Monday, June 24, 2013

Ketamine in Psychiatry

I have just updated and edited this article over the past few days.

Ketamine is a drug which has been used in general anesthesia for decades.  It is a so-called "dissociative anesthetic," which means that it causes an altered state of sensory perception without loss of consciousness.  It is a blocker of NMDA receptors;  this blockade in turn boosts glutamate release through reduced presynaptic inhition.  From there the increased glutamate increases stimulation of AMPA receptors.  These effects occur only for a few hours after a dose.  The significance of these changes would be of some debate among neuroscientists, but the bottom line is that there is a brief but marked acute alteration in one of the core aspects of the brain's dynamics and metabolism, including those aspects responsible for the management of memory, learning, and emotional processing.   

Ketamine is used illictly as a recreational drug, a fact which might bias many of us against considering its potential benefit in medicine.  

The exciting news about ketamine recently is that a single dose can lead to a dramatic improvement in symptoms of depression, even in patients who have severe, chronic, treatment-refractory mood disorders.  Aside from these case reports, there have been a number of larger studies coming out, all of which look very promising. 

Here is my literature review on ketamine, I've selected what I have thought are the best or most representative articles:

I. Reviews
- A recent brief review from The Journal of Clinical Psychiatry (May 2013)  but in discussion of mechanism, a typical example of the divide between biological and non-pharmacologically based psychiatrists:  no mention was made of the impact of the environmental milieu during the ketamine treatment.  The treatment may have part of its effectiveness because of a very positive immediate experience, permitted by an interaction of the drug with a positive or meaningful therapeutic milieu.    The drug itself, if administered in a typical sterile or detached hospital clinic environment, may have much less benefit.  It reminds me of an old episode of The Twilight Zone in which a blind person is given a treatment which would restore his sight for a few hours.  But ironically when the sight is restored, there just happens to be a power failure, and the experience is wasted.   So, in describing mechanism, it is not just a question of receptor affinities and NMDA activity etc., it is the interaction of these with experience.

II. studies showing effects in mood disorders
bipolar depressed patients randomized to get IV ketamine 0.5 mg/kg or placebo, 2 infusions, 2 weeks apart. Around 70-80% response rates and 30% remission rates, with effects lasting several days on average. The placebo group had a 0% response rate.
ketamine 0.5 mg/kg IV 3 times per week x 2 weeks, in 24 patients with refractory depression. About 70% (17/ 24) of patients had a large, substantial improvement in depressive symptoms; improvement lasted an average of about 2-3 weeks.
Archives study, randomized add on of IV ketamine for bipolar depression. 13 of 17 patients in the ketamine group completed the study, vs. 15 of 16 patients in the placebo group. The patients were hospitalized, and had not responded to a mood stabilizer and antidepressant. Only 2 infusions, 2 weeks apart. But 50-60% response rates, 20-30% remission rates, lasting for 3-4 days, with a very large difference from placebo. Dissociative side effects occurred only acutely, for a few hours.
A similar study replicating the results of the above study.
ketamine 30-120 mg intranasally, used for severely symptomatic male bipolar patients, ages 6-17, every 3-7 days.  Marked symptom improvement in multiple domains, lasting 3-4 days after each dose.  side effects diminished with subsequent doses.  but still good clinical improvement.  Average of 20 weeks duration.  But this was a retrospective chart review.  Side effects such as transient dizziness etc. but no severe side effect problems.
case series of 3 patients, treated with ketamine 0.5 mg/kg IV, every 1-2 weeks or so.  These patients had long complex histories of severe treatment-refractory depressions with comorbidities & axis II problems.  Varied response, one of the patients had marked improvement, the others had some benefit but not nearly so compelling.
case series, 50-70 mg IM  ketamine q4 days for bipolar depression, marked improvement in one patient, slight improvement in another.  In these patients intranasal and/or oral ketamine did not help. 
Side effects of headache and irritability.
bipolar depressed patients with a positive family history of alcoholism had better responses to ketamine.
a couple of cases of using oral ketamine 0.5 mg/kg to successfully treat anxiety and depressive symptoms in palliative care patients. Once again, good symptom improvement lasting about about a week. This study stands out for using oral ketamine, which would be much more convenient to use for outpatients.

