Ketamine and rapidly acting antidepressants: Breaking the speed of sound or light?

Abstract

There is an urgent need for rapidly acting antidepressants. Current therapies share a delayed onset of action, contrasting with drugs of abuse that have rapid psychotropic effects but cause tolerance and dependence. A key uncertainty is whether there is a finite speed limit imposed by the critical role of homeostatic adaptive mechanisms that underpin the efficacy and onset of available psychotropic agents and whether this is mutable with emerging agents with potential rapid onset, in particular ketamine.

In 1947, US Air Force pilot Chuck Yeager broke the speed of sound, settling the debate about whether this imposed a finite limit on travel. In contrast, the speed of light, inscribed in the standard model of physics, has proved to be an impenetrable barrier. In psychopharmacology, there is pressing urgency in the search for rapidly acting antidepressants, begging the question as to whether there is a finite limit imposed by the laws of nature on antidepressant action and whether this is mutable with current agents with potential rapid onset, in particular ketamine. Both patient and doctor preferences drive the search for rapidly acting agents.

In this context, psychotropic agents can broadly be divided into two groups. The first ‘tortoise’ group of commonly used therapeutic agents includes antidepressants, antipsychotics and mood stabilisers, principally lithium. They all share a number of common features; foremost that there is a significant delay between the onset of treatment and substantive clinical benefit. These agents also share maintenance efficacy, which in many cases is more statistically robust than their acute treatment efficacy. This is particularly so for antidepressants, where for modern agents, only modest benefits are found for acute treatment, but more robust benefits are found for prevention of relapse among those who respond to treatment. It is also a common feature of all these agents that relapse, when it occurs, is typically delayed some weeks to months after treatment discontinuation.

This significant lag to full efficacy, evident in all three major therapeutic classes, emphasises that the beneficial effects of these agents relies on downstream adaptive, homeostatic and regulatory changes secondary to treatment. For antidepressants, these appear to be related mainly to the expression of receptors, including delayed alteration in the regulatory set point of the serotonin type 1A, type 2A/C and noradrenergic alpha receptors, among others. In addition, changes to neurotrophins and neurogenesis appear to be important delayed mechanisms of action underlying antidepressant efficacy. For lithium, the mechanisms appear more complex, but include changes in the regulatory status of second messengers including glycogen synthase kinase (GSK3), inositol triphosphate, nitric oxide and possibly others (Brand et al., 2015). The clinical effects of all of these agents are thus slow to arrive, slow to dissipate on cessation and are underlying on delayed homeostatic adaptations to the persistent presence of therapy.

In contrast, the second major class of psychoactive agents, the ‘hares’ as it were, are drugs that have acute psychotropic effects, which because of their effects on the sensorium are often used recreationally and can lead to abuse and dependence. These include opiates, benzodiazepines and agents such as cocaine and amphetamines. Here, the temporal patterns are quite distinct. The psychotropic effects of the agents are evident immediately and dissipate rapidly, generally in parallel with single-dose pharmacodynamics and pharmacokinetics. Equally, homeostatic adaptive mechanisms ensure that tachyphylaxis sets in, such that repeated administration brings about serially more blunted responses to repeat administration, paralleled with the development of tolerance and dependence, at least in a subset of individuals. This phenomenon is generally absent in the ‘tortoise’ group of drugs. Historically, abuse and dependence liability have always taken longer to emerge and clarify than acute efficacy. This was certainly the case with benzodiazepines, and we are currently seeing the ugly ending to the enthusiasm for aggressive treatment of pain with opiates that began a decade or so ago. The neurobiological processes underpinning addiction are again complex and involve serial and progressive regulatory changes in key systems including dopamine and cysteine glutamate exchange as well as glial cell-directed immune-inflammatory mechanisms. Importantly, these are predictable homeostatic adaptations to the direct effects of the agent on the receptor and its subcellular signalling cascade, leading to down-regulations of those systems. Therein, we observe a significant similarity to the delayed onset of action observed with the ‘tortoise’ drugs.

It is arguably true that there are no pharmacological agents of the tortoise class of drugs that work immediately, suggesting that agents of long-term therapeutic value actually require long-term homeostatic adaptation as part of the intrinsic benefit of those agents. Equally, regarding the ‘hares’, when the process of homeostatic adaptation drives the system away from the therapeutic goal, these agents not only tend not to have long-term therapeutic value but have the potential to adversely dysregulate the pathways one wishes to target in treatment and might worsen the clinical condition (Möller et al., 2015; Swanepoel et al., 2018). The partial exceptions are electroconvulsive therapy (ECT) and deep brain stimulation (DBS) (which are not drugs); but can such unique rapid action be captured pharmacologically? It’s also true that even ECT typically needs a course of half to a dozen treatments over several weeks and DBS requires ongoing stimulation for several months for maximal benefits to accrue. The initially promising work on DBS remains to be confirmed by randomised controlled trials (Holtzheimer et al., 2017; Mayberg et al., 2005).

