Are we repeating mistakes of the past? A review of the evidence for esketamine

May combine two claims.

In the discontinuation trial, withdrawal checklist scores by group are not reported, and it is unclear how checklist items were distinguished from almost identical MADRS items.

“Although the study reports suggests that there was no evidence of a withdrawal syndrome using the Physician Withdrawal Checklist, scores for the different groups are not reported, and it is not clear how items in the checklist such as 'insomnia', 'anxiety-nervousness', 'dysphoric mooddepression', 'difficulty concentrating, remembering', 'fatigue', 'lack of appetite' were distinguished from almost”

• cites [21]Not checked yet

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One patient on esketamine experienced a non-fatal cerebral haemorrhage, a recognized risk in ketamine use due to blood pressure spikes.

“In addition to the deaths, one patient on esketamine experienced a non-fatal cerebral haemorrhage, 19 also recognised as a risk in ketamine use due to its blood pressure spikes, 3”

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• cites [3] sourceNot checked yet

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• AssumptionRests on an assumption: Esketamine's adverse effects are similar enough to ketamine's for evidence about ketamine harms to apply to esketamine.

May combine two claims.

Half (48.7%) of relapses in the discontinuation trial occurred in the first four weeks after esketamine cessation, the time most likely for withdrawal effects.

“As half (48.7%) of relapses occurred in the first four weeks following esketamine cessation, the time most likely for withdrawal effects to occur”

• cites [21]Not checked yet

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The FDA highlighted unblinding as a problem in the discontinuation trial, as in the acute efficacy studies.

“The FDA also highlighted another problem with this study design:”

• cites [21]Not checked yet

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At the Polish site, the placebo relapse rate was 100% (n=16), compared with 33% at all other sites (n=81).

“At this site there was a 100% relapse rate in the placebo arm (n=16 patients), compared with a 33% relapse rate in this arm in all other sites (n=81).21”

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In the positive trial, placebo reduced MADRS scores by 15.8 points and esketamine by 19.8 points.

“The response to placebo treatment (a nasal spray with embittering agent) was a 15.8-point reduction on the MADRS score.The response to esketamine was 19.8 points.21”

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Excluding the outlier Polish site, there is no difference between esketamine and placebo, with the p value changing from 0.012 to 0.48, so the findings are not robust.

“It has been demonstrated that if this outlier site is excluded there is no difference between esketamine and placebo (the p value changes from 0.012 to 0.48), 18 leading to the conclusion that the findings are”

• cites [18] sourceNot checked yet

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Two of the patients who died by suicide showed no previous signs of suicidal ideas during the study, either at entry or at the last visit; data was not available for the third.

“However, two of the patients who died by suicide showed no previous signs of suicidal ideas during the study, either at entry to the study or at the last visit (data was not available for the third patient).21”

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Janssen is seeking an expansion of esketamine's indications to acutely suicidal patients based on two studies showing a reduction of suicidality on a MADRS subscale at 24 hours but no effect on the pre-specified CGI-SS-R.

“Potentially paradoxically, Janssen is seeking an expansion of the indications for use of esketamine to acutely suicidal patients (on the basis of two studies that showed a reduction of suicidality on a sub-scale of the MADRS at 24 hours, but no effect on the pre-specified measure of suicidality, the CGI-SS-R).27”

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In esketamine trials, half of patients experienced dissociation, a third dizziness, and increased blood pressure, vertigo, hypoaesthesia, nausea, and sedation were each present in 10-30% of patients.

“A large range of other side effects occurred: half of patients experienced dissociation, a third dizziness, and increased blood pressure, vertigo, hypoaesthesia, nausea and sedation were each present in between 10% and 30% of patients (Table 3).21”

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The FDA noted mis-classification, under-reporting, and mis-representation of adverse events, so the presented data likely underestimates the incidence of adverse events.

“However, the FDA noted that there was mis-classification, under-reporting and mis-representation of the adverse events so that the presented data likely represents an underestimation of the incidence of adverse events 30 .”

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Participants in the positive trial would have been unblinded by esketamine's noticeable psychoactive effects, and expectation effects might inflate the apparent difference.

