Latest on Ketamine

(R,S)-ketamine

Ketamine has been prominent in the psychiatric literature and conferences for the past decade as a potential agent for both treatment resistant depression and a rapid antidepressant response.  In some communities ketamine infusion clinics are available where patient can go for a weekly infusion to maintain depression either in remission or a partial response.  At a cultural level, besides being a dissociative agent for anesthesia, ketamine is also in the collection of drugs known as club drugs and as such it is abusable.  Ketamine is not among the most commonly abused drugs.  The NSDUH survey puts lifetime abuse at about 1%.  In a practice of addiction psychiatry it is less likely to be used than LSD and much less likely to be used than dextromethorphan.  It may be one of many drugs used by polysubstance users at some point in their usage history.  Ketamine is also classified as a psychedelic drug or a drug that can cause hallucinogenic or dissociative experiences.  From the time their use was popularized there was a belief that these experiences could be potentially beneficial from the standpoint of personal growth and creativity, as an agent to enhance psychotherapy, or in some cases as an agent to treat psychiatric problems like alcoholism and depression.  Ketamine is currently a Schedule III non-narcotic drug on the DEA List of Controlled Substances.  My first professional exposure to the pharmacology of ketamine occurred in basic science courses in medical school in about 1983.  It was taught as part of the pharmacology of anesthesia agents.  It was taught as not being a first line drug at that point because of the side effects of dissociation and anesthesia.  Like most old medications there has been a recent revival of interest for rapid sedation of patients in emergency department settings.  In the linked report it had a more rapid onset of action than the usual agents, but also a significantly higher complication rate.

Alan Schatzberg, MD gave a presentation on ketamine at the University of Wisconsin Annual Update and Advances in Psychiatry in October 2013.  He presented data to show that the effects of intravenous ketamine were acute but not sustained.  Depressed unipolar subjects noticed the antidepressant effects within a few hours and they lasted about one week before returning to baseline depression scores on a standard Hamilton Depression Rating Scale.  In bipolar depression the effects last about 12 days.  He presented the results of an NIMH trial of ketamine in treatment resistant depression.  It was a small multisite trial that compared ketamine (N=47) to midazolam (N=25) as an active placebo.  The primary outcome measure was remission of depressive symptoms at 25 hours and the rates were 63.8% for ketamine versus 28% for midazolam.  Dizziness, blurred vision, nausea/vomiting, headache, and palpitations were the most common side effects acutely and at 24 hours.  There were no episodes of psychosis.  Longer term strategies were presented that might sustain the acute ketamine response including an oral form, repeated infusions, memantine, riluzole, lamotrigine, high dose d-cycloserine, and several new oral agents that were antagonists or partial allosteric modulators of the glutamate receptor, or partial agonist of the NMDA receptor glycine site.  Response to ketamine infusion at 2 hours was shown to be predictive of response and there was a 70% chance of relapse after repeated infusion but this sensitization did not occur at 2 week intervals.  Despite these limitations on therapy there is  Ketamine Advocacy Network that includes a quote about the coming ketamine today tidal wave and a page with this very dim view of psychiatric practice and the intellectual interests of the average or most (?) psychiatrists.  It is not clear to me who writes their pages or who their medical consultants are.

Barry Rittberg, MD gave a presentation at the Minnesota Psychiatric Society in May 2014 and reviewed the science, clinical trial data, and local protocols for ketamine infusions in Minnesota.  The major problems were short term benefit, unknown long term risk,  inability to drive that day,  psychotomimetic effects, and the 3-4 hour time commitment for the infusion.  The protocol discussed involved a 40 minute infusion with monitoring blood pressure, pulse and oxygen saturations every 15 minutes.  Treatments were given 3 days a week for three weeks.  In addition, insurance companies did not cover the treatment (and still don't).  The treatment is not FDA approved and therefore considered experimental by insurance companies.  

The main emphasis of research studies on ketamine and other agents is the potential importance of the glutamatergic system in the treatment of depression.  It also has a purported role in schizophrenia.  There was a good review in an excellent journal Clinical Pharmacokinetics that suggested the (S)-ketamine had a more favorable side effect profile than the racemate.  It was with that backdrop of information that I honed in on this article that popped up on my Facebook feed.  After the first few pages I knew that I was not going to be disappointed.

