Meta-analysis shows esketamine treatment has essentially no/very minimal impact on suicidality

[futureapppsy2]

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Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis - PubMed

The study findings suggest that esketamine's efficacy as an add-on to antidepressants is modest in treatment-resistant depression (similar to augmentation strategies with atypical antipsychotics) and is absent against suicidality itself. These findings need to be considered in light of...

pubmed.ncbi.nlm.nih.gov

Saw this posted elsewhere, and I think it's a good reminder how people can be really subject to the hype train for new treatments that turn out not to be so revolutionary when tested on a large scale (this is an issue across medicine, IME).

 

[aim-agm]

Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis - PubMed

The study findings suggest that esketamine's efficacy as an add-on to antidepressants is modest in treatment-resistant depression (similar to augmentation strategies with atypical antipsychotics) and is absent against suicidality itself. These findings need to be considered in light of...

pubmed.ncbi.nlm.nih.gov

Saw this posted elsewhere, and I think it's a good reminder how people can be really subject to the hype train for new treatments that turn out not to be so revolutionary when tested on a large scale (this is an issue across medicine, IME).

Key quote:
"In total, studies included 1,774 patients, of whom 979 were randomized to esketamine (55.19%) and 795 (44.81%) to placebo. The data suggest that there is a significant effect of esketamine on suicidality 2–4 hours after administration (28, 89). Data on assessment at 24 hours after administration are equivocal, with one study reporting positive results (25) and three being negative (26, 28, 89). With the data pooled from all placebo-controlled RCTs reporting data until week 1, one was positive (28) and four were negative (25, 26, 30, 31). All seven trials reporting on the effect of esketamine on suicidality around week 4 were negative (25, 26, 28, 30, 31, 34, 89)."

So another layer of the reminder us that the statements the hype is based on could be entirely true but quite overhyped. Ketamine does significantly reduce suicidality per this paper - but only for a couple hours.

There are applications for a medication that can very temporarily but quite rapidly reduce suicidality, primarily on certain inpatient units, but unfortunately the effect on suicidality appears to be of very limited significance in an outpatient setting.

 

[futureapppsy2]

Key quote:
"In total, studies included 1,774 patients, of whom 979 were randomized to esketamine (55.19%) and 795 (44.81%) to placebo. The data suggest that there is a significant effect of esketamine on suicidality 2–4 hours after administration (28, 89). Data on assessment at 24 hours after administration are equivocal, with one study reporting positive results (25) and three being negative (26, 28, 89). With the data pooled from all placebo-controlled RCTs reporting data until week 1, one was positive (28) and four were negative (25, 26, 30, 31). All seven trials reporting on the effect of esketamine on suicidality around week 4 were negative (25, 26, 28, 30, 31, 34, 89)."

So another layer of the reminder us that the statements the hype is based on could be entirely true but quite overhyped. Ketamine does significantly reduce suicidality per this paper - but only for a couple hours.

There are applications for a medication that can very temporarily but quite rapidly reduce suicidality, primarily on certain inpatient units, but unfortunately the effect on suicidality appears to be of very limited significance in an outpatient setting.

Good point! A narrow inpatient use is much less profitable than an outpatient clinic doing monthly/bi-weekly/weekly administrations, of course, so people jumped to assume that this was the cure for TRD/suicidality in large part because it was financially advantageous to do so (and also because TRD can be very difficult and frustrating clinically).

 

[Stagg737]

Key quote:
"In total, studies included 1,774 patients, of whom 979 were randomized to esketamine (55.19%) and 795 (44.81%) to placebo. The data suggest that there is a significant effect of esketamine on suicidality 2–4 hours after administration (28, 89). Data on assessment at 24 hours after administration are equivocal, with one study reporting positive results (25) and three being negative (26, 28, 89). With the data pooled from all placebo-controlled RCTs reporting data until week 1, one was positive (28) and four were negative (25, 26, 30, 31). All seven trials reporting on the effect of esketamine on suicidality around week 4 were negative (25, 26, 28, 30, 31, 34, 89)."

So another layer of the reminder us that the statements the hype is based on could be entirely true but quite overhyped. Ketamine does significantly reduce suicidality per this paper - but only for a couple hours.

There are applications for a medication that can very temporarily but quite rapidly reduce suicidality, primarily on certain inpatient units, but unfortunately the effect on suicidality appears to be of very limited significance in an outpatient setting.

WHAT? You mean that patients who get high on psychedelics feel better and less suicidal when they’re high?!?! Stop the presses!!!

