New Antidepressant class: New mechanism of action

Many unfortunate individuals suffer year after year of depression. Depressive illness becomes the defining feature of their lives, as one tablet after another fails, and the psychotherapies reveal themselves as blunt instruments.  For decades, psychopharmacologists have sought a new class of antidepressant, based on new mechanisms, rather those which target the brainstem-derived neuromodulators, serotonin, noradrenaline and dopamine. Finally, there has been a breakthrough. Ketamine, a molecule familiar to the anaesthetists, has repeatedly showed efficacy against stubborn depression. And recently, the s-enantiomer (esketamine) has been fast-tracked for clinical use in the USA after positive results in phase III trials. Ketamine necessitate intravenous administration, whereas esketamine, an intranasal spray, represents a much more practical option for wider clinical use.

The Neurophysiology: Extended consciousness, brain wiring & the personality

Ketamine blocks a receptor for glutamate, the main fast excitatory neurotransmitter in the cortex, thalamus and limbic system. This is the NMDA receptor channel, which is one of the most celebrated components in modern neuroscience, critical for short and long-term plasticity at glutamate excitatory synapses (Collingridge and Bliss, 1995).  Channel opening, and the inward flux of Ca2+, are the prime movers in boosting the strength of individual glutamate synapses, of which there are over 15,000 converging on a single neuron. Over the timeframe of seconds, NMDA receptor activation is essential for supporting conscious mental activity in the vast neural network (Ingram et al., 2018). NMDA receptor activation can also set in train processes which ultimately lead to the long-term structural enhancement of glutamate synapses, the basis for learning and memory. The personality is believed to emerge and develop as the neural network is sculpted and fine-tuned, at the level of individual synapses, by lived experience (Kandel, 1998)(DeFelipe, 2006).

Ketamine impacts upon the neural network, stimulating neurotrophic pathways and enriching neural connectivity, in keeping with the modern idea that depression stems from impoverished connectivity (McEwen et al., 2015).

The Psychophysiology: The complete transformation of lived experience & re-birth

Given the physiological importance of glutamate NMDA receptor channels for brain functioning, it is not surprising that ketamine, which blocks the channel pore and impedes the influx of Ca2+, has a profound effect on the psyche. Effects are dose-related. The anaesthetists make use of the fact that ketamine blocks conscious mental content, to the extent that surgical procedures can be carried out in otherwise awake patients, who can support their own respiration. Pain physicians also utilise ketamine, in the knowledge that chronic pain syndromes probably stem from an ingrained plastic adaptation in the cortical areas which support pain perception. For psychiatrists, there is range of ketamine doses which elicit such a complete transformation in lived experience, that some have labelled those experiences as psychotic. In fact, those experiences go much further the usual connotations of psychosis as hallucinations and delusions. Descriptions include, the cessation of time, the dissolution of the ego, near-death experiences and spiritual experiences, perhaps best demonstrated by the use of a plant-derived NMDA receptor channel blocker (ibogaine) as ceremonial entheogen in West Africa.

(There was hope and considerable investment in the idea that a new class of antipsychotic treatments, based on glutamate, could be developed, but this drug-discovery effort failed to materialise in end-stage trials. For depression however, the story has been much more encouraging, and the next phase is now unfolding.)

The Upside of NMDA channel blockers in depression

A number of clinical properties of NMDA channel blockers are highly favourable, in comparison to the older antidepressants. Above all, the NMDA channel blockers have a very rapid impact upon depression, within hours, compared to several weeks for the older drugs. The NMDA channel blockers can also impact upon the most stubborn depressions, in which the older drugs, psychotherapy and even ECT proved ineffective and frustrating. Finally, the NMDA channel blockers have a rapid anti-suicidal effect, which as experience accrues, may come to represent a specific indication in acute settings.

The downsides: NMDA channel blockers in depression: Real, potential & hyped

All effective treatments carry a downside in terms of side effects, but in comparison to much older psychiatric therapies such as clozapine, lithium and benzodiazepenes, ketamine/esketamine are remarkably safe. Of course, many patients will be put off by the idea of having psychedelic experiences and there is also a worry over possible diversion, given that ketamine is used as a club drug by people actually seeking those very same psychedelic experiences. Compared to other drugs of abuse however, ketamine addiction is a rare phenomenon, and withdrawal reactions are not recognised. Heavy, unrestrained use of ketamine is known to cause bladder dysfunction, but this appears to be a feature of recreational misuse rather than in the clinic, where bladder function can easily be monitored. 

It has been suggested that ketamine works in the same way as an opiate. Naturally this has led to scare stories, given the recent experience of opiate prescribing in the USA. However, the psychopharmacology of ketamine and opiates are quite different at the behavioural and molecular level. The most serious adverse effect of opiates is respiratory depression and death, because of overstimulation of mu receptors. Ketamine, an NMDA receptor channel blocker, does not cause respiratory depression, and the analgesic effects of ketamine in the CNS do not appear to be mediated via mu opiate receptors. 

Perhaps the major downside of NMDA channel blockers is that the antidepressant effects typically diminish after about one week. With repeated sessions, this can be extended to about three-four weeks. A major challenge for psychopharmacologists is how to extend the duration of the antidepressant effect. In the UK, ketamine treatment for depression has been available at the NHS Warneford hospital in Oxford for about a decade.  Many patients who benefitted from an initial course of intravenous ketamine return for maintenance sessions, in which the gap between sessions is individually tailored. These are patients whose lives were hitherto dominated by depression, and who found no relief from standard approaches. With maintenance treatment, they can enjoy depression free lives. Hopefully, the time-limited nature of the antidepressant effect will eventually be understood and solutions developed.

Esketamine, as an intranasal spray, now offers the possibility of more widespread and perhaps even routine clinical use for many others disabled by clinical depression. Although there are concerns, it should be realised that the prescribing of NMDA channel blockers will take place within a therapeutic relationship in which close attention is paid to how an individual patient responds, the swift recognition of any adverse effects and provision of supportive psychotherapy (and perhaps in time, even a specialised adjuvant psychotherapy). Measures to prevent diversion can be put be put in place.

History Repeats: A new Golden Age of Psychopharmacology

The old tricyclic antidepressants translated into the clinic within three years of the first positive findings in 1957, in what has been termed the Golden age of Psychopharmacology. Aside from the benefits to thousands of individual patients, a new era of neuroscience was initiated, which revealed much of the physiology of serotonin and noradrenaline (Leiberman,, 2015). Over the ensuing decades, the basic science of brainstem derived neuromodulators and monoamine-based therapeutics developed in tandem, leading to the development of safer alternatives, (the SSRIs in 1971). The positive findings with ketamine and esketamine in depression are ushering in a similar scenario. This time of course, the tools of molecular neuroscience are available, so that the pace of discovery should be quicker, and at a much more fundamental level. Already the therapeutic benefits of NMDA channel blockers are being made available for patients whose lives have been dominated by depression. Just as happened for the older antidepressants, refinements will be made over the coming years with the joint efforts of laboratory based pharmacologists and psychiatrists who treat depressed patients. Novel administration regimes, adjuvant psychotherapies, and new candidate molecules targeting other components of glutamate neurotransmission are likely to appear.

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