Ketamine, like other anaesthetic agents propofol and nitrous oxide, reduces depression scores in 2 hours. Does that make esketamine a safe and effective antidepressant? No. With @joannamoncrieff in @TheBJPsych bit.ly/3gw4cUC (thread)
We analysed studies submitted by Janssen to FDA to licence esketamine (esk) for treatment-resistant depression (TRD). TRD sounds rare and severe, but Janssen’s defn - people who have ‘failed’ two different ADs - likely to include many current AD users. (1/25)
Esk is one of two mirror image molecules that make up ket. Esk is 2xpotent as ket. 3 trials conducted for 4 weeks to compare esk to placebo. In 2 of these trials there was no sig. difference between esketamine and pbo. (2/25)
In the last trials the diff was statistically sig but not clinically significant – as usually measured (6-7 MADRS points) + set out by Janssen itself (6.5 MADRS points). The different was 4 MADRS points. (3/25)
By comparison the pbo treatment (seeing tech 2x week for 1 hour) had a whopping effect: 17 MADRS points! In other words this ‘game-changing’ drug had one quarter the size of the placebo effect. (That is not true for insulin or anti-HT, for instance) (4/25)
The FDA, normally sets a very low bar for drug approval (2 positive placebo-controlled studies) but against its own precedent, lowered the bar even further and allowed a discontinuation study, a controversial study design. (5/25)
In the discon study people already on the drug for several weeks were either continued on the drug or abruptly stopped. The patients who stayed on the drug relapsed less than those who stopped. (6/25)
Interpreted as protective effect of the drug. But ket has known withdrawal syndrome with anxiety, insomnia, depression so ‘relapses’ in abrupt stopping group almost certainly withdrawal. Even more likely b/c most ‘relapses’ occurred in the first 4 weeks after stopping. (7/25)
There were some very worrying ‘safety signals’. There were six deaths in the esketamine group and none in the placebo group in Stage 2 and 3 trials. That is, 0.3% of people in the esketamine group died, in trials that mostly lasted a few weeks. (8/25)
The deaths were 3 suicides, one fatal motor vehicle accident, and two cardiovascular deaths. They were all dismissed as ‘unrelated to the treatment’ by Janssen. However, all these causes of death are well recognised from recreational and medical ketamine use. (9/25)
Recreational ketamine use is increasing in UK (and elsewhere). There have been increasing deaths related to ketamine use. These include suicides, car accidents. Ketamine impairs hand-eye co-ordination and balance. (10/25)
In Hong Kong 9% of all fatal traffic accidents in 1990s involved ketamine. There were 5 non-fatal traffic accidents in esketamine group in Janssen trials (none in placebo). So not isolated event. (11/25)
From anaesthetics, ket known to spike blood pressure increasing risk of heart attacks, brain haemorrhage. 1 non-fatal cerebral haemorrhage as well as 2 cardio deaths in esketamine group in studies. 10% of esk users showed a spike in blood pressure (3.5 in pbo). (12/25)
The 3 suicides were thought to be consistent with a severe withdrawal reaction by some commentators, and suicides are known to occur with this drug. 0.2% of pts in esketamine group completed suicide. (none in placebo) (13/25)
0.9% of pts reported worsening suicidal ideas on esk (0.5% on pbo). 1.4% of pts on esk reported worsening depression (0.2% on pbo). So suicides not isolated events. Worse depression also seen in recreational use. (14/25)
Recreational use and medical use v. different, right? Not so. A rec dose is 60-250mg (EMCDD) normally by snorting. Esk is 2x as potent as ket. Doses in Janssen studies were 56-84mg, equiv to 112-168mg of ketamine. Delivered by nasal spray so same mode as recreational users. (15)
Half of users reported dissociation, hallmark of ket intoxication (‘k-hole’). 10% users also showed bladder irritation, similar to a well known side effect of ketamine use (‘ketamine bladder’). Safety trial used a lower dose of esk than is intended in clinical use. (16/25)
Ket first came to prominence because it demonstrated ‘acute-onset antidepressant effects’ at 2 hours. Difficult to distinguish this from what rec users call ‘getting high’. Long term users of ketamine report impaired cognition, memory and depression. (17/25)
NICE has issued draft guidance recommending esk not be used for ‘treatment-resistant depression’ because not evidence that drug is clinically effective or cost-effective. (18/25)
Lots of pressure on NICE to reverse this. Hope they hold out for long-term studies of efficacy and further safety studies. 4 weeks not long enough. Even shorter than completely uninformative 6-8 week studies for other ADs. Where did 4 week time point come from? (19/25)
If approved the safety studies will occur in unwitting patients in the NHS. Recent Publich Health England report prescient: “Recurring patterns are evident in the history of medicines that may cause dependence or withdrawal. New medicines are seen as an important…(20/25)
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,.. (21/25)
efforts are made to curtail prescribing. The repetition of this pattern is striking.” Let’s try and learn quicker this time and not introduce known drug of abuse with long-term increase in depression, cog issues, memory, bladder probs. (22/25)
Worth noting that janssen did discover an amazing breakthrough treatment: 1 hour 2x/week with human reduces depression scores (in treatment resistant depression no less!) by 17 MADRS points, 4x bigger effect than this new drug they also trialled. (23/25)
Bonus tweets: Janssen in its NICE submission argued placebo response was too high and should be ‘adjusted down’. Flabbergasting. (24/25)
Also used ‘statistical model’ to show esk reduced mortality even though 6 deaths in esk group and 0 in placebo (model used reduction of depression scores in creative manner). (25/25)
