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. 

Monday, June 3, 2013

Omega 3 update

Here is an update about omega-3 supplementation:

For a bit of background on omega-3 supplementation, see my other posts about this:

A meta-analysis from 2012 and some ensuing discussion has led to a few more recommendations (see

1) acute beneficial effects for mood may be present only for more severe symptoms.  However, I am curious about the preventative effects from continuous supplementation over a period of years; the data does not give us a clear answer about this yet. 

2) the EPA dose may need to be as high as 4 grams per day, certainly much higher than the 1 gram per day range frequently used in some of the studies. 

Risk factors for psychotic relapse

Alvarez-Jimenez et al. have done a good meta-analysis looking at risk factors for relapse of psychotic symptoms, published in Schizophrenia Research (2012;139-116-128).

The authors conclude that there are four major factors associated with increased risk of relapse in schizophrenia and other psychotic disorders:

1) non-compliance with meds (increases risk x4)
2) substance use (increases risk x3)
3) criticism from caregivers (increases risk x2.3) -- conversely better social support is associated with reduced risk of relapse
4) poorer premorbid adjustment (increased risk x2.2)

Interestingly, the authors conclude that factors such as diagnosis, length of illness, length of untreated symptoms, demographic variables, and cognitive function, are not associated with relapse risk.

Clearly, these findings add to the recommendations for helping patients who have had psychotic symptoms, and their families:
1) medication compliance is extremely important!
2) substance use must be avoided!
3) caregivers must work hard to avoid hostile or critical comments towards the patient

One question I have about these findings, however, is how causative some of these factors are.  It could be argued that an individual who is already more likely to relapse may be more likely to be non-compliant with medication, be more likely to engage in substance use, and may be more likely to behave in a way which elicits more criticism from other people.  The existence of these "risk factors" may indicate that the underlying disorder was more severe.  So, some or all of these risk factors may simply be non-causal associations.

In order to more definitively show that risk factors #1-#3 are causative (and therefore controllable or reversable), we would have to show evidence that externally improving medication compliance in a previously non-compliant person would clearly reduce relapse rate.  And we would need to show that a change in caregiver environment would produce a change in subsequent relapse rate. 

There is some such evidence, but I think it would be good to see a careful meta-analysis looking at risk-factor management in reducing relapse rate. 

Another thought I have about these findings is that the recommendations are appropriate not just for people who have had psychotic symptoms, but for all psychiatric conditions, and even for all members of the whole population!  That is, avoidance of substance abuse and having good social support with minimal hostility and criticism is probably good and protective for everybody's mental and physical health!   But we would have to look further at the research to see if this thought of mine has been proven.