I’ve been following the research on treating depression with ketamine and its analogue, esketamine, for over three and a half years. Since I wrote “Falling Down the K-Hole,” that research has progressed—as has the hype and unbridled enthusiasm for ketamine and esketamine as fast-acting antidepressant treatments. It seems there was also a recent media blitz extolling esketamine as “a promising new depression treatment.” Not-so-coincidentally, Janssen researchers (and others) recently published the latest results of their ongoing research with esketamine in The American Journal of Psychiatry.

The American Journal of Psychiatry study by Canuso et al. reported the results of a completed Janssen clinical trial (ClinicalTrials.gov Identifier: NCT02133001). It follows another Janssen study by Daly et al. published in JAMA Psychiatry on the efficacy and safety of intranasal esketamine. The Daly et al. study reported the results of another completed Janssen clinical trial (ClinicalTrials.gov Identifier: NCT01998958).

The Daly et al. study was published in February of 2018, while the Canuso et al. study was published on April 16, 2018. The Fix published an article on the “new study” (Canuso et al.) on April 20^th, as did The Washington Post, where it was said to be a potential “major advance in the treatment of suicidal depression.” WebMD discussed the study in an article published on April 17^th, and Medical News Today published its “announcement” on April 18^th.  Additional articles include ones by Business Insider, Newsweek and BBC News—all on April 16^th—to name just a few news organizations.

Janssen Pharmaceutical Companies of Johnson & Johnson is ahead in the “race” to bring its esketamine nasal spray to market as the first of a new class of psychiatric medications known as “glutamate receptor modulators,” which are also being investigated as treatments for bipolar disorder and schizophrenia. The FDA awarded esketamine “breakthrough” status in 2016, meaning it is fast-tracking the drug through the approval process. The above two linked articles report the results of Phase 2 clinical trials, while a Phase 3 trial in underway (ClinicalTrials.gov Identifier: NCT02782104).

On May 5, 2018 Janssen and J&J announced the completion of two Phase 3 Clinical Trial studies. FierceBiotech noted J&J’s intention to present the results from the studies at the American Psychiatric Association’s annual meeting the weekend of May 5^th-6^th. The study of adults with treatment resistant depression met its primary endpoint, demonstrating a statistically significant improvement in patients’ depressive symptoms. Three secondary endpoints were not met. The study of elderly patients with treatment resistant depression “narrowly missed” its primary endpoint. FierceBiotech reported J&J said the elderly patient group often has lower response rates to antidepressants, which could explain the result.

A review of the two studies by Health News Review suggested Janssen had highlighted insignificant findings alongside modest results with its esketamine nasal spray. They noted where the press release gave a good deal of information about trial protocols and specific differences in the depression scale that was used, but didn’t address cost. “While there may be promising results to report, the findings are reported in a way that makes it difficult to understand the advances — or even to tell the advances from the things that were inconclusive.”

This release is, frankly, confusing. Hundreds of words are spent describing a trial for which there were no statistically significant findings, with the pharmaceutical manufacturer arguing that the findings should be considered anyway. The release also refers repeatedly to the “newly initiated oral antidepressant” used in both the control and placebo groups for both studies, without any information about which antidepressants were used. The release does refer to two pages on ClinicalTrials.gov, which contain relevant information on the first trial and on a second trial focused on older adults. But honestly, that’s not good enough. And the failure to address cost, even in general terms, is deeply problematic. What’s more, the primary efficacy endpoint (i.e., how they could tell whether the drug worked) is described in technical terms that are difficult to parse for many readers.

Nevertheless, as FierceBiotech noted: “J&J remains confident it is on course to file the nasal spray formulation for approval in treatment-resistant depression in the second half of the year.”

The Daly et al. study in JAMA Psychiatry reported that intranasal esketamine appeared to have a rapid antidepressant effect for more than 2 months with continued, but reduced frequency dosing. The Canuso et al. study in The American Journal of Psychiatry supported the conclusion of a rapid improvement in depressive symptoms, adding there was also evidence of improvement with some measures of suicidal ideation among patients at imminent risk for suicide.

However I’m concerned the media hype on the benefits of esketamine may sometimes be running ahead of the results. You have to carefully read the above articles in order to get through the praise for the “fast-acting benefits” of esketamine nasal spray before getting to get to the limitations of the research and the concerns with using ketamine and esketamine to treat depression. One of the first limitations to realize with both Daly et al. and Canuso et al. is that all participants in those studies were still taking their prescribed antidepressants in addition to intranasal esketamine. And as with previous ketamine studies, the beneficial effects of esketamine were temporary.

There were significant improvements noted in depressive symptoms at four and twenty-four hours, but at the 3-day mark, the initial dramatic improvement had flattened out, according to The Washington Post. “And by the end of the trial, at four weeks, there was no difference between the esketamine group and the control group.”  Medical News Today added that there was a significant improvement in measures of suicidal thoughts after 4 hours, “but not after 24 hours” or the end point of the study at 25 days.

