Thursday, November 21, 2013

Oral Ketamine for Depression and Anxiety in Hospice

by: Alex Smith, @alexsmithMD

Journal of Palliative Medicine recently published a nice exploratory open label study of daily oral ketamine for depression and anxiety in hospice patients.  We discussed this paper in our last palliative care fellow's journal club, with the esteemed fellow Dr. Virginia Dzul-Church presiding.

I won't regurgitate the whole article - although Eric Widera just pointed out that one of the take home points of discussing this article is the importance of actually reading the article.  In brief, the wonderful Dr. Scott Irwin recruited 14 hospice patients with depression and anxiety and treated them with 0.5mg/kg of ketamine by mouth daily.  He found a significant reduction in both anxiety (starting at day 3) and depressive symptoms (starting at day 14) with few adverse side effects.

Sounds great, right?

Some points to consider:

  • No placebo.  Without a placebo we can't tell how well this drug would have performed above and beyond the placebo effect.  SSRI antidepressants are effective something like 45% of the time.  Placebo is effective something like 30% of the time.  So you're really talking about a small additional benefit,  ~15%, from the active ingredients.
  • Regression to the mean.  Symptoms have a normal variation.  Depression gets worse, depression gets better.  When do we tend to start medications on patients?  Or notice that they have severe symptoms and consider them for a trial?  When they have severe depression.  And yet, just due to the natural variation in symptoms, we would expect depressive symptoms to decrease over time.    Voila!  It appears the treatment worked.  But by doing nothing, the symptoms would likely have improved.
  • Intention to treat.  The above impressive results on depression and anxiety were for the 8 out of 14 subjects who completed the study.  What happened to the other 6?  4 withdrew after day 14 due to lack of response, and two withdrew due to changes in condition unrelated to the medication (that happens in hospice!).  But if you include the subjects you intended to treat, the results would be much less impressive.
All that said, consider - you have a hospice patient.  The patient is depressed and anxious, and has a short time to live.  You've tried methylphenidate, it didn't work.  Raise your hand if you'd consider trying oral ketamine?

My hand is going up.  

Why?  We don't have many good options for treatment of depression and anxiety on a short time frame.  SSRI's take weeks to work.  IV ketamine has been shown to work for depression but IV isn't great for the hospice setting.  When used for pain, oral ketamine at these doses has relatively few side effects.  And then we have this flawed data suggesting it might work, and isn't too harmful.  

What would you do?

5 comments:

Anonymous said...

If I were the patient's caregiver, I would request my loved one be given oral ketamine. If I were the patient, I would ask my medical staff to give me the oral ketamine. Hospice is known for compassion and helping people control pain. Anxiety and depression are mental pains that are far reaching regarding one's quality of life. I wholeheartedly give a thumbs up to using this medication.

Bruce Scott said...

I've been itching to give it a go.

I've used subanesthetic dose IV ketamine for treatment of complex regional pain syndrome with very good results. I've used it with mixed results in cancer pain with very high opioid requirements. I've just about got my ducks in a row to start using it in a few patients with sickle cell disease who tend to have extended hospitalizations with their vaso-occlusive crises.

The time I looked at trying to get PO ketamine compounded for me, the price was astonishing. (The Twycross 2nd Ed Hospice and Palliative Care Formulary USA and the San Diego Hospice folks before the fall both suggested that the price should not be so bad.) Nobody wanted to allow for the idea that a patient could mix their own solution up (which is actually what HPCFUSA and SD Hospice recommended), so I dropped it.

I've got two nursing home patients that I've been pondering using it in. Both with chronic pain on large opioid doses (one with suspicion for OIH), both with significant psych issues that I've not been able to get on top of (and are likely exacerbating the pain). I've started to ask around to see if it would be permissible to RX oral ketamine.

Paul McIntyre said...

I think its a stretch to say "iv ketamine has been shown to work for depression", based on single dose studies. I'd also add selection bias & confounders to the critique of this article. Dr. Irwin stresses that this was a proof of concept study now requiring RCT or other methodological approaches, etc. So, no, I am not going to prescribe ketamine for depression. Compassion and good science are not mutually exclusive - quite the contrary. Paul McIntyre, Halifax, NS

Bruce Scott said...

Paul McIntyre expresses concern about whether or not we should really say "IV ketamine has been shown to work for depression".

Is this the trial in question?
http://www.ncbi.nlm.nih.gov/pubmed/23982301

I'd agree with the provisional withholding of opinion that it works if you are doing it based on the study being unreplicated or based on the study having design issues.

It had an "active" placebo control, which I'm not sure is ideal. It is midazolam. I'm not sure whether we should consider this to be blinded from a patient's perspective.

However, the NNT is <3, which is quite robust, and much better than our NNTs for oral agents. Half relapsed a week later. The study isn't so poorly designed that accepted it as a basis for doing your own N-of-1 interventions should be considered cowboy medicine. You might not want to be an early adopter, but I think there is enough initial evidence that use isn't inappropriate.

It may depend on how much access you have to psychiatry specialty care. my access is limited regionally. The specialists I have access to DON'T want to see my palliative care patients (heaven forfend they would ever consider seeing a *gasp* hospice patient). I don't have anybody within 30 miles doing ECTs. The state doesn't like my prescribing pscyhostimulants for depression. It might be wishful thinking (or the cult of the new), but I'm really considering trying use of this agent.

Eric Widera said...

Bruce,

They used an active control in that study because in a previous study in 2006 a major limitation was the individuals knew that they were getting ketamine versus the saline control:

http://www.ncbi.nlm.nih.gov/pubmed/16894061

I also personally like the following review of ketamine for depression:

Biol Psychiatry. 2012 October 1; 72(7): 537–547. doi:10.1016/j.biopsych.2012.05.003.

Eric