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.

Psychiatry - Science and Pseudoscience

I finished the first chapter in Philosophy of Pseudoscience: Reconsidering the Demarcation Problem by Pigliucci and Boudry.  I became aware of Massimo Pigliucci and his work back in 2002 when I read his book on Intelligent Design and since then have discovered his blog Rationally Speaking where he has recently posted his best papers from his careers as a scientist and a philosopher.  He writes very clearly on the philosophy of science and has such a command of the field that he can include a history lesson of relevant references.  He also does not shy away from controversy or the apparent lack of a clean solution to a problem.  One of the central concepts in his chapter is this chart of empirical knowledge versus theoretical understanding. (click to enlarge)

The purpose of this essay is to look at possible boundaries between science and pseudoscience as well as a couple of interesting observations as they apply to psychiatry.  One of his key concepts is that the lines of demarcation are not necessarily sharp and the variables are not necessarily linear.  He uses the above graph of empirical knowledge versus theoretical understanding as an example.   Starting in the upper right corner of the diagram we have hard sciences with particle physics given as the most clear cut hard science.  I like to think about my undergraduate chemistry experience as being hard science.  Even introductory chemistry exposes the student to an amazing array of facts, observations, and theories that are incredibly accurate.  From there, chemistry majors build on their ability to measure specific compounds, synthesize them and study the theory in Physical Chemistry.   I don't think that there is any doubt that chemistry as a field is not too far removed from particle physics in terms of empirical knowledge or theoretical understanding.  String physics has much theory but is low in terms of empirical support.  He refers to evolutionary psychology,  scientific history and Search for Extraterrestrial Intelligence (SETI) as a "proto-quasi science" cluster with decreased amounts of theory and empirical support.  Other fields like the so-called "soft sciences" of sociology, economics, and psychology have a fair amount of empirical knowledge but less theoretical understanding.  The true pseudosciences are in the zone with astrology, HIV denialism, and Intelligent Design.  From the history of psychiatry - Freudian psychoanalysis and Adlerian psychology would also be included here but there is also a list of theories from general medicine and surgery that would also qualify.

In psychology and psychiatry a central philosophical problem is the so-called hard problem or the explanatory gap between the neurobiology of conscious states and subjective experience.  This is exactly where psychiatry resides.  A lot of political criticism of psychiatry involves the ability to parse these states and accurately classify different conscious states.  Resolving the hard problem would move psychiatry and psychology firmly to the right in the demarcation diagram but probably not nearly as far as particle physics or maybe not even as far as molecular biology.

The relevant question for me of course is where psychiatry fits on the plane of empirical knowledge x theoretical understanding.  What about medicine in general?  Could we plot a plane of medical and surgical sub specialties on this plane instead of the hard and soft sciences?  Does medicine and surgery have theories or practices end up in the same zone as Freudian psychoanalysis.  Of course they do.  A great example from my days as a medicine intern was highlighted by Ghaemi as "The cult of the Swan-Ganz catheter."  In the places where I trained, anyone with moderately serious cardiopulmonary problems was at risk for placement of a Swan-Ganz catheter.  The actual person inserting the catheter could be a medicine resident, a cardiologist, or an anesthesiologist.  Since the intern is responsible for doing the initial history and physical exam, I witnessed the placement of a large number of these catheters.  Once placed they gave an impressive number of parameters on ICU monitors.  We were routinely grilled about the meaning of these parameters by attending physicians on rounds.  It all seemed very scientific.  The cult of the Swan-Ganz catheter was subsequently disproved by randomized clinical trials.  This standard of care from the 1980s and 1990s disappeared much faster than Freud.

The best way to plot medicine and psychiatry on Pigliucci's empirical knowledge versus theoretical understanding plane would be to consider the clinical basic sciences taught in the first two years of medical school.  In my experience that was anatomy, neuroanatomy, histology, microbiology, biochemistry/molecular biology, genetics, pathology, physiology, pharmacology, epidemiology, and statistics.  Practically all clinical specialties carry these basic sciences forward in one form or another.  The research literature in any particular specialty in full of theory and techniques from these basic sciences.  The psychiatric literature cuts across all of the basic sciences in the same way as other specialties.  At the minimum, some of psychiatry will be at the level of molecular biology on the diagram in some areas and at the level of psychology in others.  Hopefully the unscientific theories will be relegated to the lower left hand corner of the diagram as unscientific and not stand the test of time.

I think that Professor Pigliucci's conceptualization is a very useful one.  I expect that he will continue to refine these ideas.  I think that measurement precision and categorization may be important dimensions to add to these concepts.  As Merskey has pointed out both the phone book and the periodic table are much more accurate forms of categorization than any scheme of medical classification.  I think that probably says a lot about the underlying scientific dimensions and how measurement is done.


George Dawson, MD, DFAPA

Ghaemi SN.  A Clinician's Guide to Statistics and Epidemiology in Mental Health.  (2009) Cambridge University Press, Cambridge, UK.  p. 91.