III. effect on other psychiatric symptoms
no improvement in OCD symptoms with IV ketamine.
no exacerbation of PTSD symptoms in patients with trauma history exposed to a ketamine dose

IV. use for treating pain disorders on an outpatient basis
a chart review showing that transdermal ketamine can be useful for treating neuropathic pain.  I include this here to show that a transdermal route is possible, and also to show evidence of safety in other areas of outpatient medicine.
another study looking at outpatient ketamine to treat chronic pain successfully. It was a 5-year retrospective study.    Here they used infusions, generally at a higher dose than the psychiatric studies (0.5-1 mg/kg), repeated every 3-4 weeks.   The treatments were successful and generally well-tolerated with no severe side effect problems.

This article (**) discusses ketamine use in palliative care, according to the authors' experience. In this population they suggest a starting oral dose of about 25 mg, up to 4 times daily, increasing if necessary to a maximum of 200 mg 4 times daily. As the first reference of my post suggests, it may be that IM ketamine is more effective than oral or nasal ketamine.
a negative study, showing that adding ketamine to high-dose opioids for pain patients was not particularly useful in the long-term, in terms of reducing long-term high-dose opioid dose requirement.
ketamine 20 mg orally twice daily, relieved neuropathic pain from MS

V. toxicity & risks
 One of the clear long-term medical risks of ketamine use is vesicopathy.  Up to 20-30% of individuals who abuse ketamine recreationally have bladder symptoms, such as urinary frequency, urgency, and dysuria (pain).
This 1-year longitudinal study shows substantial cognitive and functional impairment in heavy users of ketamine (many of whom using 20 doses per month). But there was no evidence of cognitive impairment in ketamine users who had less frequent use or lower doses.
this study found that daily 1 mg/kg doses of IV ketamine caused signs of neurotoxicity after 6 months in monkeys.  Once again, this is a dose which is 14 times higher than the proposed weekly protocol for depression!   Consider how many other helpful agents (such as vitamins, water, oxygen, protein, etc.) would be dangerously toxic if taken at a dose 14 times higher than recommended!
no cognitive deficits were found in ex-users of ketamine
In this review by Enarson (1999), he describes long-term use of oral ketamine in chronic pain patients.  3 patients out of 21 found ketamine very beneficial after over 1 year of daily use, with doses 100-240 mg per day, with improvements in pain, mood, energy, activity, and sleep.  Other patients did not like the ketamine due to short-term immediate effects, and discontinued early.  Others did not have much benefit but did not complain of side effect problems, even with over 100 mg/d for a year.  One patient was taking 500 mg/d for a year, with no side effect complaints.
case series following 4 neuropathic pain patients treated with oral ketamine 0.5 mg/kg up to 4 times per day for over 9 months.  No side effect problems or tolerance, and was effective for pain relief. 

According to Blonk et al. (2009), "Ketamine has been used in some patients for more than 1 year without observed tolerance or adverse effects associated with long-term use" (Enarson et al.,
1999; Furuhashi-Yonaha et al., 2002; Sakai et al., 2004).

V. Pharmacology (from the Monograph)**

Ketamine comes in 10, 50, or 100 mg/ mL solutions (the 100 mg/mL needs to be diluted for IV).
Parenteral use does not impair pharyngeal reflexes, therefore is safe for airway management. With IV administration, redistribution & metabolism causes duration of action of 45 minutes, and a half life of 10-15 minutes; a partially active metabolite has a half life of 2.5 hours.

There is a possible acute elevation in blood pressure with a rapid parenteral dose. Overall, it has a wide margin of safety in anesthesia.  There is respiratory depression only with rapid high-dose IV doses.

