This commentary review (2014) highlights the strength of evidence from recent proof-of-concept studies of ketamine which bear promise for the rapid treatment of depression which currently lacks efficient treatment alternatives. However, the authors disagree about the underlying mechanism mediating these effects and doubt whether there is a sufficient degree of preclinical evidence to warrant the initiation of novel treatment approaches or widespread availability of the drug in clinical settings.
Large ‘real world’ studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr. Sanacora and Dr. Schatzberg share their opinions on these issues and discuss paths to move the field forward.
Sanacora and Schatzberg frame ketamine as a treatment that has challenged conventional views of antidepressant therapy by producing rapid-onset antidepressant and anxiolytic effects, including in patients with treatment-resistant depression. Earlier research has shown that most approved antidepressants require weeks to exert clinically meaningful effects and act primarily on monoaminergic systems; ketamine’s apparent ability to induce fast, robust, but temporally limited improvements has therefore reinvigorated interest in novel mechanisms of action for mood disorder therapeutics. This Circumspectives piece sets out to evaluate what is known and uncertain about ketamine’s antidepressant effects. Sanacora presents evidence and interpretation that emphasise NMDAR antagonism and downstream glutamatergic modulation as key mechanisms, whereas Schatzberg offers a countervailing view that other mechanisms (including opioid, sigma and monoaminergic effects) may be critical and that an exclusive focus on NMDAR antagonism risks misdirecting drug development. Together the authors review preclinical and clinical data, highlight methodological challenges in the field, and discuss implications for future therapeutic development and safety evaluation.
Papers cited by this study that are also in Blossom
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F. et al. · Journal of Affective Disorders (2014)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Papers in Blossom that reference this study
Sapkota, A., Khurshid, H., Qureshi, I. A. et al. · Cureus (2021)
This paper is a narrative, opinion-style review (a Circumspectives piece) composed of two complementary essays by Sanacora and Schatzberg. Rather than reporting a systematic review or original experimental data, the authors synthesise and interpret animal and human preclinical and clinical literature to make contrasting arguments about ketamine’s mechanism(s) of action and clinical utility. The extracted text does not describe a formal literature search strategy, inclusion criteria, or systematic quality assessment. The authors draw on a variety of sources including rodent models (behavioural assays and molecular signalling studies), small clinical proof-of-concept trials, phase II and phase IIb studies of NMDAR-targeting compounds (for example CP-101,606 and AZD6765/lanicemine), and observational data related to safety and abuse. They also discuss mechanistic biomarkers and imaging modalities proposed for measuring target engagement (for example PET ligands sensitive to glutamatergic changes, 13C-MRS, fMRI and EEG), and consider genetic moderators such as the BDNF Val66Met polymorphism. Because this is an interpretive commentary, analytic methods are limited to qualitative synthesis and critique of existing findings rather than meta-analytic statistics.
Both authors agree on a central empirical observation: a single administration of ketamine produces a transient but often rapid improvement in depressive symptoms that typically endures for several days. Preclinical data consistently show that various NMDAR-antagonising agents produce antidepressant-like effects in rodents, and several downstream molecular cascades have been implicated: ketamine induces a transient glutamate surge, activation of AMPA receptors, engagement of mTORC1 signalling, increased synaptic protein synthesis, enhanced synaptogenesis, and BDNF-dependent plasticity. Evidence cited includes blockade of ketamine-like effects by AMPAR antagonists in animals, dose-dependent activation of mTORC1 and synaptic protein markers, and genetic data showing reduced ketamine effects in mice carrying the BDNF Val66Met allele; a preliminary human study is noted to suggest lower response rates in met allele carriers. Clinical trial data are mixed. Small trials suggest that NR2B-selective antagonists (for example CP-101,606) and low-trapping NMDAR blockers (AZD6765/lanicemine) can produce rapid, short-lived antidepressant effects. A phase IIb study administering repeated lanicemine infusions (three times per week for three weeks) reported significant antidepressant efficacy and maintenance over weeks, but a subsequent larger follow-up failed to replicate sustained clinical efficacy; that larger study encountered a high placebo response rate of 39% at the primary 6-week endpoint. Memantine, an NMDAR antagonist