The authors of a Nature article (1) review the information in the above paragraphs as a rationale for their research and rapidly describe their series of experiments.  The animal research done in this paper is all rodent research to test the potential antidepressant, self-administration, drug discrimination, chronic corticosterone induced anhedonia, and motor coordination effects effects of various glutamatergic compounds.  All of these paradigms and much more are detailed in the supplementary and methods section of the online paper.  Tissue distribution and clearance of ketamine and metabolites was determined in both plasma and brain at 10, 30, 60, and 240 minutes post ketamine administration.

In the first set of experiments, the researchers showed that (R)-ketamine had greater antidepressant potency in three antidepressant predictive tasks - the mouse forced swim test (FST), the novelty-suppressed feeding task (NSF) and the learned helplessness task.  They also showed that this was not due to higher brain levels (R)-ketamine versus (S)-ketamine.  The NMDAR antagonist MK-801 was also shown to not exert the same effects as ketamine, suggesting that the mechanism was more complex than inhibition.  The most interesting part of this paper was the examination of ketamine metabolites and their potency as potential antidepressants.  Ketamine is metabolized by CYP3A and CYP2B6 hepatic enzymes mostly to norketamine, but a number of transformations including dehydrogenation, and hydroxylation to a broad array of metabolites as shown in the authors' graphic below (click on the graphic for a more readable version).

The HNK (hydroxynorketamine) metabolites are the major metabolites found in the plasma and brains of mice after ketamine administration and the plasma of humans.  When greater antidepressant effects were noted in female mice, it was determined that the levels of (2S,2S;2R,6R)-HNK were three times higher in females than males.  In order to confirm that this metabolite was the most potent, a deuterated form of ketamine was synthesized.  The deuteration significantly slowed the metabolism of the parent compound and the antidepressant effects were eliminated largely by blocking the formation of  (2S,2S;2R,6R)-HNK.  The (2R,6R)-HNK derived from (R)-ketamine was subsequently determined to be the most potent metabolite (as highlighted in the above metabolic map).

The authors went on to confirm that (2R,6R)-HNK increased glutamatergic signalling in a number of paradigms.  They also demonstrated that administration led to expected changes in AMPARS (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors).  Drug discrimination and self-administration tests showed no tendency for self-administration with the (2R,6R)-HNK as opposed to ketamine.  In the same experiments ketamine was self administered and increased amounts were taken.   The (2R,6R)-HNK metabolite also did not cause motor incoordination or increased locomotion like ketamine did.

The implications of this paper are far reaching in terms of possible therapeutic agents.  It clarifies that the molecule involved in treating depression may be a significantly different structure than ketamine.  Second, that structure seems to have none of the side effects of the parent compound in animal models.  This paper also has implications for human research.  A search on HNK in the medical literature shows no evidence that it has ever been administered to humans.  A search on ClinicalTrials.gov shows no current research with the compound.  People are receiving infusions of ketamine for both chronic pain and chronic depression.  The infusions are done in clinics where patients need to monitored closely largely because of the side effects of ketamine.  The research done in this paper suggests that the administration of the active metabolite of ketamine may open the door for a less invasive and time intensive treatment for chronic depression.  I liked the idea that this paper discussed the relevant chemistry and pharmacology - undergraduate and medical school knowledge that is still relevant.  I also liked the idea that it potentially demystifies a hallucinogenic drug.  I have seen the newspaper headlines: "Club drugs to treat your depression."  I doubt that they will be replaced by: "(2R,6R)-HNK to treat your depression" anytime soon.

But the nullification of another urban drug legend is always a positive from my perspective.


George Dawson, MD, DFAPA      



References:

1: Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016 May 4. doi: 10.1038/nature17998. [Epub ahead of print] PubMed PMID:27144355.

2: Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet. 2016 Mar 30. [Epub ahead of print] Review. PubMed PMID: 27028535.

Supplementary:

1:  The figure labelled Extended Data Figure 1 is from reference number 1 (above) and is used with permission from the Nature Publishing Group - license number 3863110054693 obtained on May 6, 2016.

2:  Shortly after writing this post I came across this reference suggesting the postsynaptic signalling mechanism responsible for the "ketamine" effect.  I have not read the article yet since it is not open access, but if they were really using ketamine to induce the effect it would be more interesting if they compared (2R,6R)-HNK to ketamine and other metabolites in this model.  It could provide confirmatory data on whether (2R,6R)-HNK is in fact the active metabolite.

Harraz MM, Tyagi R, Cortés P, Snyder SH. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry. 2016 Mar;21(3):313-9. doi: 10.1038/mp.2015.211. Epub 2016 Jan 19. PubMed PMID: 26782056.

