Intro
What did they classify as treatment resistant depression?
Failure of 2 antidepressants
What questionnaire did they use to quantify depression?
MADRS
When did they start seeing a difference between esketamine and placebo?
24 hours (-3.3 difference)
Are these results generalizable to the real world? Why/Why not?
Yes. Each patient had quantified tx resistant depression and one tx failure was confirmed during the initial 4 week phase
What receptor does ketamine act on? agonist/antagonist?
NMDA antagonist
What percentage of people with depression have treatment resistant depression?
30%
What were the two dosage of IN esketamine and how long?
56 mg and 84 mg twice weekly for 28 days
What aspect was NOT statistically significant?
Sustained response endpoint. Basically, the people who responded within 24 hours, it is not statistically significant that they were likely to maintain that response for the entire 4 weeks. Overall the difference is statistically significant but not that the rapid responders maintained that same response.
What do you think is the most important result to come out of this study? Is it worth the trouble of the side effects in your opinion?
NNT for response and remission
Response: 69.3% vs 52.0% → NNT ≈ 6
Remission: 52.5% vs 31.0% → NNT ≈ 5
What neurotransmitter does ketamine act on?
Activates Glutamate
What is one issue with typical antidepressants that the researchers hope to bypass by using ketamine?
The long time for it to produce clinical effects, multiple weeks in which anything bad can happen
What were some exclusion criteria?
Points if you get 3
Psychotic disorder, HI/SI within 6 months, suicide attempt within 1 year, bipolar, personality disorders, OCD, ASD, ID, substance use disorder within last 6 months, seizures, uncontrolled htn
What was the effect size of 4 week difference in MADRS score between tx group and placebo
0.30 (modest)
What are some limitations to the population selection process that makes it less generalizable to the real world?
did not include suicidal people which is a big portion of MDD patients, did not include substance use patients which commonly co-occurs with MDD, did not include MDD with psychotic features
What vital was effected by esketamine?
BP. +11.9 systolic (+5 in control), +8.1 diastolic (+4.5 in control) peaked by 40 min and back to normal by 1.5-2 hrs
What is esketamine compared to ketamine and why did they choose it?
Enantiomer of ketamine and has higher affinity for NMDA receptor
Which antidepressants did they use in conjunction with treatment/placebo?
Standard of care SSRI (escitalopram, sertraline), or SNRI (duloxetine, venlafaxine ER)
From day 1 to 28 what were each groups difference in MADRS score?
-21 for esketamine + tx and -17 for just tx (both started around 37). -4 difference
(statistically significant)
The -4 difference is statistically significant but not as high as they hoped (-6.5). Why?
For the “placebo” they started a new antidepressant so it is a novel treatment to the person and not one of the already failed med. Also they cannot do an inert/no tx cause this is a high risk population
What were the top 5 side effects of esketamine?
Need to get at least 3 out of 5
dizziness, dissociation, dysgeusia (metallic/bitter/salty taste in your mouth), vertigo, and nausea
How did they qualify non-response to treatment?
From week 1-4 of the initial phase, less than or equal to 25% difference of MADRS score
What were the 3 phases?
1) a 4-week screening and prospective observation phase during which treatment response to the current ongoing oral antidepressants was assessed
2) a 4-week treatment phase during which participants received a new oral antidepressant combined with either esketamine nasal spray or placebo nasal spray
3) a posttreatment follow-up phase of up to 24 weeks.
What were the NNT for response and NNT for remission?
6 for response and 5 for remission
This means that for every 6 patients treated with esketamine and a new antidepressant instead of just a new antidepressant, one additional patient achieved response. And 5 for remission
This was intended to be double blinded but why do you think it may have not been actually blinded?
IN ketamine can have some intense side effects such as dissociation, dizziness, sedation so a person receiving IN ketamine could reasonably know after a few treatment sessions which group they were a part of. Same can be said of the researchers observing the patients. If they knocked out or are dissociating (which happens more often in the first sessions), the researchers would also not be blinded anymore
In the study, patients receiving esketamine were required to start a new oral antidepressant at the same time. Why was this important to the study design?
It allowed researchers to test whether esketamine provided additional benefit beyond a newly initiated antidepressant (standard of care)