with many pharmacodynamic similarities to ketamine, has not produced consistent antidepressant effects in trials. Other glutamatergic approaches—partial agonists at the glycine site (GLYX13), glycine transporter inhibitors, and high-dose D-cycloserine—have shown suggestive results in animals or early-phase studies, but detailed human efficacy data remain limited or unconfirmed. Schatzberg highlights alternative or additional mechanisms. Ketamine interacts with sigma receptors, mobilises midbrain catecholamines (notably dopamine), potentiates prefrontal serotonin release via nicotinic receptors, and binds to opioid receptors (mu, lambda and kappa). Preclinical data indicate ketamine can increase mu-opioid receptor density and enhance mu-opioid signalling; analgesic effects in mice were blocked by mu and lambda, but not kappa, antagonists. These findings have led to concern that opioid receptor activity could contribute to both therapeutic and abuse-related effects. Clinical observations include frequent acute dissociation and psychotomimetic effects, and in a comparison trial ketamine produced dissociation in 60% of patients versus 30% with midazolam, an active control. Safety signals discussed include transient cardiovascular effects (elevated blood pressure and heart rate), occasional hypotension and bradycardia, and long-term risks suggested by abuse literature and animal models (cognitive effects, urinary cystitis associated with very high chronic use). Limited controlled data on repeated dosing report general tolerability, but the authors stress that long-term safety is insufficiently characterised. Other trial design and interpretive problems are emphasised: difficulty maintaining blinding because of distinctive subjective effects, high placebo response rates that can obscure small-to-moderate drug effects, and heterogeneity in dosing/regimens and outcome measures across studies. The authors also note that first placebo-controlled data showing sustained effects with repeated dosing were only recently presented but remain preliminary.
Sanacora interprets the accumulated evidence as broadly consistent with a model where NMDAR antagonism initiates a glutamate-dependent cascade—transient glutamate release, AMPAR activation, mTORC1 signalling, BDNF release and synaptogenesis—that underlies ketamine’s rapid antidepressant effects. From this vantage, NMDAR and glutamatergic modulation represent promising targets for developing new, rapid-acting antidepressants, but the complexity of glutamatergic transmission means that factors such as receptor trapping, subunit selectivity, half-life and effects on synaptic versus extrasynaptic receptors will influence whether candidate drugs can reproduce ketamine’s therapeutic profile. Schatzberg cautions that NMDAR antagonism may not be the sole or even primary mechanism. He highlights discordant findings—memantine’s lack of consistent efficacy, mixed outcomes with other glutamatergic agents, and signals that NMDA agonists or glycine-site modulators can produce antidepressant-like effects in some models. He emphasises alternative mechanisms including sigma receptor activity, catecholamine and serotonergic mobilisation, and opioid receptor agonism; the latter is especially consequential because it raises regulatory, abuse liability and ethical issues for developing ketamine-like treatments. Both authors therefore stress the need for more definitive mechanistic studies, including attempts to block putative pathways (for example with opioid antagonists), and better biomarkers of target engagement. Methodological limitations and uncertainties are explicitly acknowledged. The field faces problems of high placebo responses, functional unblinding due to dissociative effects, small sample sizes in many trials, variable replication (notably the lanicemine programme), and sparse long-term safety data for repeated administration. The authors call for well-controlled clinical trials that assess clinically meaningful short-term outcomes (for example reductions in suicidal behaviour or hospitalisation) and examine sustainable response beyond a few weeks. They also recommend a range of additional studies: abuse-liability assessments across populations, biomarker and imaging work (PET for mGluR5 or mu opioid binding, 13C-MRS, fMRI, EEG) to document target engagement, pharmacogenetic investigations (for example BDNF Val66Met), and head-to-head or mechanistic trials using antagonists such as naloxone to probe opioid involvement. In terms of translational implications, the authors agree that while ketamine demonstrates proof of principle for rapid-acting antidepressant effects, it is premature to conclude that any single mechanism explains the clinical response. Future drug development should remain agnostic about a unique mechanism and prioritise both safety and validated biomarkers of engagement. They also advocate open discussion about the potential opioid-related properties of ketamine and careful long-term monitoring if broader clinical use is pursued.