A dose of 2 mg/kg IV produces surgical anesthesia in 30 sec, lasting 5-10 minutes.  Doses of 9-13 mg/kg IM produce surgical anesthesia within 3-4 minutes, lasting 12-25 minutes. In surgery, low dose IV diazepam (under 20 mg) is used with the ketamine.

The LD50 in rats is about 20 times the equivalent human IM surgical dose.   

VI. Mode of Administration   **

Oral ketamine has about 20% the bioavailability of IV, but leads to equal bioavailability of the active metabolite.  So overall it would be conservative practice to start with the same dose orally as parenterally, and adjust (probably upwards) from there. An oral dose might need to be 3-4 times higher than a parenteral dose, to cause the same effect.  But an oral dose is likely to have an acute effect which lasts about twice as long as parenteral (approximately 4 hours of acute effects instead of 2 hours).   The qualitative difference of oral vs. parenteral effects may be due to the difference in levels of the metabolites.  The reference shown above suggest that IV doses may work better to treat mood symptoms, compared to non-parenteral dosing.   Yet, I see that this is not necessarily the case.  Some individuals may do just fine with oral dosing, so it makes sense to consider this the preferred initial mode of administration, since it is simpler, safer,  and more comfortable. 

Possible routes of administration include oral, intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (nasal spray),  transdermal (skin creams or patches), and rectal. 

Some of the questions I have about ketamine use in psychiatry are:

1) how safe or useful is it in patients with strong histories of psychotic symptoms? 

2) to what degree does the environmental setting during the dose impact its effectiveness?  I wonder if the environment in the moment might act as a catalyst for its effects.  I suspect that a very positive, peaceful, meaningful environmental setting would consolidate the experience of symptom relief much more positively than exposure to the drug without any regard to the external situation.  This would be akin, I am thinking, to temporarily relieving a physical disability (as a prelude to working towards permanent improvement) being much more effective if the resources were in place during that temporary relief, to fully enjoy and appreciate the regained function in the moment.  This is why I suspect that the recreational use of agents such as ketamine in socially desolate or agitated settings (e.g. on the street, in a marginalized or socially impoverished situation, or in noisy parties, etc.) could have an emotionally harmful effect rather than any sustained benefit. 

3) if the ketamine is effective, what is the best long-term dosing interval?  (current studies suggest every 1-4 weeks, but not enough data to be sure)   My reading of the evidence suggests weekly dosing, with diminished frequency or dose  if symptoms remain stable.  Also, what is the role of other antidepressant therapies, including other antidepressants, in patients having ketamine treatments?  (some of the articles quoted above suggest that some drugs such as benzodiazepines may reduce ketamine's effects--I wonder if this is true for other drugs such as mood stabilizers)

4) if it is effective, does it remain effective for very long-term followup (over many years).  And if there is repeated use over this time, are there emergent side effect risks not appreciated in the present short-term studies?   

5) given that this is a new and exciting area of research, should this not warrant intense widespread research scrutiny, including large multicentre trials?  A new SSRI trial may well be more easy to fund and organize, due to the present funding and political structure of the research system, but perhaps a ketamine trial would be of greater good for patients. 

6) Ketamine has been used so far only in treatment-resistant severely ill patients.  Could ketamine have a role as a first-line agent for less severe cases? 

7) Could ketamine be useful as a component of therapy for other problems (e.g. personality disorders, eating disorders, relational disorders, etc.)

8) Because part of ketamine treatment is very immediate and acute (an effect lasting hours), could there be some type of psychotherapeutic activity during this time which might optimize its effect?

So, in conclusion, a very promising new area to be researched further.   I will be curious to find out more answers to these questions. 


Anonymous said...

Thank you for the post.
I highly recommend this review if you haven't seen it yet. It's a systematic review of all available published data on the antidepressant effects of ketamine, including completed, ongoing and planned studies.

GK said...

Thanks. The article supports further research, but I find the authors quite lukewarm about data which appear far more exciting and promising to me. They are quite negatively toned even about such very simple issues such as mode of administration. I think it is completely unnecessary, for example, for ketamine to be given as an IV infusion!

