding site: the agonist still binds there unhindered, but nothing happens.

Glutamate binding to NMDA usually acts to suppress its own transmission in a feedback loop that works like a thermostat. By antagonising the NMDA receptor, ketamine disrupts this feedback loop and thus enhances glutamate activity. More glutamate is so crucial because this once obscure neurotransmitter is now thought to be central to depression.

An early theory: the monoamine hypothesis

For decades the dominant theory of depression has been the monoamine hypothesis. Here the culprits are the neurotransmitters serotonin, noradrenaline and dopamine. But several observations have cast doubt on the theory. One anomaly is the time lag between the monoamine rise produced by traditional antidepressants (hours) and the improvement in clinical symptoms (weeks).

Meanwhile around one third of patients experience no improvement at all, even though their monoamines have risen.

Such limitations have sent researchers looking for new types of antidepressants, and other neurotransmitters they might affect.

Glutamate appeared as an obvious candidate. Not only is glutamate the brain’s major excitatory neurotransmitter, but its metabolites are decreased in depression. Researchers have noted this especially in the frontal cortex and correlated these levels with the severity of depressive symptoms.

This is not to say that monoamines are not involved. The traditional serotonin, noradrenaline and dopamine are certainly part of the complex web of neurotransmitters that underpin the regulation of mood. The new view of depression sees glutamate as the final channel through which these monoamines exert their effect. And ketamine is the agent known to boost it.

What is ketamine

Ketamine come as a mix of two molecules in mirror-image called enantiomers. S-ketamine and R-ketamine are akin to left and right-handed versions of the same glove. For its slighter stronger activity at the NMDA receptor, S- ketamine (or “Esketamine”) is the variety chosen to be the next antidepressant, and it differs is several crucial ways from its predecessors.

While regular ketamine required an intravenous dose, Esketamine is delivered via a nasal spray. The single dose avoids the inconvenience of taking daily medication, although patients may require regular follow-up doses to maintain the antidepressant effect.

The frequency depends on the individual case, with typical regimens weekly, fortnightly or monthly. Since Esketamine exerts its effect through a different neurotransmitter, patients unresponsive to traditional antidepressants have more chance of success than from simply switching to another one. For the same reason, Esketamine can be safely added to these antidepressants without “doubling-up” and the almost inevitable side effects that brings.

The Esketamine’s most important advance is the speed of its effect.

The usual wait before a traditional antidepressant kicks in is four to six weeks. Since side effects lack the same tardiness, patients often give up on their treatment before it has had a chance to work, while those with treatment-resistant depression endure repeated waits with no guarantee that their symptoms will depart in end.

For ketamine, early studies reveal that many patients experience substantial improvement not after weeks, but within hours. For the minority who do not respond, at least this is known quickly so that that other treatments may be explored immediately.

Ketamine and suicide

Another startling and perhaps game-changing difference is ketamine’s reduction in suicidal thinking and the risk of suicide. Other antidepressants have only ever shown this effect by reducing the depression itself.

Ketamine appears to dampen suicidal tendencies over and above its effect in raising mood.

Along with its rapid action, ketamine suddenly appears as a possible treatment for the thousands of patients every year who need suicidal risk addressed immediately. While the anti-suicidal effect has so far only been identified with intravenous ketamine, the same results are expected when studies are completed on Esketamine.

While all these benefits are undoubtedly exciting, many psychiatrists and patients remain naturally sceptical of a drug most known for its role in the rave scene.

Accordingly, Esketamine will initially be reserved for patients who have had adequate but unsuccessful trials of traditional antidepressants, as well as having no active or recent drug abuse. Caution will also be needed for patients with a history of psychosis.

Psychiatrists remain optimistic about such potential side effects because Esketamine’s dose is vastly lower than amounts required for the anaesthetic or hallucinogenic effect. Nor have negative cognitive effects have been found: in fact, early studies indicate the reverse. By enhancing glutamate transmission in the frontal lobe, ketamine may actually improve cognition – and again, possibly in excess of what improved mood alone would predict.

Of course, this is not an artificially-enhanced IQ as in Flowers with Algernon, but more the restoration of pre-depressed function. In the immediate aftermath of treatment there is also likely to be confusion (patients need monitoring and must not drive home afterwards) but this resolves within a few hours.

Ketamine research: the quest continues

Most of the excitement in research circles has revolved around these more subtle cognitive effects of ketamine. Studies have shown that enhanced glutamate transmission leads to increased neuronal factors involved with synaptic growth, such as BDNF and mTORC1.

Just as depression rewires the brain, ketamine may do likewise but in a beneficial way. This ties in with the burgeoning field of neuroplasticity which promises to be the next frontier in our evolving understanding of the brain.

Already fascinating findings are coming to light, such as ketamine appearing to increase the volume of the hippocampus and restore connectivity in the prefrontal cortex. Sleep is also involved, with ketamine increasing both total sleep and the slow-wave activity of deep sleep.

Researchers have theorised that it is these changes in cognition and sleep that provide the rapid relief of suicidal risk: perhaps enhanced sleep and executive thinking breaks the stranglehold of negative emotion and allows a person to assess their problems more objectively. The picture is exceedingly complex and much remains to be understood, but we can at least have hope that the long-awaited next generation of antidepressants has arrived.

For references and further reading, please refer to:

Matveychuk D, Thomas RK, Swainson J, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020;10:2045125320916657. Published 2020 May 11. doi:10.1177/2045125320916657

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