Tuesday, 13 November 2012

An interesting article: Ketamine and depression

A few days ago, I came across an article published on YaleNews, regarding new evidence on how the drug ketamine may be used to alleviate the symptoms of depression in treatment-resistant patients. In this article, it was reported that small doses of ketamine may produce an immediate, albeit temporary, relief of symptoms of severe depression. Indeed, though the effect ketamine has on the symptoms of depression has been known for some time, the exact mechanism has allegedly eluded scientists until now.

Before delving into the proposed mechanism, it may be useful to first look at the drug itself. Ketamine is an general anaesthetic, and in combination with other sedatives, may be used to induce and maintain general anaesthesia. It is chemically related to other drugs with similar structures, namely tiletamine and phencyclidine, and as such is considered to be a dissociative anaesthetic. It has also found use in veterinary medicine, for inducing general anaesthesia in animals.

Oh ketamine, you crazy anaesthetic! Humans, animals, what won't you sedate?

As with many drugs prescribed for use in a medical setting, recreational use of ketamine is not unheard of. Since ketamine is used for anaesthesia, recreational doses are typically in the sub-anaesthetic range. The effects at this particular dose resemble two other well-known dissociatives, phencyclidine and dextromethorphan. As a recreational drug, ketamine is considered to have a short half-life, and acts as a hallucinogen.

Of particular note is that ketamine, like the related compounds mentioned above, can produce what is known as a "dissociative state", whereby an individual experiences a sense of depersonalisation. To put it more plainly, the user may experience a strong detachment from physical reality. Higher doses may cause users to experience an effect known as a "K-hole". This is where the degree of dissociation from reality becomes so severe, that the effects are considered to mimic catatonic schizophrenia, near-death experiences and out-of-body experiences.

Crystals of ketamine on a glass slide. Pretty.
(Photo courtesy of Wikipedia)

As I was reading about ketamine, and in particular, recreational use of this cute little chemical, I was surprised to find that Richard Feynman, an American theoretical physicist of some note, explored the use of marijuana and ketamine to study the nature of consciousness. Indeed, in his semi-autobiographical book "Surely You're Joking, Mr. Feynman!", he describes his experimentation with ketamine. After being given 10% of a normal dose, thereby avoiding induction of anaesthesia, the following effects are described:

"I got this strange kind of feeling which I've never been able to figure out whenever I tried to characterize what the effect was. For instance, the drug had quite an effect on my vision; I felt I couldn't see clearly. But when I'd look hard at something, it would be OK."
... 
"Although I had a feeling of complete disorientation, a feeling of an inability to do practically anything, I never found a specific thing that I couldn't do."

Certainly an interesting bit of information, though it is perhaps best if we depart this tangent and get back to the purpose for this post. The article published on YaleNews indicates that current evidence suggests that ketamine may, in fact, regenerate the synaptic connections between brain cells. This is interesting, as it is these connections that may be damaged by stress and psychological conditions such as depression. The specific mechanism which has been proposed is that administration of ketamine results in the release of the neurotransmitter glutamate, which is responsible for stimulating the growth of the connection between synapses.

The review article, co-authored by Yale professors Ronald Duman and George K. Aghajanian is titled "Synaptic Dysfunction in Depression: Potential Therapeutic Targets", is honest with regards to the efficacy of ketamine in the treatment of depression. As previously stated, ketamine may produce an immediate improvement in the symptoms associated with depression. However, in the YaleNews article, author Bill Hathaway notes that:

"The improvement in symptoms, which are evident just hours after ketamine is administered, lasts only a week to 10 days"

Though this recent article Duman and  Aghajanian does highlight specific limitations regarding the use of ketamine in the treatment of treatment-resistant depression, knowledge of the specific mechanism by which symptoms of depression are alleviated provides a viable avenue for future research into this field.

The short-term cessation of symptoms associated with depression reported by Duman and Aghajanian has been described in literature previously. Indeed, another article, published in the Journal of Biological Psychiatry, and authored by James Murrough et. al., describes a similar issue with the short-term effect of ketamine with regards to depression. In particular:

"[Though] ketamine was associated with a rapid antidepressant effect in TRD (Treatment-Resistant Depression)... future controlled studies will be required to identify strategies to maintain an antidepressant response amongst patients..."

In addition, the work of aan het Rot, et. al., studies the effect of sub-anaesthetic intramuscular doses of ketamine in relation to the treatment of depression and the side effects encountered. It was found that the administration of ketamine at the dose range reported in this article elicited minimal psychotic symptoms, as well as "significant but transient dissociative symptoms". This result is interesting, as aside from using the mechanism of ketamine in treating depression to explore alternate chemical treatments for depression, it may well be possible, if not practicable, to manage the symptoms of treatment-resistant depression with repeated infusions of ketamine over regular periods of time.

In case all this talk of depression was depressing, here's a... oh...

Another potentially interesting avenue of research regarding the use of ketamine in the treatment of psychological conditions comes a letter to the editor in the American Journal of Psychiatry. In this letter, Cusin et. al., describe two cases where ketamine was used to successfully treat Treatment-Resistant Bipolar II depression. In a slight parallel to the research of Duman and Aghajanian, it was found that the cessation of symptoms was temporary, though it was found that repeated doses of ketamine every few days allowed for a potential long-term treatment for this specific condition. It should be noted that this treatment was not without its problems. Several negative side-effects were reported, and included headaches, irritability, nightmares and mild dissociative states.

On that note, it may be prudent to note that though ketamine has a history of both medical and recreational use, some care should be taken with regards to novel therapeutic applications. Aside from a range of short-term side effects associated with the use and abuse of ketamine, other negative long-term effects have also been reported. Olney's lesions, associated with the long-term use of drugs like ketamine and phenylcylidine, are cytotoxic variations in brain structure that were discovered in rat models. However, the relationship between use of dissociatives and formation of these lesions is controversial, as no causal relationship has been found in the human model.

So there you have it. Recent work by Duman and Aghajanian has provided some new insights into the mechanism by which ketamine may treat the symptoms of depression. Though some limitations have been noted, this provides a new avenue for research into the treatment of depression and ailments.

Until next time,
Nathan

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