"Our brightest blazes of gladness are commonly kindled by unexpected sparks."
There is little disagreement over the need for improved antidepressant therapeutics, yet in recent years, the pharmaceutical industry has been abandoning this therapeutic area at an alarming rate. The discovery of ketamine's rapid antidepressant effects has reinvigorated the field and revolutionized our thinking about antidepressant medications in several respects. First, ketamine's ability to induce a rapid onset of antidepressant and anxiolytic effects demonstrates that it is not necessary to wait weeks to achieve a clinically meaningful level of improvement. Second, ketamine has proven effective in patients who were highly resistant to the existing armamentarium of antidepressant medications, thus suggesting it may also address the problem of "treatment resistant depression". Lastly, ketamine appears to work via a unique mechanism of action (MoA), not directly targeting the monoaminergic neurotransmitter systems, suggesting that it is possible to develop novel classes of antidepressants with unique targets of engagement. Understanding the true clinical utility of this novel treatment approach and identifying the mechanisms mediating ketamine's antidepressant effects have become a focus of many researchers and pharmaceutical companies, and serves as the motivation for this perspective.
There is now incontrovertible evidence that a single administration of ketamine is associated with a transient improvement in depressive symptoms lasting for several days. However, the mechanisms underlying this effect remain unclear. Conventional wisdom suggests ketamine's effects are mediated through actions on the glutamatergic N-methyl-D-aspartate receptor (NMDAR). Although ketamine has been shown to have effects on several neurotransmitter and neuromodulatory systems (see Dr. Schatzberg's section), the majority of ketamine's known pharmacological effects are mediated through the NMDAR, where it acts as an open channel, non-competitive antagonist, binding within the ion channel and blocking ion influx. Over two decades ago, Skolnick and collaborators initially speculated that a dampening of NMDAR function could be a common mechanism underlying antidepressant efficacy. This was based on observations that chronic treatment with various classes of antidepressant agents impacted NMDAR function, and reports of abnormal NMDAR binding in the brains of suicide victims, and rodents subjected to chronic stress conditions(seefor reviews). However, the strongest evidence that actions at the NMDAR are mediating the antidepressant effects of ketamine comes from the fact that other drugs with NMDAR antagonist properties also show antidepressant-like effects. Several drugs that effectively either block or antagonize NMDAR activity, such as the competitive NMDAR antagonists CGP 37849 and CGP 40116, the non-competitive, nonsubunit selective NMDAR antagonist MK-801, and the NR2B selective antagonist, have repeatedly and fairly consistently been shown to have antidepressant-like properties in rodent models; although, possible differences in the onset and duration of the antidepressant-like effect have been observed. There is also emerging evidence from clinical trials. A relatively small clinical trial suggested that the NR2B selective drug, CP-101,606, led to robust, sustained antidepressant effects in SSRI non-responders. Two small proof-of-concept studies with AZD6765 (lanicemine), a non-selective, low trapping NMDAR blocking drug suggest a single infusion can have rapid but short-lived antidepressant effects above the relatively strong effect of a placebo (saline) infusion, in the absence of appreciable psychotomimetic effects. A third, larger phase IIb study examining the adjunctive use of repeated lanicemine infusions (3 infusions/week for 3 weeks), provided strong evidence of the drug's antidepressant efficacy and showed that the response could be maintained for a period of weeks. A recently completed follow up study exploring the longer-term efficacy of lanicemine was unable to replicate the findings of clinical efficacy. However, this study met with the field's age-old problem; placebo administration produced a 39% response rate at the primary endpoint of 6-weeks. The issue of high placebo response rates has become an increasingly problematic obstacle in the meaningful evaluation of clinical trials in major depressive disorder. It would not be surprising if this same issue complicates the evaluation of these novel rapid acting antidepressant medications, especially if the randomization blind can be adequately maintained. Overall, the combined data from preclinical and clinical studies using a variety of different NMDAR modulating drugs provide generally consistent evidence that antidepressant effects are associated with NMDAR antagonism, and that this is probably the primary mechanism through which ketamine is generating its antidepressant effects. The fact that memantine, an NMDAR antagonist that shares many pharmacodynamic features with ketamine, has not been consistently shown to have antidepressant effectshas been used to argue against the role of the NMDAR in mediating the antidepressant effects of ketamine. However, it is important to note that there are several differences in the way these molecules functionally interact with the receptor. For example, memantine does not inhibit the phosphorylation of eukaryotic elongation factor 2 (eEF2), nor does it augment subsequent expression of brain derived neurotrophic factor (BDNF), which appear to be critical determinants of ketamine-mediated antidepressant efficacy(see below). These differential effects could be related to relative differences in the drugs' abilities to change glutamate binding at rest, differing trapping properties of the drugs, or to uniquely different effects on synaptic and extrasynaptic receptors.
