Question
Asked 20th Feb, 2015

At what point would you consider introducing low-dose ketamine in treating depression?

We use many agents "off label" (eg carbamazepine for bipolar) yet given history of abuse and psychotic reactions to both ketamine and phencyclidine we need to be cautious. In what situations should clinicians cross the line and administer ketamine?

Most recent answer

14th Mar, 2015
Jennifer M. Giddens
Tampa Center for Research on Suicidality, Tampa FL & Harm Research Institute, Tampa FL
Upon re-reading my prior response to this question it is clear that I wasn’t as specific as I should have been in my response. Yes, there have been individuals that have been on ketamine for 5+ years and there are short-term studies being conducted. However, 5 years in a limited sample size isn’t enough data to know that low-dose ketamine treatment is safe in the longer-term. By ‘longer-term’ I mean 20+ years. One of the subjects of some of my recent papers had experienced daily suicidality for more than 20 years. If this patient was given low-dose ketamine treatment, responded positively with a reduction in suicidality, and 5 years from now researchers find that such extended use of low-dose ketamine results in organ failure (which we can’t possibly know at this point in studying low-dose ketamine), which requires this subject to stop taking the ketamine, this may be devastating to this subject. I seriously doubt any informed consent about using ketamine off label acknowledges this potential and the potentially devastating impact this would have on a patient. Imagine being the subject I described. After more than 20 years of consistent suicidality (that didn’t respond to antidepressants, mood stabilizers (including lithium and lamictal), antipsychotics, or even 2 rounds of ECT) a treatment finally works. The subject starts to adjust to a life without suicidality. The quality of their life increases and they form new relationships that aren’t influenced by the constant fear of their suicidality. Then after 5 or 10 years of being able to actually function, they are told they can no longer use the treatment that has enabled them to be stable because of some horrible side effect that no one knew about when they started the treatment. It is possible that no other treatments will be available at this point and the subject must return to the consistent suicidality that previously dominated their life. I strongly suspect that potential scenario might cause the patient to consider suicide to avoid countless more years of consistent suicidality.
In my experience, researchers and clinicians want an immediate solution to the issues their patients present. Using low-dose ketamine may be simply punting the issues a number of years down the road. Yes, it is possible that such issues won’t be found, but at this point we simply don’t know. If such treatment is going to be used, the potential of this issue must be included in the informed consent of using the ketamine off label.
Now, in response to some of the other comments…
In one response, Dr. Opler stated:
I make sure patients understand options; if they are suicidal I hospitalize them (usually for ECT); but if they are not ACUTELY suicidal I offer them options, including IV ketamine with someone else and outpatient ECT with someone else.
Most (not a huge number! N=17, the first being started one year ago on 2/25/2015) choose low dose intranasal ketamine with me.
Can you seriously blame the patients for selecting this option? Three of your options to them were hospitalization for ECT, outpatient ECT, or IV ketamine treatments - all of which can potentially incredibly disrupt their lives by forcing them to miss work or school and increasing the potential for family life stressors related to their suicidality. Is it such a surprise that the patients would prefer the option that is less disruptive to their lives?  I know this isn't your fault.  Treatments for suicidality are extremely limited, but this highlights the need for more treatment options.
I think it is excessively cautious for hospitalization to be the only option for acute suicidality. I understand the desire to save lives and even the legal obligation for you to do what you can to ensure the patient is safe, however, what about their options of informed consent? If subject A is likely to die from cancer without additional treatment, but opts to reject treatment, this subject is allowed to die with dignity. If subject B is likely to die from their suicidality without additional treatment (hospitalization), but opts to reject treatment, this subject is involuntary hospitalized until they convince someone they are not likely to die as a result of their illness. This double standard is ridiculous!
For some patients, involuntary hospitalization every time their suicidality becomes acute further disrupts their lives and the net result is actually an increase in their suicidality. One patient I have communicated with told me that every time her suicidality causes her to go to the hospital her entire family becomes very upset with her, to the point that they do not speak to her for months after the hospitalization, because they are (according to her) “tired of having to deal with [her constantly] being suicidal to get attention”. The family assumes this is attention-based and refuses to interact with her if a clinician decides she needs to be hospitalized. This patient told me that this has resulted in her being less honest with clinicians, particularly at the times when her suicidality is the most acute and she needs more help keeping herself safe.
I do agree with the need to have guidelines.  I hope any guidelines would have specifics for what data should be collected to determine what effect the ketamine is actually having for the depressed or suicidal patients.  It is also important to include a way to collect that data and a manner that data sets collected at various sites can be merged.  I don't think there is even a consensus on how to determine if a non-serious suicidal adverse event happens in a clinical trial.  All of these issues need to be considered when creating such guidelines.