BBC News reported where the Royal College of Psychiatrists said the Canuso et al. study was significant, bringing esketamine “a step closer to being prescribed in the NHS.” It also pointed out how the effects had leveled out by 25 days. WebMD said psychiatrists “were cautiously optimistic” about the potential for ketamine in treating depression. Again the limited effects were noted. They added the potential for ketamine (and esketamine) to be misused. The most common side effects among participants taking esketamine included nausea, dizziness, dissociation (a sense of detachment from reality), headache and an unpleasant taste.

There was a rare editorial signed by the majority of the board of the American Journal of Psychiatry, the journal that published the Canuso et al study. They noted how the effects of intranasal esketamine were similar to those found with intravenous ketamine. If positive, longer-duration results emerged for intranasal esketamine, “it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies.” After reviewing the history of what “led to a national epidemic of opioid-caused deaths,” they noted how preventing abuse was seldom raised as a concern in the rise of prescription opioid use.

Ketamine drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. Some patients use the intravenous formulation intranasally repeatedly without supervision. Diversion of ketamine intended for pediatric and veterinary anesthesia, its current approved use, is occurring already.Canuso et al. observed an attenuation of ketamine-specific clinical response over time; the failure to demonstrate longer-term benefits raises questions about the risk versus the benefit of long-term use.

The authors of the editorial referred to “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders,” published online on March 1, 2017 by the American Psychiatric Association. The Consensus Statement only has intravenous ketamine in mind, but many of the expressed concerns also apply to intranasal esketamine.  The report said its main intent was to highlight the current state of the field and the critical issues to be considered when contemplating the use of ketamine for treatment-resistant depression. The following excerpts are from the APA Consensus Statement:

Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow-up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicion of ketamine abuse is present. Moreover, the number and frequency of treatments should be limited to the minimum necessary to achieve clinical response. Considering the evidence suggesting that the mechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice of frequent ketamine administration. At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected. Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected. The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain in our knowledge about the longer-term efficacy and safety of ketamine infusions. Future research is needed to address these unanswered questions and concerns.

Clearly, the American Psychiatric Association is concerned with longer-term efficacy and safety concerns with ketamine, particularly its potential for misuse and abuse. But that isn’t the end of concerns for ketamine and esketamine.

Janssen said esketamine belonged to a new class of drugs in psychiatry known as “glutamate receptor modulators.” They speculated that esketamine could “help restore synaptic connections in brain cells in people with major depressive disorder.” Yet two Cochrane studies questioned the efficacy of ketamine and other glutamate receptor modulators for depression and bipolar depression. Cochrane is a global independent network of researchers, professionals, and others who “work together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest.” Their work is recognized as an international gold standard for high quality, trusted information.

“Ketamine and other glutamate receptor modulators for depression in adults,” by Caddy et al., sought to find out if ketamine and other glutamate receptor modulators were more effective than placebo or other antidepressants and whether they were more acceptable than placebo and other antidepressants. Only ketamine was more effective than placebo at reducing symptoms of depression. However, “These effects lasted no more than one week after treatment and clearly disappeared after two weeks.” Ketamine also caused more confusion and emotional blunting than placebo. “There was no evidence of a difference between the other nine glutamate receptor modulators included in this review and placebo or other medications.” The review concluded there was limited evidence that ketamine reduced symptoms of depression when compared to placebo.

“Ketamine and other glutamate receptor modulators for bipolar depression” sought to answer the same questions, namely if ketamine and other glutamate receptor modulators were more effective than placebo or other antidepressants and whether they were more acceptable. It was possible that ketamine could be an effective add-on medication to mood stabilizers for people with acute bipolar depression, “but due to the small amount of data usable for analysis we are unable to draw any firm or reliable conclusions.

Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did not show any better efficacy in terms of remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. Ketamine’s psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.

A very small pilot study done by the Black Dog Institute in Sydney Australia was published March 15, 2018 in the Journal of Psychopharmacology. The study sought to investigate how repeated use of intranasal ketamine might work for patients with severe and treatment-resistant depression. All participants were trained to self-administer the ketamine nasal spray; the process was similar to other commonly used nasal spray medications. But the study participants could not get through the needed ten sprays to get the full dose.

As soon as the ketamine hit their bloodstreams, the subjects started losing motor coordination, which got so bad that none of them managed to do all the sprays without the help of research staff monitoring the treatment. When the researchers tried to space out the nasal sprays with a five-minute interval, things only got worse – the subjects’ blood pressure shot up, and they started experiencing psychotic-like effects as well.

The study had to be cut short because of the adverse side effects. The researchers pointed to an earlier ketamine nasal spray trial where the drug was well tolerated. They speculated the 2014 trial had better tolerance because of a lower dose (50mg instead of 100mg) and their study’s participants being trained to use the nasal spray, resulting in their subjects ending up with higher levels of the drug in their blood streams. “Our results suggest that absorption via the intranasal mucosa may be too rapid when careful attention is paid to the administration technique, resulting in the development of rapid and intense side effects.”

So despite the hype and unbridled enthusiasm for the potential of ketamine and its analogue esketamine as fast-acting antidepressant treatments, the existing evidence is not conclusive. And the safety and efficacy concerns, particularly with regard to long-term use and addiction, are not known. Existing evidence with intravenous ketamine suggests the real potential for abuse. And it doesn’t look like it will be a good idea for subjects to self-administer intranasal ketamine or esketamine in the privacy of their homes.