In a previous article, we explored the enantiomers of ketamine, an enigmatic compound that has held scientists’ attention in the field of neuroscience due to its dualistic properties that make it interesting for both schizophrenia and depression researchers.
To give you a window into what it is like to work with this exciting compound, we have secured an exclusive interview with Kjartan Frisch Herrik, in which he delves into the applications, mechanisms, and future prospects of ketamine research. Kjartan is a Research Fellow at Lundbeck, a Danish pharmaceutical company which focuses exclusively on brain diseases, so we’re sure you will find his insights into the industry illuminating.
Ketamine's allure emanates from its intriguing properties – it has been shown to have both psychotomimetic/dissociative (induces transient, psychosis-like symptoms) and rapid-acting antidepressant effects. As Herrik elucidates, he has been scrutinizing ketamine’s effects on how neurons behave using electrophysiology and simple rodent behavioural methods.
For the uninitiated, electrophysiology is a technique that allows researchers to measure and analyse electrical signals produced by cells – in this case, neurons in the brain. A neuron at rest is slightly negatively charged compared to it’s surroundings, but through manipulation of many sodium (Na+) and potassium (K+) ions around it, it can become positively charged for a moment in order to fire a signal to other neurons it is connected to via connections called synapses. This is called an action potential, and the mass influx and efflux of positively charged ions are caused by neuron(s) as they cycle through action potentials and the rest generate measurable changes in their chemo-electric environment. In vivo studies, such as the ones performed by Kjartan and his team often employ an implanted electrode for maximum signal quality. A simplified diagram of such a setup can be seen in Figure 1. To dig deeper into electrophysiology, an approachable guide can be found in the further reading section at the end of this article, and in 3 x 1 min videos in one of Kjartan’s articles: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.737295/full#supplementary-material.
Figure 1: A simplified overview of an in vivo electrophysiology setup. The microelectrode tip is situated amongst the neurons in a brain region of interest. As neurons fire, they cause influxes and effluxes of charged ions, which causes chemo-electric changes in their surroundings. The changes in current detected by the microelectrode are transmitted to an amplifier, the background noise detected at the ground electrode is used to de-noise the signal from the brain electrode, and the denoised signal is split into frequency bands (different speeds of neuronal firing) for analysis.
On ketamine’s mechanism of action…
Defining the mechanism of ketamine's antidepressant properties remains an interesting challenge. Herrik outlined some of his findings in the journey to understand ketamine’s effects better.
Firstly, he found that when rodents are anaesthetized, ketamine inhibited both pyramidal neurons and GABAergic interneurons DOI: 10.1016/j.neuropharm.2018.04.022. This first discovery was very interesting because the common hypothesis is that ketamine increases the firing of pyramidal neurons by inhibiting GABAergic interneurons.
They decided to use awake rodents to see if being unconscious is relevant to the outcome – even today many experiments are performed while the rats are anaesthetised. This is when they observed the expected increase in pyramidal firing, but curiously, not a reduction in GABAergic interneuron firing doi.org/10.1016/j.neuropharm.2019.107745. This means two things: 1) the conscious state of the animal can strongly influence the result, 2) the increase in pyramidal firing may come from changes to the neuron’s functioning, perhaps switching from NMDA receptors, which are blocked by ketamine, to a different type of receptor with a similar function called AMPA.
As explained before ketamine has two main effects: antidepressant and dissociative/psychotomimetic. Kjartan and co tried to understand the link between these effects and the frequencies of neurons firing registered in the rodent’s brains. They hypothesized that activity in the lower frequency bands could be seen as a fingerprint for the dissociative effect DOI: 10.3389/fpsyt.2022.737295. They also found that the dissociative fingerprint of brain activity was reversed by giving the rat an antipsychotic, and that activity in higher frequencies may be linked to antidepressant activity. Whether the rodents were sitting or running also had a significant impact on their brain activity, sometimes brain activity from running masked important drug effects.