development "There's no limit to how complicated things can get, on account of one thing always leading to another."
The simple fact that ketamine's antidepressant effects grow in magnitude after the drug has cleared from the body indicates that more durable downstream effects, beyond immediate blocking of the NMDAR, are critical in generating and sustaining the response. A rapidly expanding series of studies suggest that ketamine-induced enhancement of spine-remodeling and synaptoplasticity are critical in generating the sustained antidepressant effects (see figurefor model overview). These effects appear dependent on a transient increase in glutamate transmission through the post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), as the co-administration of AMPAR antagonists can block the antidepressant effect of ketamine and other NMDAR antagonists in animal models. Studies showing the dose dependence of ketamine's activation of the mammalian target of rapamycin Complex1 (mTORC1) signaling pathway, synaptic protein synthesis and antidepressant-like behaviors, parallel ketamine's dose dependent effects on glutamate efflux as determined by microdialysisand 13 C-MRSsuggest the transient increase in glutamate release may be a key proximal event in the cascade. Other studies showing mGluR 2/3 antagonists, that also lead to an increased release of presynaptic glutamate, produce ketamine-like biochemical and behavioral effects which are blocked by AMPA receptor blockade, provide additional support to this model. Additionally, it has also been proposed that ketamine is capable of increasing AMPA neurotransmission through suppression of spontaneous NMDAR-mediated neurotransmission that elicits a rapid eEF2-and BDNF-dependent potentiation mediated through increased surface expression of AMPA receptors. Other studies demonstrate the requirement of BDNF/TrkB-activation showing that synaptogenic and behavioral actions of ketamine are blocked in mice with a knock-in of the BDNF Val-66-Met allele, and in conditional BDNF mutant mice. Interestingly, a preliminary study found a lower rate of response to a ketamine treatment in met allele carriers. The strong evidence of ketamine's rapid onset antidepressant effects and emerging early evidence that other drugs targeting the glutamatergic system have antidepressant properties, considered in the light of pathophysiological changes within the glutamatergic system that are associated with stress and psychopathology, makes the glutamatergic system a highly attractive target for antidepressant drug development. However, the glutamatergic system is highly complex and there are still many unanswered questions surrounding the optimal means of modulating the system in order to provide safe, effective treatments for individuals suffering from mood and other neuropsychiatric disorders. Future studies will be required to determine if pharmacological factors such as trapping, half-life or selective action on subsets of NMDARs, moderate a drug's efficacy in the treatment of mood disorders.
That intravenous ketamine administration often causes an acutebut generally transientimprovement in mood in refractory depressed patients) has generated considerable excitement on the parts of clinicians and researchers as well as industry who all hunger for rapidly effective new antidepressants. The putative MoA of antagonism of post-synaptic glutamatergic NMDA receptors, has led companies to attempt to develop other agents with similar MOA's in the hopes that the shortlived effects can be overcome and the side effects related to acute parenteral administration of ketamine can be avoided. To date, many of these strategies have not been effective--leaving some of us to argue that other MoA's may be in play and that some of these pose major problems for the field. This perspective reviews evidence in support of the argument that ketamine's antidepressant properties reflect something other than NMDA antagonism, and discusses the possible consequences of misdirected development efforts.