The Myth of "Rescue" Medications

First off a clarification.  I am talking about the specific case where a short acting medication is added to a long acting form of the same medication and not "as needed" medication in order to determine the correct daily dosage.   In my line of work it occurs in two situations, long acting stimulants and their immediate release versions and long acting opioids and their immediate release versions.  I will illustrate that these practices are driven by myths about the medication rather than pharmacokinetics.  There is always the additional consideration about addiction lurking in the background, but the conscious and unconscious determinants of addiction frequently depend on the myths that I will be discussing about medication effects.

The example that I will use here is Concerta (long acting methylphenidate) compared with immediate release methylphenidate.  The graph from the package insert above shows the plasma concentration from a single 18 mg dose of Concerta and three successive 5 mg doses of immediate release methylphenidate.  As noted in the comparison of the curves and additional pharmacokinetic parameters the curve associated with three successive doses of immediate release methylphenidate is nearly identically replicated by a single dose of Concerta.

What is happening when additional doses of a immediate release methylphenidate are prescribed to a person who is already taking Concerta?  I  have seen this happen with sustained release stimulants and sustained release opioids.  I have seen it happen as a single dose of the immediate release preparation or multiple doses over the course of the day.  The patient is usually advised that this is a "rescue" medication that they should take if needed.  The first possibility is that the dose of sustained release medication has not been optimized and a higher dose of the sustained release medication needs to be given.  That is usually not the case.  The most frequent reason for taking the rescue medication is that the patient believes they are experiencing breakthrough symptoms and for a moment they need a higher dose of a medication.  There are serious problems with that concept.  As can be seen from the curves comparing Concerta and methylphenidate it does not make pharmacokinetic sense.  Any additional dose of immediate release methylphenidate on top of Concerta would greatly increase the expected plasma concentration at that point.

The main problem is that both ADHD and non-cancer pain are chronic conditions.  By definition they do not respond well to medications and they will not resolve typically with any amount of the medication.  Many people who take stimulants for ADHD assume that the human brain can be fine tuned with a medication.  There is also a widespread myth that they are cognitive performance enhancing drugs.  The real effects of stimulants are modest at best and there is no good research evidence to support a cognitive enhancing effect.  A similar bias exists for the use of opioids for chronic non-cancer pain.  The person believes that "If I take enough of this medication - my pain will be gone."  Study after study of opioids for chronic non-cancer pain shows that pain relief with opioids is modest at best, with results very similar to what would be expected with non-opioid medications like gabapentin and antidepressants.

There are secondary problems with believing a medication will produce perfect cognition or perfect pain relief.  The first is a tendency to see any medication with such powerful abilities as being able to solve a number of problems that are not the primary indication for the medication.  As an example, with a stimulant - if this medication has such a profound effect on my cognition maybe it can help with with other difficult problems like excessive appetite and weight problems or feeling like I don't have enough energy at certain times during the day.  With the opioid the  thought typically is that it can be used for mental pain as well as physical pain and it is used to treat anxiety, depression, and insomnia.  Whenever a medication is not used strictly for the prescribed indication there is a risk that it will be used for "what ails you."  The danger is dose escalation and addiction.  There is also the risk of attributing too much of an effect to the medication when it does not appear to be doing much.  A person may start to believe that they can't function without the medication but a detailed review of their target symptoms and ability to function shows that there has been a negligible effect.  And finally there is the danger of taking a medication that may produce euphoria, increased energy, and create a sense of well being and not realizing that at some point that is the only reason the medication is being taken.  I have had many people tell me that the medicine did nothing for their pain or cognition but that they kept getting refills because they "liked taking it."

There is what I call the Talisman effect, but probably to a lesser extent than with benzodiazepines.  Many people develop the idea that they are taking a medication that is much more effective than it really is and therefore they have to take it with them wherever they go.  They are conferring what are essentially magical properties to the medication and at some level thinking that they are unable to function in life without it.  They get anxious if they think about not having it or running out.  This not only causes a lot of unnecessary anxiety, but it also prevents the person from using other psychological or conditioning techniques that may work as well or much better than the medication.

These are some of the problems with the idea of taking a rescue medication if you are already on a long-acting form of the medicine.  Physicians in general do not do a good job of explaining these potential problems or even the basic problem of taking a medication that causes euphoria or reinforces its own use.  A more widespread recognition of these problems would go a long way toward curbing overprescription, overuse, and addiction to these medications.    

        

George Dawson, MD, DFAPA

References:

1.  Graph of plasma concentrations of Concerta and methylphenidate is from the package insert on FDA web site at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021121s014lbl.pdf