All Answers (18)

20th Feb, 2015
Jennifer M. Giddens
Tampa Center for Research on Suicidality, Tampa FL & Harm Research Institute, Tampa FL
Although I'm not in a position to administer ketamine to anyone, I would be very wary of using it at all at this point.  Little is known about long-term use of ketamine at the levels regularly used in the recent clinical trials.  At this point I would not consider ketamine a long-term solution to the depression or suicidality a patient may be experiencing.  I know that a number of clinicians would consider using ketamine in the short-term to 'save' the patient from the severity of their acute symptoms.  However, doing so may ultimately have the opposite effect.  A patient that is chronically depressed (or suicidal) may feel relief from the treatment while it is administered in the short-term.  This same patient may find their symptoms reemerging once the ketamine treatment is discontinued.  For some patients, this short 'reprieve' from their symptoms may increase the frustration they experience because they now know of a treatment that will help them feel better, but are unable to access it for the long-term.  I know a number of patients that have had short breaks in the severity of their symptoms of depression or suicidality only to have the severity increase again.  Some of these patients reported feeling even worse and more hopeless than before the break in severity because the break in severity allowed them to function more normally and they were reminded all the parts of their life they had been missing due to their illness.  To me, treating a patient with ketamine in the short-term and refusing to allow the patient long-term access seems unusually cruel. 
In other words, I would only consider ketamine treatment after a version of ketamine is available that can be used in the long-term.
21st Feb, 2015
Lewis Alan Opler
Long Island University
I agree with the need for a longterm ketamine-like agent without the dissociative and psychotomimetic effects of intravenous ketamine.
Super low dose INTRANASAL ketamine can be given repeatedly, although more data is needed.
I agree that denying a patient who requires ECT and/or inpatient treatment is wrong.
1 Recommendation
22nd Feb, 2015
Devin Hosea
King's College London
The folks at Yale-New Haven have been doing this for years - I would contact them for some real-world advice.  As I understand it, they administer a sedative (BZD or in some cases barbiturate) while ketamine is injected IM or IV - this substantially controls the adverse effects - when the patient regains full consciousness, depression has abated substantially.  I think they require an injection once about every 3 weeks to a month.    The Yale team has definitely published on this, and again, have been doing it for a decade+.  I can get you cites and contacts if they aren't readily available on MEDLINE.  I just can't remember the name of the fellow who spearheaded the program - I spoke to him perhaps 5 years ago.  
22nd Feb, 2015
Lewis Alan Opler
Long Island University
Yale definitely has played a prominent role in making people aware of the therapeutic potential of ketamine, including:
John Krystal, MD--present chairman
Carlos Zarate, MD--now at NIMH, but was I believe a resident in psychiatry at Yale
Dennis Charney, MD--now Dean at Mt Sinai Medical School and before that at NIMH, Professor Charney is arguably the 'mover unmoved' as regards clinical studies of ketamine for depression
Amy Arnsten, PhD--it was Professor Arnsten's insights that lead to our recently published paper
Others -- Aghajanian introduced the concept of synaptogenesis; Arnsten, however, correctly points out that this cannot account for the immediate effects of of ketamine in people, although it could explain the longer lasting effects
Lewis A. Opler, MD, PhD
PS--YES! I WOULD LIKE CONTACT INFORMATION RE: WHO AT YALE NOW IS USING KETAMINE IN CLINICAL SETTINGS! 
23rd Feb, 2015
Angus James Bell
Tees, Esk and Wear Valleys NHS Foundation Trust