Ketamine clearly antagonizes the NMDA receptor. That NMDA antagonism may be the key MoA underlying rapid antidepressant effects has led not only to much work on other NMDA antagonists but also on exploring other glutamatergic agentse.g., agonists or antagonists at linked glycine transporter sites on the NMDA receptor, agents that decrease synaptic glutamate concentrations, modulators of other glutamate receptors, etc. Animal data indicate that although ketamine is effective in animal models of antidepressant response, so too are agents that act essentially as agonists at the NMDA receptor. Contradictory data could be viewed as indicating the complex nature of glutamatergic function but also that NMDA antagonism may not be ketamine's key MoA. To date, other NMDA antagonist strategies have not proven effective in mansome of which preceded recent ketamine excitement. For example, memantine is an NMDA antagonist that has not been shown to be effective in several depression studies. However, differences in half-lives and on phosphorylation of eukaryotic elongation factor 2 and BDNF expression have been thought to paly a role here. Astra Zeneca's agent lanicemine (AZD6765) that traps synaptic glutamate was minimally effective in a single dose pilot study. However, thrice-weekly dosing over 3 weeks of lanicemine at 100mg per dose produced significant separation from placebo at weeks 2 and 3; 150mg separated at week 3. More recently, in a larger scale, multi-center trial lanicemine at both 50mg and 100mg failed to separate from placebo. Another agent GLYX13 is a partial agonist for the glycine site such that it likely acts an NMDA agonist. Intermediate doses have positive effects on mood without causing dissociationand a recent press release on a Phase II-B trial reported it produces longer-term responses with repeated administration (Naurex Press Release -May 6, 2014). However, as of this writing, detailed data have not been presented that it is significantly more effective than placebo. A Taiwanese group recently reported that another glycine transporter inhibitor that acts essentially as an NMDA agonist was effective in animal models of antidepressant effects, and notably more effective than citalopram in depression. This is also supported by an Israeli study that augmenting antidepressant efficacy was possible via high doses of D-cycloserine, an NMDA agonist with potential antagonist properties as well. Taken together, the data suggest that agonism at the NMDA receptor may be as, if not more, important than antagonism and that dissociation is not needed for a glutamate mediated antidepressant effect. Added to this web of glutamatergic confusion is the specter that we have been historically unsuccessful in our development of glutamatergic agents for major depression and schizophrenia. One notable strategy has been to focus on metabotropic glutamatergic (m-GLU) 2 or 3 receptors, and these have not been successful in either depression or schizophrenia. For example, an mGluR2 allosteric modulator recently failed to separate from placebo in anxious depression (Addex Press Release -February 7, 2014) and others have not done well in Phase III trials in schizophrenia after showing initial promise. Thus, neither glutamate nor the NMDA receptor may be the key to further drug development. Of course, our field's recent poor track record of antidepressant development makes interpretation of the studies difficult. One possible exception has to do with another postsynaptic glutamate receptor -AMPAthat can be activated by a putative marked increase in glutamate efflux secondary to ketamine. Since AMPA antagonists can block ketamine's pharmacological antidepressant properties in preclinical models including affecting mTOR) (see below), AMPA agonism could be a route for glutamatergic antidepressant development. Agonists are, however, historically difficult to develop for psychiatry because of potential tachyphylaxis; and, receptor potentiators are often partial agonists. The use of an antagonist for one receptor having an effect on another that are heterodimers or are co-localized has been hypothesized to occur for glucocorticoid antagonists' affecting mineralocorticoid receptor activity. To my knowledge, there are not data indicating antidepressant efficacy for AMPA agonists in man.
