A concluding summary of the efficacy and safety of esketamine from the data presented by Janssen to the FDA
We thank Jauhar and Morrison for their effort to re-engage with the substantive topic. Unfortunately, they still do not address the fundamental lack of evidence of esketamine’s efficacy and its long-term safety.
There is no debate over the addictive nature of ketamine, and its S- (more active) enantiomer, esketamine. Ketamine is known to produce tolerance  and repeated use is associated with a recognised withdrawal syndrome [2,3]. Craving and drug-seeking behaviour are commonly encountered in its use as a recreational drug. Contrary to Jauhar and Morrison’s assertion, and as evidenced in other drugs of abuse, when a drug can cause tolerance, dependence and withdrawal, it does not matter what population it is administered to – its dependence-inducing properties are characteristics of its pharmacology, and addiction will always be a risk.
Public Health England (PHE) has just published a review of drug classes causing dependence and withdrawal, including opioids, benzodiazepines, z-drugs, gabapentinoids, and antidepressants, concluding that one in four Britons are on these drugs, a widespread issue of concern . When each of these classes of drug were introduced into clinical practice they were said to have ‘safe profiles’, and were approved for use based on short-term studies in the absence of comprehensive long-term safety studies. Recognition of the damage these drugs have done to many patients caught in a cycle of dependence and withdrawal effects has taken decades.
The PHE report comments on these “recurring patterns”: “New medicines are seen as an important part of the solution to a condition, resulting in widespread use. Their dependence or withdrawal potential are either unknown at this point, due to a lack of research, or perhaps downplayed. As evidence of harm from dependence or withdrawal emerges, efforts are made to curtail prescribing. The repetition of this pattern is striking.”.
But dependence is not the only concern. Long-term use of ketamine can be associated with irreversible damage to the urinary tract, which can lead to renal failure, and cognitive dysfunction, a portion of which may be irreversible .
We summarise the four efficacy trials submitted by Janssen to the FDA, to ensure that there is no selective citing: there were three 4-week trials, and one discontinuation study. Two 4-week trials demonstrated no difference in MADRS scores between placebo and esketamine in depressed patients [5,6]. The third showed a difference of 4.0 points between esketamine and placebo at 4 weeks on the MADRS scale, favouring esketamine . For reference, placebo alone reduced MADRS scores by 17.0 points. Therefore, ketamine had an effect one quarter that of the placebo effect, even though the trial would inevitably not have been double-blind. We leave it to the reader to decide whether this difference in a 60-point scale, present in only one of three trials, suggests any real clinical value.
The discontinuation trial followed sixteen weeks of esketamine treatment . Such trials are problematic because of adverse effects associated with stopping a drug that has been used repeatedly. Physiological withdrawal symptoms can be mistaken for relapse, and the process of withdrawal may also precipitate or bring forward a relapse that may not otherwise have occurred. Discontinuation trials are not normally accepted as evidence of efficacy by the FDA but in this case the FDA made an exception because of the ‘breakthrough’ nature of esketamine  .
We thank Jauhar and Morrison for drawing attention to the investigators’ attempt to measure withdrawal effects. They employed the Physician Withdrawal Checklist (PWC-20), a checklist developed for benzodiazepine withdrawal . The results are not reported, but it is simply stated that ‘no evidence of a distinct withdrawal syndrome was observed during the 2 weeks after cessation of esketamine’ .
Given that the PWC-20 includes the symptoms ‘insomnia’, ‘anxiety-nervousness’, ‘dysphoric mood-depression’, ‘difficulty concentrating, remembering’, ‘fatigue’, ‘lack of appetite’, which are identical, or overlap, strongly with 70% of the items on the MADRS one wonders how the authors distinguished relapse from withdrawal.
Indeed, ketamine withdrawal is most commonly associated with fatigue, poor appetite, drowsiness, anxiety, and dysphoria in other studies . Most relapses in the discontinuation study occurred in the first few weeks after esketamine was abruptly stopped, a time period when withdrawal effects are likely to be most relevant, further suggesting confounding by withdrawal.
Furthermore, and especially alarming, there were six deaths, including three suicides, that occurred in the patients assigned to esketamine, and none in those assigned to placebo, in the Phase 2 and 3 studies conducted by Janssen . One death was a motorcycle accident 26 hours after esketamine administration. Two others involved an MI and cardiac failure days after esketamine use, which is known to cause blood pressure spikes (one in a patient with pre-existing risk factors) . Three suicides occurred 4, 12 and 20 days after the last dose of esketamine . Although Janssen sought to explain these deaths as due to ‘the severity of the patients’ underlying illness’ two of the patients had no previous suicidal ideas at baseline or during the study (data was not available for the third patient) . These suicides were dismissed as not drug-related by Janssen, “given the small number of cases … and the lack of consistent pattern among these cases”. However, others have argued that these cases fit with a pattern of a severe withdrawal reaction, and are significant enough in number to constitute a worrying signal .
It appears that history is repeating: a known drug of abuse, associated with significant harm, with scant evidence of efficacy, is being submitted for licensing, without adequate long-term safety studies. ‘Scrupulous monitoring’ has not been previously adequate in preventing the rise in prescribed drug dependence.
We hope that the MHRA will ask for further safety and efficacy studies performed in the long-term before this drug is licensed for use in the UK, a point that Jauhar and Morrison seem to be in agreement with us on. No one will thank the MHRA if they introduce another drug that leads to long-term medical complications and significant problems with dependence and withdrawal, just because it has a ‘novel’ mode of action.
1 Gerb SA, Cook JE, Gochenauer AE, et al. Ketamine Tolerance in Sprague-Dawley Rats after Chronic Administration of Ketamine, Morphine, or Cocaine. Comp Med 2019;69:29–34. doi:10.30802/AALAS-CM-18-000053
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3 Li J-H, Kasinather V, Cheung, et al. To use or not to use: an update on licit and illicit ketamine use. Subst Abuse Rehabil 2011;:11. doi:10.2147/sar.s15458
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6 Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol 2019;40:1–30. doi:10.1093/ijnp/pyz039
7 Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study. Am J Psychiatry 2019;176:428–38. doi:10.1176/appi.ajp.2019.19020172
8 Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients with Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry 2019;08560:893–903. doi:10.1001/jamapsychiatry.2019.1189
9 Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry 2019;176:422–4. doi:10.1176/appi.ajp.2019.19040423
10 Rickels K, Garcia-Espana F, Mandos LA, et al. Physician withdrawal checklist (PWC-20). J Clin Psychopharmacol 2008;28:447–51. doi:10.1097/JCP.0b013e31817efbac
11 Janssen. Efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceuticals, Inc., for the treatment of treatment-resistant depression. 2019;:1–135.
Competing interests: No competing interests