We have a Ketamine service now based in the ECT suite and have treated 5 patients so far with low dose iv ketamine - lets turn the question around - you have a patient with TRD and nothing else has worked you are considering risky and expensive other treatments so where in that pathway would ketamine sit? I liaise with Oxoford on this who have patients who have had upwards of 100 treatmentsand we both agree that Ketamine seems to be very safe and in our view preferable to ECT.  I regard it as like dialysis for TRD - it can work to an amzing degree and be life transforming but will inevitably relapse so pulsed therapy is the order of the day and work needs to be done with psychology to enhance resilience.  Re dissociation there is some evidence that is the therapeutic necessity!
23rd Feb, 2015
Lewis Alan Opler
Long Island University
My only experience with prescribing and administering ketamine myself is using intranasal ketamine-because I am doing so in a private office I have erred on the side of caution, eg, starting some patients as low as 20 mg every other day and rarely going above 80 mg/daily.
I make sure patients understand options; if they are suicidal I hospitalize them (usually for ECT); but if they are not ACUTELY suicidal I offer them options, including IV ketamine with someone else and outpatient ECT with someone else.
Most (not a huge number! N=17, the first being started one year ago on 2/25/2015) choose low dose intranasal ketamine with me.
23rd Feb, 2015
Tomislav Franić
University of Split
I think Tomas Fernandes is in Yale team dealt with ketamine.
23rd Feb, 2015
Petru Ifteni
Psychiatry and Neurology Hospital, Transilvania University Brasov, Romania
I don't have such experience. I noticed a trend in using 2 or 3 concomitant antidepressants in high doses in those patients with history of ,,refractory depression'', sometimes from the very beginning with good results.
23rd Feb, 2015
Devin Hosea
King's College London
Here in the US we pretty much define TRD patients as those who don't respond to first-line antidepressants (SSRIs SNRIs lithium etc). ECT is considered a second-line therapy and ketamine is considered "investigational" at this point. It shows considerable promise but also has considerable risks/issues that need to be worked out. But for some patients it has been literally a life-saving medication. 
25th Feb, 2015
Tim Howard
Mental Health Care UK
I wouldn't.
25th Feb, 2015
Lewis Alan Opler
Long Island University
And I wouldn't  use intravenous ketamine nitrous oxide inhalation because I am not set up to do so; but how about if it lifted anhedonia/suicidality and you had run out of other options?
25th Feb, 2015
Tim Howard
Mental Health Care UK
Sorry, I should restrain my flippancy.
There are other options. Perhaps I've been lucky but so far when I've need to save life, which mercifully hasn't been often, ECT has been sufficient, eventually. The number of patients treated with IV Ketamine so far is small. It is unclear as to what constitutes effective prophylaxis after treatment. If I was absolutely stuck with a treatment- resistant, depressed, acutely suicidal patient, unresponsive to ECT I'd refer them to a specialist centre. Which is my point really.
1 Recommendation
25th Feb, 2015
Angus James Bell
Tees, Esk and Wear Valleys NHS Foundation Trust
This is not just about saving life it is about achieving remission ie quality of life. I have a tertiary patient who was considered for leukotomy and ended up with a VNS implant and ketamine got him into remission.  Also the risk issue is relative ie relative to other treatments and relative to not getting better and the consequences of that. Having investgated Ketamine for the last 2 years and having used ECT for the last 25 years with patients I would definitely prefer to have ketamine therapy before/instead of ECT (no anaesthetic, and improved cognition versus anaesthetic and memory problems)  if I was a patient. This view is also shared by a leading ketamine researcher. 
1 Recommendation
25th Feb, 2015
Lewis Alan Opler
Long Island University
I agree with both tim howard and angus bell!!!
In fact, when I was Director of the Research Division of the New York State Office of Mental Health I was HORRIFIED to learn that our premier research institution NYPI was doing a funded study on single dose IV ketamine.
But later I learned that excellent clinicians/clinical researchers like Dmitris Papolos in collaboration with persons I hold in high regard (e.g., Martin Teicher @ Harvard) were writing papers on the use of intranasal ketamine in CHILDREN/ADOLESCENTS with juvenile bipolar disorder (yes, I know...that no longer exists because it's not in the DSMV...but I do think it exists....but that's another discussion)