“Furthermore, participants would have been unblinded by the noticeable psychoactive effects of esketamine (dissociation was reported by the majority of participants); expectation effects might therefore inflate the apparent difference between placebo and esketamine.”

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A 7-9 point MADRS reduction corresponds to a minimally improved CGI rating, while 16-17 points corresponds to much improved.

“A 7 to 9 point reduction on the MADRS has been found to correspond to a clinically noticeable (”

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These causes of death have been observed previously in ketamine use: blood pressure spikes cause heart failure and myocardial infarction in at-risk patients, and impaired coordination and dissociation increase motor vehicle accident risk.

“These causes of death have been observed previously in ketamine use: blood pressure spikes cause heart failure and myocardial infarction in patients at risk; impairment of hand-eye coordination and its dissociative effects increase the risk of motor vehicle accidents.3,4,8,9”

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• AssumptionRests on an assumption: Esketamine's adverse effects are similar enough to ketamine's for evidence about ketamine harms to apply to esketamine.

May combine two claims.

In the discontinuation trial, placebo participants would notice the absence of esketamine's psychoactive effects, and negative expectations would tend to increase their chance of relapse.

“The absence of esketamine's psychoactive effects would be noticed by participants randomised to placebo and consequent negative expectations would tend to increase their chance of relapse.21”

• cites [21]Not checked yet

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The 4-point MADRS difference for esketamine is less than minimal clinical change and about one quarter the placebo response, so its clinical relevance is doubtful.

“A 4-point difference therefore corresponds to less than”

• cites [18] sourceNot checked yet

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• AssumptionRests on an assumption: The MADRS-CGI mapping derived from mirtazapine studies applies to the esketamine trial population.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ketamine induces ulcerative cystitis, found in 30% of regular UK ketamine users, known as ketamine bladder.

“Ketamine also induces ulcerative cystitis, found in 30% of regular UK ketamine users, known as 'ketamine bladder'.3”

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Ketamine is addictive, quickly induces tolerance, and stopping regular use causes a withdrawal syndrome characterized by anxiety, dysphoria, depression, shaking, sweating, palpitations, and craving.

“Ketamine is also addictive.3,11 It quickly induces tolerance 3 and stopping regular use causes a withdrawal syndrome characterised by anxiety, dysphoria and depression, shaking, sweating and palpitations, and craving the drug.3,11”

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

This requirement has been criticised because short-term trials do not accurately reflect long periods of use and discount negative trials.

“This requirement has been criticised because short-term trials do not accurately reflect the long periods many drugs are eventually used for in practice, 19 and discount negative trials.”

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Intravenous ketamine was demonstrated to improve depression scores in the 2000s, with a trial showing rapid-onset antidepressant effects in as little as 2 hours.

“Intravenous ketamine was demonstrated to improve depression scores in the 2000s, 13,14 with a trial showing 'rapid-onset antidepressant effects' in as little as 2 hours.13”

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Ketamine commonly elevates blood pressure and heart rate, which has been associated with fatal heart failure and myocardial infarction, as well as stroke and cerebral haemorrhage, more often in those with pre-existing risk factors.

“Ketamine commonly elevates blood pressure and heart rate, 4 which has been associated with fatal heart failure and myocardial infarction, 4 as well as stroke and cerebral haemorrhage 3 more often in those with pre-existing risk factors.”

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Themes from history are repeating: a known drug of abuse associated with significant harm is increasingly promoted despite scant evidence of efficacy and without adequate long-term safety studies.

“It would seem that themes from history are repeating: a known drug of abuse, associated with significant harm is increasingly promoted despite scant evidence of efficacy, and without adequate long-term safety studies.”

• AssumptionRests on an assumption: The historical pattern of prescribed medicines described by Public Health England applies to esketamine.

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

It is difficult to distinguish ketamine's rapid-onset antidepressant effect from the high or altered state it induces.

“It would seem difficult to distinguish this 'rapid-onset antidepressant effect' from the 'high' or altered state known to be induced by ketamine, however.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The NICE appraisal did not question the published interpretation of the efficacy data and lacked focus on harms of treatment, including suicides, which might be more marked in real-life, longer-term use.

“However, the NICE appraisal did not question the published interpretation of the efficacy data, and lacked focus on the harms of treatment, including suicides, which might be more marked in reallife, longer-term use.”