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.

Abstract

“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.”

Authors: Gerard Sanacora & Alan F. Schatzberg

Summary

Large “real world” studies demonstrating the limited effectiveness of existing antidepressant medications have highlighted the need for the development of new therapeutic strategies for major depression and other mood disorders. Ketamine may provide a unique, rapid onset of sustained, but still temporally limited antidepressant effects.

Ketamine’s rapid antidepressant effects have reinvigorated the field and revolutionized our thinking about antidepressant medications in several respects. 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”.

Ketamine’s effects are mediated through actions on the glutamatergic N-methyl-D-aspartate receptor (NMDAR). Ketamine acts as an open channel, non-competitive antagonist, binding within the ion channel and blocking ion influx. Over two decades ago, Skolnick and collaborators speculated that a dampening of NMDAR function could be a common mechanism underlying antidepressant efficacy. 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.

Clinical trials have shown that NR2B selective drugs, CP-101,606, and AZD6765, can treat depression in SSRI non-responders.

A phase IIb study of lanicemine showed that the drug had an antidepressant effect and that the response could be maintained for a period of weeks. However, a follow up study was unable to replicate the findings of clinical efficacy. The data from preclinical and clinical studies using a variety of different NMDAR modulating drugs suggest that NMDAR antagonism is the primary mechanism through which ketamine generates its antidepressant effects. However, there are several differences in the way these molecules functionally interact with the receptor.

Studies suggest that ketamine’s antidepressant effects are generated by more durable downstream effects, beyond immediate blocking of the NMDAR. These effects include enhancement of spine-remodeling and synaptoplasticity, which are dependent on a transient increase in glutamate transmission through the post-synaptic AMPAR.

Ketamine is a potent neurotransmitter that has been shown to have rapid onset antidepressant effects. 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.

NMDA ANTAGONISM MAY NOT BE THE KEY MECHANISM OF ACTION FOR KETAMINE’S

Ketamine has been shown to cause an acute but transient improvement in mood in refractory depressed patients, and this has led to several companies trying to develop similar drugs without success. Ketamine antagonizes the NMDA receptor and may be the key moa underlying rapid antidepressant effects. However, other NMDA antagonists have not proven effective in man, and lanicemine (AZD6765), an NMDA receptor trapping agent, was minimally effective in a single dose pilot study.

Lanicemine at 100mg per dose separated from placebo at weeks 2 and 3, but at 50mg it failed to separate. A partial agonist for the glycine site of the NMDA receptor, GLYX13, has positive effects on mood without causing dissociation, and a Phase II-B trial reported that it produces longer-term responses with repeated administration. However, detailed data have not been presented that it is significantly more effective than placebo. The development of glutamatergic agents for major depression and schizophrenia has historically been unsuccessful. However, the recent poor track record of antidepressant development makes interpretation of the studies difficult.

One possible exception is AMPA, a postsynaptic glutamate receptor that can be activated by a putative marked increase in glutamate efflux secondary to ketamine. AMPA antagonists can block ketamine’s pharmacological antidepressant properties in preclinical models including affecting mTOR. Ketamine may act by stimulating sigma receptors, releasing brain derived neurotropin factor, and mobilizing midbrain catecholamines. However, self-administration of d-amphetamine reinforces sigma 1 receptor agonist use, whereas ketamine’s antidepressant effects are independent of dopaminergic/sigma 1 interactions.

Ketamine is a dissociative drug that potentiates release of prefrontal serotonin through central nicotinic acetylcholine receptors. Its stimulant-like properties may generate worries for potential abuse. Ketamine’s pharmacology is troubling because it produces dissociation and psychosis, is subject to abuse, and does bind to mu, lambda and kappa opioid receptors. However, rodent studies indicate that ketamine does not affect kappa receptors, and does affect mu opioid receptors.

12 studies on reinforcing properties of ketamine have been mixed. It does seem to produce behavioral effects through binding to mu receptors, and a positive family history of alcohol abuse is a predictor of ketamine antidepressant response. Ketamine is an effective treatment for obsessive compulsive patients, but we need to understand its mechanisms of action (MoA) if we are to develop effective follow on treatments, particularly orally administered agents. Otherwise, we may be left with repeated administration of an agent that could lead to dependence.

The MoA of NMDA receptors is important to understand because biotech and pharmaceutical companies base development strategies on putative MoA’s. If the MoA involves opioid receptor agonism, we can openly discuss and perhaps debate the wisdom of pursuing this approach. The primary goal of the field is to provide safe, effective treatment options for people suffering with mood disorders. In line with this goal, several controlled studies are currently underway examining the short-term clinical benefits of ketamine in crisis settings.

The first placebo controlled data demonstrating sustained effects with repeated dosing of ketamine was only recently presented (Singh, 2014). 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. The second step in optimizing the use of ketamine for the treatment of mood disorders is to improve its safety.

Although serious adverse events are relatively rare, single administration of sub-anesthetic doses of ketamine appear to have a very low risk of serious adverse events.

Depressed patients have been observed to have hypotension and bradycardia, but repeated administration of ketamine to mood disorder patients has been generally well-tolerated. There have been no reports raising the level of concern related to cognitive difficulties for mood disordered patients. Ketamine is a drug of abuse and may have long-term side effects. It is not clear whether the selective S-enantiomer of ketamine 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. Studies could be conducted to assess risk, such as abuse liability studies. Enhanced risk of psychosis could be studied by applying a biological test, combining it with assessments of personal and family history, and studying pharmacogenetic markers.

The mechanism of action for ketamine is not well understood. There is disagreement on whether ketamine’s effects on glutamatergic neurotransmission are the most likely mechanism of action, or whether other, non-glutamatergic systems, may be playing the critical roles. Ketamine has effects on the glutamatergic system, opioid system, inflammation, and monoaminergic system that could be critical in generating the antidepressant response.

Consider all options to examine the antidepressant mechanism of action. PET, 13C-MRS, fMRI, and EEG could be used to evaluate target engagement, and mu antagonists could be used to block the antidepressant effects in animal models as well as in patients.

We remain in disagreement over the mechanisms mediating the effects of ketamine on mood disorders, and the potential for acting on what we know to initiate novel treatment approaches.

Dr. Sanacora has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Hoffman La-Roche, Merck, Naurex, Noven Pharmaceuticals, and Takeda, and has received free medication for an NIH sponsored study by Sanofi-Aventis. Dr. Schatzberg has received speaking fees from Merck.