Also, as is unfortunately typical and expected in a paper from Biological Psychiatry, there was no discussion of the psychotherapeutic or environmental milieu in place during administration of the ketamine (e.g. during the administration, presence of a trusted therapist, physical comfort, music, etc. rather than simply administration alone on a hospital stretcher with beeping monitors, etc.). So there was no discussion of its possible effect as a potent augmenting agent for psychotherapeutic change.
Even the best augmenting agents only work well in conjunction with something else happening at the same time.

So it is quite a limited and narrow review.

Ellen Diamond said...

I work with a Ketamine treatment clinic in AZ. As a clinical psychologist with almost 30 years experience treating mood disorders, I can honestly tell you the results of Ketamine treatment are dramatic and impressive. I would also like to respond to the questions you have posed.
1. Ketamine is generally not recommended with persons who are actively psychotic. We have utilized the treatment with people who have had limited history of psychosis, including personality disorders which often have a greater predisposition for psychosis, without difficulty or change in efficacy. That is however, something that should be monitored closely before and during treatment. Other clinics have reported episodes where people have had “bad trips”, but that has not been our experience.
2. We believe the environment plays an important support role. Beyond the setting in which the drug is administered, we utilize CBT to help structure the person’s internal environs or thought process to maximize the benefit of the infusion experience. Clearly, the drug reduces “ego boundaries”, so providing a safe, calm environment allows for the person to relax and take in both the drugs benefit and therapeutic ideas previously given.
3. Best dosing protocols are still being explored. What is generally agreed upon, is the benefit is initially short-term, with the need to reinforce (through further treatments) in a few days. Over the course of the first few treatments, effect seems to be “built up”, with gains being retained longer. Our patients receive twice weekly treatments for the first 2-3 weeks. This is followed by weekly treatments for another 2-3 weeks. For some individuals, this is all they need. Other people may require regular treatments every 3-4 weeks.
While some people may no longer feel the need to maintain any other psychiatric medications, many of our patients continue to take mood stabilizers without any lessening of ketamine benefit. Other medications, including narcotics and benzodiazepines may affect the treatment benefit.
4. Unfortunately, there is little long-term information.
5. There is a substantial amount of research. I agree a large research project would help clarify some of the questions raised. Unfortunately, this may have to be left to drug companies who are attempting to repackage the drug in a manner that will allow them to recoup their investment, and place their version of the drug on patent.
6. We have treated persons with mild depression, as well as those for whom this is a first-line treatment. Both groups benefitted from this, but the costs and the intravenous protocol is likely to make this less desirable.
7. We have treated persons suffering from concurrent PTSD, which Ketamine seems to offer some relief. We have not utilized it for treatment of impulse control disorders
8. We are utilizing psychotherapy specifically for depression with ketamine treatment. Patients report that despite having heard some of the same things before in previous therapies, they were able to absorb it in a manner that allowed them to utilize it in their daily life. Think about clinical hypnotherapy. The suggestions are not unique, but the context in which the individual receives the information allows for better utilization. We believe the same thing occurs with Ketamine assisted therapy , in addition to actual changes from the medication itself. Alleviating the burden of depression allows the individual to be able to focus on other therapeutic issues or life goals with current providers.

GK said...

Thanks a lot! What a great informative comment!

I find that oral dosing is simple and convenient for the patient and for office setup. But I am planning to explore the possibility of IM dosing as possibly more effective for some people.

Ellen Diamond said...

At Depression Recovery Centers in Scottsdale, AZ we have experimented with intranasal, IM, and oral dosing. I agree IV is less convenient for patients and most office practices, but we found the results far surpass other administrations. Some of our patients had unwanted side effects such as loss of smell (temporary) with intranasal, and others just did not receive the same benefit as they had with IV.

Anonymous said...

Looking forward to another blog post on another topic. I enjoy your blog

GK said...

I'm hoping to add some more posts before the end of 2013.