Investigators have developed other hypotheses for ketamine's effects including second messenger effects on m-TOR) that are shared with parenteral scopolamine, as well as release of brain derived neurotropin factor). An intriguing putative MoA is ketamine's ability to stimulate sigma receptors, which appears to account for the drug's dissociation effects and may prove an important clue to how ketamine may be acting. Perhaps related, ketamine is a powerful mobilizer of midbrain catecholamines, particularly dopamine, and these properties could account for both the psychotomimetic and antidepressant properties. However, a recent rat study indicated that although self-administration of d-amphetamine reinforces sigma 1 receptor agonist use that can be blocked by dopamine antagonists, similar effects on sigma agonist use are not observed for ketamine. These data suggest that ketamine's antidepressant effects are independent of dopaminergic/sigma 1 interactions. Others have noted that ketamine may both induce neuronal growth and be effective in a forced swim test rat model, with the former not blocked by sigma receptor antagonists, although, the latter is --suggesting the sigma receptor may play a role in some of ketamine's antidepressant effects. These studies do not address the putative role of sigma receptors in the dissociative properties of ketamine. Ketamine also potentiates release of prefrontal serotonin (and perhaps other monoamines) through central nicotinic acetylcholine receptors. The mTOR and stimulant-like properties may provide rationales for developing other antidepressants with similar pharmacologic effects and these could be pursued. However, stimulant-like properties may generate other worries for potential abuse (see below). Sigma receptor agents were targets of development more than a decade ago with some notable failures as well.
There are a number of troubling findings regarding ketamine's pharmacology that should give us pause. For one, the drug does produce dissociation and psychosis and is subject to abuse. These suggest that potentially other systems may be affected. For one, ketamine does bind to mu, lambda and kappa opioid receptors. Preclinical studies indicate ketamine increases muopioid receptor densities in hippocampal tissueand enhances mu opioid induced ERK1/2 phosphorylation in cell lines, as well as, speeds wait time for re-sensitizing ERK1/2 signaling. Moreover, in anti-nocioception studies of ketamine in mice, analgesic effects were blocked by mu and lambda, but not by kappa, antagonists. However, an earlier study did report that ketamine produced kappamediated disruption of cognition in rodents, suggestive of its dissociative properties in man. NMDA plays a role in opioid induced analgesiaand there are studies that point to ketamine's pain properties involving both opioid and NMDA receptors. Taken together data do indicate ketamine has agonistic effects on mu opioid receptors that do suggest a potential risk of abuse. However, rodent studies on reinforcing properties have been mixed. Intracranial self-stimulation appears not to be increased by the drug; although, as others have pointed out, this does not eliminate risk of abusesince choice preference-based use can be increased with ketamine. (Ketamine has R and S enantiomers that also appear to differ in reinforcing effects.) Still recent data that the drug does seem to produce behavioral effects through binding to mu receptors provides a rather different framework for assessing its positive and negative pharmacological properties. Indeed, studies combining ketamine with the mu-antagonist naloxone in rodents and man, could be informative. Perhaps related to mu opioid effects are the observations that a positive family history of alcohol abuse is a predictor of ketamine antidepressant response.
One may wonder if and why knowing its MoA's are really important. If the drug is effective, why not just use it? For one, we have virtually no follow on treatments that are effective, and we need to understand the MoA if we are to develop both follow on approaches, particularly orally administered agents. Otherwise, we may be left with repeated administration of an agent that could lead to dependence. The possible negative consequences are profound for patients, the public and our profession. In fact if we step back for a moment and look at where we arean intravenously administered agent that is a street drug of abuse, works rapidly and whose enantiomers are being studied by industry for intranasal use-we should be anxious. It may be that patients do not feel the exhilarated high of cocaine but they do experience dissociative often as part of a key predecessor to the transient mood elevating effects. Thus, we need to be as careful and conservative as possible and understand how it is acting and rule out whether it acts as an opioid. Indeed, as I recently pointed out elsewherethe report of Rodriguez et al.of intravenous ketamine being effective in obsessive compulsive patients parallels Koran et al's observations that oral morphine was also effective in patients with the disorder. A related reason we need to understand the MoA better is that biotech and pharmaceutical companies base development strategies on putative MoA's and an emphasis on NMDA may lead to over emphasis on glutamate and NMDA antagonism at the expense of other mechanisms. The competition for dollars invested will mean the loss of other opportunities. If the MoA involves opioid receptor agonism, we as a field can openly discuss and perhaps debate the wisdom of pursuing this approach. Indeed, one company -Alkermeshas announced positive Phase II results of a combination of an agonist and antagonist to provide antidepressant relief and to minimize tolerance and abuse (Alkermes Press release-April 2013). Employing mu agonists as antidepressantswhether they are ketamine or otherswill require an open dialogue about the risk/benefit of such approaches.