Figure 2: A graphical abstract from Kjartan’s research. The electrodes for recording brain electrical activity and the accelerometer for recording and detecting activity states are depicted feeding into the activity-separated brain activity at the bottom of the figure. The effect of clozapine on restoring the lower frequency effects is only seen when the rat is inactive.
Herrik further investigated these phenomena in collaboration with King’s College London DOI: 10.1007/s00213-022-06272-9. Together, they compared the effects of ketamine and D cycloserine (another compound with antidepressant effects) on healthy volunteers. Both antidepressant compounds caused similar increases in high-frequency oscillations (the suspected anti-depressant fingerprint). Interestingly, the low-frequency effects (fingerprint of dissociative effect or psychotomimetic) seen in rodents given ketamine (and reversed by the antipsychotic clozapine) were seen in humans given ketamine, but not D cycloserine. This also paired nicely with the results of a psychosis symptom interview, which showed that subjects given ketamine had a psychotomimetic experience while D cycloserine did not produce these side effects.
On limitations of animal models of depression…
The absence of a truly bulletproof rodent model of depression sparked a pioneering approach in Kjartan’s research - back translation. This strategy takes the known result in humans – that ketamine acts as an antidepressant – and attempts to find compounds with comparable effects in naïve (i.e. not depressed) animals. Herrik’s team compares behaviours and neuronal firing properties induced by ketamine to those produced by other compounds.
Herrik notes that while he’s not sure a true depression model exists in rodents, he has seen in his own research that rodent’s behaviour in the Porsolt swim test (a test for coping to a stressor in rodents) is modified by ketamine, psychedelics and other NMDA antagonists. He suggests their behaviour in the test is somewhat predictive of antidepressant efficacy even if the animals themselves are not truly depressed.
On compound optimization…
When contemplating ketamine's molecular structure and its optimization, Herrik speculates on the minimal leeway for modification given its binding to the NMDA receptor's pore region. However, selective targeting of NMDA subunits (situated higher up the receptor) or modulation at the glycine site emerge as alternative strategies that warrant exploration. He points out that some compounds which negatively modulate the NR2B subunit have shown more benign side effects but still appear to have antidepressant effects. Additionally, he points to the results from his study comparing D cycloserine discussed earlier, which binds to the glycine site on NMDA and also appears to have antidepressant effects.
On legislation and enantiomers…
The racemic mixture of ketamine dominates in experimental settings, but Herrik acknowledges the differing impacts of its enantiomers. Through in vitro studies, his team has seen that S and R enantiomers exhibit variance mainly in their potency, with the S enantiomer, sometimes called esketamine, producing greater psychotomimetic effects.
On the future of ketamine…
As the interview winds to a close, the trajectory of ketamine's future takes center stage. Herrik notes that both D cycloserine and ketamine are old compounds, and therefore have limited interest to many companies. He envisions a niche role for ketamine, serving as a last resort for patients unresponsive to traditional antidepressants due to its limitations - particularly psychotomimetic side effects. The researcher believes the ideal path forward lies in mitigating these side effects while retaining the antidepressant potency. The journey into understanding ketamine's mechanism of action will undoubtedly persist, and to future neuroscientists he stresses the importance of examining the dynamic interplay between compound response and the locomotor state of the animal. In the future he hopes to explore how ketamine effects sound perception, and probe whether hallucination or dissociation is essential for its antidepressant properties.
The article was written by Lorenzo Cianni and Christien Bowman
Disclaimer:
The views and opinions expressed by me in “Unlocking the Enigma of Ketamine: Insights from a Neuroscientist's Perspective” are solely my own and do not necessarily reflect the views or opinions of the company I work for. I am providing these statements based on my personal experiences, knowledge, and beliefs as an individual. Any reference to the company is purely for context and should not be construed as the official position of the organization.
I am solely responsible for the accuracy and completeness of the information provided during the interview. The company holds no responsibility for any statements or claims made herein. This disclaimer applies to all forms of media and communication where this interview is presented or referenced.
Kjartan Frisch Herrik, PhD
Research Fellow
H. Lundbeck A/S