I am in the process of getting permission from patients who tell me I saved their life/job/marriage/etc because I was willing to start them on low doses of intranasal ketamine after all else, including ECT, had failed.
Yes we need guidelines! And we need better drugs that act like ketamine but without its side effects! But at present, faced with a patient who is desperate because nothing is working, I am willing, with the patient's permission and signed consent, to start low dose ketamine.
25th Feb, 2015
Devin Hosea
King's College London
I agree too.  The psychotic reactions (during and immediately after administration) can be controlled by various means -- see the work that Dr. Deborah Mash has done with ibogaine/noribogaine - similar neuroleptics can control the "k-hole" effect of IV administration.  The long-term opioid use disorder risks are SUBSTANTIAL - the drug is widely misused for non-therapeutic purposes and cannot be discontinued (after even a few months of administration) without proper detoxification, usually inpatient.  [At the same time, I agree with Dr. Opler that single-dose IV ketamine is somewhat pointless].
It may be that the primary anti-depressant effects of ketamine come from its opioid-agonist properties.  If so, then I'm not so optimistic about the long-term use of the medication for depression.  There was a study done in the 1980s at McLean (?) where TRD inpatients were administered oxycodone - and guess what?  Not surprisingly, it worked very well -- in the short term.  It achieved immediate remission in most patients - but obviously was not sustainable as a long-term medication because they developed tolerance and also opioid use disorder (in many cases).  
If ketamine's anti-depressant properties are mostly a result of its opioid binding affinity, then I don't think it's going to be a great option for the vast majority of patients.  (And if so, why not use opioids? -- I ask rhetorically)
I think that the jury is still out on ketamine, and that we need a better understanding of its psychopharmacology/neurophysiology before we can start putting together Tx guidelines.  The short term (psychosis) and long term (addiction) risks are just too great to make it a standard treatment just yet, in my opinion.  That said, it shows great promise, from all the work done at Yale and elsewhere, as a treatment for patients who face devastating TRD with no signs of response or remission from other options.  (May be better than ECT but depends on the patient.)
2 Recommendations
26th Feb, 2015
Devin Hosea
King's College London
I found this article to be pretty interesting as an overview of mechanism of action for ketamine...I think I may be wrong about the opioid up-regulation being the main cause of anti-depressant effect - looks like glutamate may be doing most of the work - makes it a much safer approach.  The attached review I found useful, and it's quite recent as well.  
1 Recommendation
13th Mar, 2015
Angus James Bell
Tees, Esk and Wear Valleys NHS Foundation Trust
Great article thanks Devin (I cant work out how to attach articles as I just get an error message!) - I think it is fairly obviously a secondary cascade following ketamines acute effect on the nmda subset of glutamate.  I found this article discussing the meta plasticity changes particularly in the structure and function of the hippocampus to be illuminating as that would have implications on recovery from trauma ie inducing resilience (NMDA Receptors and Metaplasticity: Mechanisms and Possible Roles in Neuropsychiatric Disorders. Neurosci Biobehav Rev. 2012 March ; 36(3): 989–1000)
.  We are about to publish a case report postulating that ketmine could be an adjunct to psychological interventions to deal with depression associated with trauma.
Incidentally all this concern over psychosis being caused by Ketamine - I am concerned that people are confusing the acute dissociation effects for psychosis and they are very different - Oxford have seen zero zilch psychotic effects as have we ie none!! But dissociation certainly!!
2 Recommendations

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