Ultimately the primary goal for the field is to provide safe, effective treatment options to people suffering with mood disorders. In line with this goal, how can we build on the findings showing ketamine to produce a rapid transient antidepressant effect? The first step is to clearly establish the true clinical efficacy, effectiveness, and safety of ketamine through additional well controlled and monitored clinical trials. Showing clinically meaningful short-term improvement (such as decreased risks of suicidal behavior, decreased hospital admission rates or lengths of stay) and/or sustainable response lasting more than a few weeks is essential in proving true clinical utility. Based on reports of ketamine's rapid effects on suicidal ideation, several controlled studies are currently underway examining the short-term clinical benefits of ketamine in crisis settings such as in the emergency department with suicidal patients. The results from these studies will begin to provide us with information related to the actual clinical utility of ketamine as a crisis intervention. Although several case series have suggested long-term effects of repeated administration, the first placebo controlled data demonstrating sustained effects with repeated dosing was only recently presented. However, the functional unblinding associated with ketamine at this dose continues to cloud the interpretation of the studies, especially considering the dissociative properties of ketamine have been shown to be a significant predictor of response. In the comparison trial of ketamine vs midazolam, dissociation was twice as likely to occur in ketamine treated patients than in those treated with the benzodiazepine (60% vs 30%). To fully control for the placebo response an improved "active placebo" with greater dissociative effects would be optimal. Alternatively, a soon to start multicenter NIMH-sponsored trial exploring the dose response relationship for ketamine may allow for better comparison with midazolam as a control. One strategy might be to find a higher dose of midazolam that could produce higher rates of, and perhaps more intense, dissociative symptoms that could provide a better control for this side reaction, and preserve the blind. Another alternative might be to use an agent that has dissociative properties as a control, although, some of these may be other drugs of abuse. (As discussed below, given the possible opioid properties of ketamine, a comparison trial with an opioid such as parenteral morphine would be of interest as well.) The second step is to optimize the safety of the treatment approach, either improving the delivery of ketamine itself, or through the development of novel medications that share ketamine's critical mechanisms of antidepressant action but have improved safety profiles. Several factors currently limit the broader use of ketamine in the treatment of mood disorders. Although serious adverse events are relatively rare, acute risks of ketamine treatment include cardiovascular effects such as elevated blood pressure and heart rate, and psychological emergence events. Single administration of sub-anesthetic doses of ketamine, such as those primarily used in the existing proof of concept studies appear to have a very low risk of serious adverse events, but rare transient episodes of hypotension and bradycardia have been observed in depressed patients. Of potentially greater concern are the relatively unknown risks of repeated administration. Studies examining ketamine abusers and rodent models suggest repeated ketamine exposure can have deleterious effects on brain structure and function under certain conditions (age of exposure, dose and duration). However, the limited studies involving repeated dosing of mood disorder patients, report the treatment has been generally well-tolerated, and there have been no reports raising the level of concern related to cognitive difficulties for mood disordered patients (aan het. The known risk of urinary cystitis associated repeated ketamine administration appears to be associated with very high levels of use for prolonged periods, but it remains another concern that needs to be considered with longer-term treatment strategies. Moreover, ketamine is known to be a drug of abuse, raising the additional concerns that repeated administration of the drug could have a liability for drug abuse. These potential complications, while not necessarily ruling out future development of ketamine for broader clinical use, are clearly going to require closer long-term follow up in controlled studies if the drug is going to be used with any regularity in the clinics. It remains to be seen whether the use of the selective S-enantiomer of ketamine, which appears to have similar antidepressant effectsalso carries the same level of risk. Identifying factors that could improve the risk benefit ratio is one way to mitigate the risks of ketamine exposure. Findings that family history of alcoholism is a significant predictor of ketamine responsesuggest one potential group with an enhanced likelihood of benefit but may also suggest the drug's pharmacologic actions may be closer to those of abuse than one might want. There are a number of studies that could be undertaken to assess risk. For one, abuse liability studies could be conducted in depressed patients, casual drug users, and healthy controls. These studies would involve blinded comparisons of ketamine and other agents of abuse with the rating of subjective experiences, including blinded self-assessment of acute and longer subjective effects and placing monetary values on different compounds. Enhanced risk of psychosis could be studied by perhaps applying a biological test such as sensory gating as a predictor of psychotic response, and combining it with assessments of personal and family history. This might yield a useable test battery for the field. Lastly, pharmacogenetic markers, such as the val66met BDNF SNP mentioned above, could be especially useful if the effects can be replicated and shown to be meaningfully predictive.