Seriously though, while I do think psychedelics (including ketamine) probably have their place in depression treatment, I see plenty of patients who are getting Spravato whose actual underlying issue isn’t treatment resistant MDD or dysthymia. I also know several clinics are more than happy to give Spravato (or other ketamine formulations) to anyone hitting the criteria who can pay or get insurance approved, so not surprised by the mixed results at all. After working with researchers and seeing the methods used, I always question how well they’re actually capturing treatments for specific disorders like they claim vs just catch-all screening.

 

[Taddy Mason]

…while I do think psychedelics (including ketamine)…

Sorry, can’t resist being that guy and letting my OCPD getting the best of me but it’s a dissociative.

 

[TexasPhysician]

Surprising to me. My Spravato success rate is incredibly high.

 

[futureapppsy2]

Surprising to me. My Spravato success rate is incredibly high.

What does your patient population for it look like?

 

[Stagg737]

Sorry, can’t resist being that guy and letting my OCPD getting the best of me but it’s a dissociative.

Sure, sure. By psychedelics I just meant illicit drugs possibly useful to psych (ketamine, psilocybin, LSD, etc). I think I’ve had this discussion in another thread before, but I had friends in college that used ketamine for psychedelic effects and other users were insistent that’s not how it works. Which typically it doesn’t, but idk, that’s how they used it *shrugs*.

ETA: previous discussion was about whether MDMA has dissociative properties. So what I struck through above I was wrong about the previous discussion.

 

[Taddy Mason]

Sure, sure. By psychedelics I just meant illicit drugs possibly useful to psych (ketamine, psilocybin, LSD, etc). I think I’ve had this discussion in another thread before, but I had friends in college that used ketamine for psychedelic effects and other users were insistent that’s not how it works. Which typically it doesn’t, but idk, that’s how they used it *shrugs*.

ETA: previous discussion was about whether MDMA has dissociative properties. So what I struck through above I was wrong about the previous discussion.

Lol - I was just giving you crap and got the point you were making. Proper drug classification is just a (somewhat off putting) pet peeve of mine…among others…

 

[TexasPhysician]

What does your patient population for it look like?

Where I use it, TRD commercial insurance population that can’t afford cash pay. No government plans.

 

[Merovinge]

Where I use it, TRD commercial insurance population that can’t afford cash pay. No government plans.

Same for us, all commercial insurance that gets Spravato covered and doesn't have to pay for IV ketamine. I do wish the later had insurance coverage but then there is the reality of the world.

 

[FatherPsychiatry]

Here's a fresh new article from 7/2/2025 showing it does have benefit in T R D!

Esketamine Monotherapy in Adults With Treatment-Resistant Depression​

"Meaning These findings support esketamine as a monotherapy option for patients with TRD, especially for those experiencing treatment-limiting tolerability concerns or nonresponse with oral antidepressants."

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2836115

Lead authors (actually, 4 of the 8 authors) are from the illustrious "Johnson & Johnson" University, which I never heard of but I'm assuming they are renowned and successful since they have sits from San Diego to New Jersey to Belgium.


Right around the same time, ol' Dr. Ghaemi posts this video:

"Treatment resistant depression: another wrong psychiatric concept"​

Some good grist for the scientific-psychiatric mill.

 

[futureapppsy2]

Here's a fresh new article from 7/2/2025 showing it does have benefit in T R D!

Esketamine Monotherapy in Adults With Treatment-Resistant Depression​

"Meaning These findings support esketamine as a monotherapy option for patients with TRD, especially for those experiencing treatment-limiting tolerability concerns or nonresponse with oral antidepressants."

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2836115

Lead authors (actually, 4 of the 8 authors) are from the illustrious "Johnson & Johnson" University, which I never heard of but I'm assuming they are renowned and successful since they have sits from San Diego to New Jersey to Belgium.


Right around the same time, ol' Dr. Ghaemi posts this video:

"Treatment resistant depression: another wrong psychiatric concept"​

Some good grist for the scientific-psychiatric mill.

The meta in the OP found modest effectiveness for TRD as a whole, just not for suicidality outside of the immediate effect. It’s probably like most treatments that look like huge game changers out of the gate—it’s another useful option for some patients but hardly a cure-all (and then, of course, you have actual game changers like Gleevec/TKIs every now and then).

I’d guess most (or at least a lot of) TRD is actually misdiagnosed bipolar or BPD.

 

[clozareal]

I’d guess most (or at least a lot of) TRD is actually misdiagnosed bipolar or BPD.

I'm more in the personality disorder camp.

 

[futureapppsy2]

I'm more in the personality disorder camp.