Are the observed delayed effects with currently available antidepressants and antipsychotics merely an artefact of the available agents, or is there some natural speed limit inherent in the divergent patterns of homeostatic adaptation to psychotropic agents? Indeed, pharmacologically tampering with these homeostatic mechanisms may have far-reaching consequences. For instance, dampening auto-receptor suppression of neurotransmitter release with a 5-HT1A receptor antagonist like buspirone or pindolol can prompt a faster onset of antidepressant action (Harvey, 2008). However, methamphetamine, a known neurotoxin and drug of abuse, is capable of lifting mood in the acute period post administration. However, the ensuing massive release of monoamines engenders a homeostatic process that seeks to curb this action, so that beneficial effects on mood are short-lived (Mouton et al., 2016). This may even culminate in the opposite effect later in life, that is, worsening of depression and the development of treatment resistance. An improved understanding of the mechanics of signal transduction affords us the opportunity to better control and predict the outcome of indiscriminately targeting certain receptors and pathways. In this regard, cortical glutamate N-methyl-D-aspartate receptors (NMDAR) play a central role in modulating downstream release of monoamine and other transmitters, thus representing a putative target regulating release mechanisms and onset of action.

Although the precise molecular mechanism of ketamine remains to be elucidated, its primary mode of action has been thought to be due to its non-competitive antagonism of the NMDAR (Workman et al., 2018). More recent work has suggested that its antidepressant actions might be independent of its antagonism of NMDAR and might instead be mediated by the activity of its metabolite, hydroxynorketamine, on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (Zanos et al., 2016). Nevertheless, it is becoming increasingly apparent that its efficacy rests on forming new synapses resulting in increased excitatory drive and that this action requires the enhancement of rapamycin complex 1 (mTORC1) signalling and a mutual interaction between γ-amino-butyric acid (via type B receptor; GABABR) and glutamate (via NMDAR) function (Workman et al., 2018). Inhibitory versus excitatory function mediated by GABAB–NMDA receptors subsequently engages in neuronal homeostatic mechanisms required for effects on mTORC1-dependent translation. Importantly, ketamine has molecular effects that overlap with other rapid acting agents of potential therapeutic benefit, such as scopolamine (Wohleb et al., 2017).

Considering the mutual involvement of GABA-glutamate pathways in ketamine’s action, and that abrupt cessation of regular ketamine use is, as with other drugs of abuse, associated with a discontinuation syndrome (Short et al., 2018), one wonders how engaging homeostatic plasticity following intermittent repeated ketamine challenge may determine later long-term outcome of the illness. Indeed, altering homeostatic plasticity may have both positive and negative attributes, as has been put forward for the role of brain-derived neurotrophic factor (BDNF) in depression (Harvey et al., 2013). Interestingly, it has been proposed that repeated inappropriate antidepressant discontinuations, as is commonly the case with poor patient compliance, drives perpetuating imbalances in NMDA-GABA-mediated pathways (perhaps via kindling mechanisms; Harvey and Slabbert, 2014; Harvey et al., 2003) that drive another series of subcellular events, like that of the nitrergic system (Harvey et al., 2006). Intermittent use of ketamine, or single or repeated administration but against a backdrop of prior repeated treatment discontinuations using traditional agents, may lead to mobilisation of an alternate subcellular cascade that drives neuroplastic processes that adversely affect long-term outcomes, as noted with other drugs of abuse (Bonnet, 2015). It is evident that the current use of ketamine does involve a discontinuation syndrome. Whether ketamine use under such conditions will adversely affect treatment outcome, possibly leading to treatment resistance and more severe intractable depression needs to be studied in sufficiently long-term studies.

Ketamine is unique in that its psychotropic properties were harnessed for recreational use before it was identified as having pharmacotherapeutic properties (notwithstanding that it was first used as an anaesthetic). Single administration brings rapid mood improvement, and while there are reports of ‘super-responders’ who may enter remission for months after a single treatment (Gálvez et al., 2014), more typically there is an often rapid return of symptoms, which can be ameliorated, at least for a period of time, by serial administration. However, it is possible that the magnitude of the response may decline with repeated administration and very few studies have extended beyond the 6-week time point, where the addictive liability of the other agents of known abuse potential becomes prominent. For example, in the studies by Murrough et al. (2013) and aan het Rot et al. (2010) who used repeated ketamine infusions, there was a weak suggestion that the change from baseline was greatest with the initial administration, and this might have declined with subsequent administration. Indeed, street experience includes the development of dependence, where repeated use drives increasingly blunted responses and a worsening depression from which repeated use provides even more limited escape.

Nevertheless, there are several encouraging reports of longer term use of ketamine to counterbalance these concerns. And it’s also true that maintenance of ketamine has promise in chronic pain. Although ketamine can be abused and is associated with dependence, there are quite different patterns of demographics and circumstances in ketamine addicts compared to patients getting ketamine for treatment-resistant depression, including differences in drug availability, doses, dosing frequency, supervision and safety assessments. There are parallels in the use of opioids, benzodiazepines and stimulants, which have established therapeutic uses, and it is possible to at least theoretically manage the potential for diversion or abuse by control of prescriptions and dosing. However, the current crisis in opiate and benzodiazepine use in the United States highlights the complexity of this issue and begs the question of risk benefit ratio at a population level (Lembke et al., 2018). There is also a body of evidence describing the value of drugs like lysergic acid diethylamide (LSD), psilocybin, mescaline and others in the management of psychiatric illness, which is likely to raise similar abuse and risk benefit questions. For all these agents, including ketamine, because of both their potential benefits and these concerns, further research is needed to better understand their place in treatment.

A critical question of the field is whether ketamine and other potentially rapid acting antidepressants are truly capable of breaking the sound barrier, or whether the speed of onset of antidepressants will prove to be more like the speed of light, an impenetrable barrier. Will ‘inappropriate targeting’ of this barrier lead to further unexpected problems, as we … ‘boldly go where no man has gone before …’, as immortalised by the intrepid Star Trek crew? Moreover, while we are aware of their short-term benefits, their long-term effects require further study, especially considering the chronic nature of the illness.