Understanding the MoA is important to provide clues for the development of alternative glutamatergic agents that might produce similar benefits with greater convenience (e.g., route of administration), better longer term efficacy, fewer and less severe side effects, and/or reduced longer-term risk. As outlined above, there is some disagreement on what mechanisms are most likely underlying ketamine's antidepressant effects. Dr. Sanacora maintains the hypothesis that ketamine's effects on glutamatergic neurotransmission are critical in initiating a cascade of events that ultimately facilitate an antidepressant response, while Dr. Schatzberg suggests other, non-glutamateric systems, may be playing the critical roles in the drug's mechanism of action. These distinct positions on the mechanism of action arise largely from differences in the interpretation of the existing data. Do the preclinical studies demonstrate glutamatergic modulation is necessary for ketamine to have effects on mood? Do the existing clinical studies show other NMDAR antagonists to have efficacy? Could alternative MoA's account for ketamine's mood effects? However, we both agree that it is best to keep an open mind when evaluating the underlying mechanisms of action related to ketamine's unique antidepressant effects. In addition to ketamine's effects on the glutamatergic system, there is increasing evidence that ketamine has effects on the opioid system, inflammation, and yes even the monoaminergic systemsthat could be critical in generating the antidepressant response. Until more definitive studies are completed at both the clinical and preclinical levels, it is wise to consider all options. In order to examine the antidepressant mechanism of action it will be important to develop and validate clear measures of target engagement. Since there are no readily available ligands for the NMDAR to allow PET imaging studies, alternative measures are needed. A recent paper suggests it may be possible to indirectly monitor ketamine's effects with the use of a PET ligand, [ 11oxime, that has high affinity for the mGluR5 receptor which is sensitive to changes in endogenous glutamate. Preclinical and small clinical studies suggest other imaging methods such as 13 C-MRS measures of glutamate cycling, or fMRI studies of brain network connectivity could be used to evaluate target engagement, and perhaps may even be more closely related to the critical down stream mechanisms generating the antidepressant response. Other recent studies also suggest that EEG measures could be used to detect NMDAR target engagement, a tool that may actually be useful in determining clinical dosing. To explore the effects of ketamine on the opioid system, one could use PET to explore mu opioid binding pre-and post-ketamine in either patients or controls. Mu antagonists such as naloxone could be used to attempt to block the antidepressant effects in animal models as well as in patients. Similarly, kappa and lambda antagonists could also be applied. In sum, we remain in disagreement over what we have learned from our experience with ketamine and another NMDAR drugs to date for the treatment of mood disorders. We agree there is clear evidence that ketamine can produce rapid transient antidepressant-like effects, but remain divergent in our opinions on the mechanisms mediating these effects and the potential to act on what we know to initiate novel treatment approaches or suggest novel pathways for drug development. We agree that it is premature to conclude that any single mechanism is solely responsible for the antidepressant response, and that the response is potentially mediated through complex pathways downstream from ketamine's direct actions at any receptor. We strongly agree that preclinical studies should explore potential alternative MoA's and that more clinical studies are needed to clearly establish the true clinical effectiveness and safety of the treatment before it is made widely available in the clinical setting. Proposed mechanism of ketamine's antidepressant action, whereby ketamine, through a blockade of tonic GABAergic inhibition, causes a surge in glutamate release and cycling. The resulting increased glutamatergic transmission through AMPA receptors (whose surface expression may be independently up regulated by suppression of spontaneous NMDARmediated neurotransmission)leads to increased BDNF-dependent [4] levels of synaptogenesisthat ultimately contribute to the rapid and sustained antidepressant effects.
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