Yeah, I agree, hence the BPD. Enough “TRD” suddenly improves greatly on lamictal that I think there’s a good deal of missed Bipolar II in the mix too, though,

 

[calvnandhobbs68]

I also think people tend to underdiagnose or aren't willing to call PDD/dysthymia. There's definitely a subset of people who have just straight up "Eeyore" personalities who will come in for years saying they're "depressed" every visit when it's really this baseline kind of dysthymic negative personality. Often won't respond to many different med trials and seem to improve over time with life changes lol.

I guess this skews towards the personality disorder camp too though honestly since there used to be a depressive personality disorder.

 

[comp1]

Personality disorders are so much more common than stuff like schizophrenia or bipolar disorder and extraordinarily underdiagnosed. IMHO, there needs to be extremely strict proactive screening (requirement to concretely rule OUT a personality disorder) and then frank exclusionary criteria around PDs for stuff like ketamine. And no, it's not "comorbid," the mood problems are part of the PD. I think we'd see a good deal more efficacy both in studies and the real world. Ketamine is exactly the wrong treatment for someone with dissociative problems at baseline, but much like repeating past traumas with new relationships, we definitely see people seeking it out just for that purpose.

 

[Stagg737]

Personality disorders are so much more common than stuff like schizophrenia or bipolar disorder and extraordinarily underdiagnosed. IMHO, there needs to be extremely strict proactive screening (requirement to concretely rule OUT a personality disorder) and then frank exclusionary criteria around PDs for stuff like ketamine. And no, it's not "comorbid," the mood problems are part of the PD. I think we'd see a good deal more efficacy both in studies and the real world. Ketamine is exactly the wrong treatment for someone with dissociative problems at baseline, but much like repeating past traumas with new relationships, we definitely see people seeking it out just for that purpose.

While I pretty much agree with all of this, I’ll slightly push back on the bolded. That is often true, but I have seen more than a couple of patients referred for ECT by our TRD clinic where I thought it would be pointless due to their depression being a symptom of their PD where they actually got much better. Yes, depression and anxiety are symptoms of many PDs. However, for some patients it is a co-morbid disorder and for those patients I do think these treatments can be helpful.

That just further supports your point that assessments of these patients need to be really thorough though. If we just use a categorical checklist there’s no way it will differentiate between patients who will actually benefit from these treatment modalities vs those who won’t, which I believe can absolutely be done.

 

[FatherPsychiatry]

but I have seen more than a couple of patients referred for ECT by our TRD clinic where I thought it would be pointless due to their depression being a symptom of their PD where they actually got much better. Yes, depression and anxiety are symptoms of many PDs. However, for some patients it is a co-morbid disorder and for those patients I do think these treatments can be helpful.

Interesting. ECT can be diagnostic and therapeutic.

 

[aim-agm]

While I pretty much agree with all of this, I’ll slightly push back on the bolded. That is often true, but I have seen more than a couple of patients referred for ECT by our TRD clinic where I thought it would be pointless due to their depression being a symptom of their PD where they actually got much better. Yes, depression and anxiety are symptoms of many PDs. However, for some patients it is a co-morbid disorder and for those patients I do think these treatments can be helpful.

That just further supports your point that assessments of these patients need to be really thorough though. If we just use a categorical checklist there’s no way it will differentiate between patients who will actually benefit from these treatment modalities vs those who won’t, which I believe can absolutely be done.

Also, just because a depressive process is a part of a PD doesn't mean that it won't respond to antidepressant tx. OCPD is not an anxiety disorder, but there is an anxious process underpinning it and my experience has been those patients respond very well to usual treatments for anxiety (SRI, buspirone, NRI) and can have effective remission of the OCPD.

Additionally, having a depressive PD might be depressing. Depressive disorders that are a product of a PD can still respond well to antidepressant tx, e.g. depression secondary to a chronic narcissistic insult is a common reason NPDs present (although they usually don't have insight) and my experience is that the depression responds well to antidepressants even though the NPD itself doesn't get any better.

 

[aim-agm]

Interesting. ECT can be diagnostic and therapeutic.

ECT is too effective for too many things for response to tell you much diagnostically, although failure to respond to ECT may support a finding that what they have is not one of those things.

 

[comp1]

I'm not saying people with PDs aren't depressed. They definitely are, often and much more than the general population. I'm saying the examples of efficacy above are...rare. Much more common is someone where the core, primary issue is the PD and chasing the shiny and loud mood symptoms are not helpful. Essentially, with a PD, the number needed to harm with something already as tenuously effective as ketamine is much lower than the number needed to benefit. Sure, go right ahead and give the person a SSRI, but when you get to these 3rd or 4th or 5th line treatments, maybe focus on the PD instead.