Research conducted in the past few years shows that ketamine leads to a
rapid antidepressant effect within hours of administration. A recent study has
demonstrated how this mood change translates into a tangible protection
against suicidal ideation in treatment-resistant patients with depression (see
Ketamine Leaves BDNF Unchanged for more on ketamine treatment).
Ketamine is an anesthetic given intravenously that is often used in surgery
and in veterinary medicine. It is known to cause psychosis and has raised
abuse concerns.
FIG1
In a paper published in the September 1 Biological Psychiatry,
researchers at Mount Sinai School of Medicine, Rutgers University, and Harvard
University conducted two clinical studies in which they assessed suicidal
ideation in patients with treatment-resistant depression. The study was funded
by the National Institutes of
Health.
Twenty-six patients participated in the first study, in which each received
a single infusion of ketamine at a dose of 0.5 mg/kg and was then kept in the
hospital for 28 hours. Outcomes were measured 24 hours after the infusion
using the single suicide-related item in the Montgomery-Asberg Depression
Rating Scale (MADRS-SI). Scores ranged from 0 to 6, with a score of 6
indicating "explicit plans for suicide when there is an
opportunity" or "active preparations for suicide."
Subjects' mean score on the MADRS-SI scale decreased from 2.85 before the
ketamine infusion to 0.77 at 24 hours after the infusion, which was
statistically significant. Before the infusion, 13 patients had a score of 4
or above on the scale. Twenty-four hours after the infusion, eight of the 13
patients had a score of 0 or 1 and three had a score of 2 or 3; two remained
at or above a score of 4.
Ten of the 26 patients also completed the Implicit Association Test, a
behavioral-assessment instrument the researchers used to measure the implicit
suicidal intention before and after the infusion. The implicit and explicit
suicidal association scores also decreased significantly after the ketamine
infusion.
Ten of the patients who had been deemed responders in the first study
participated in the second study and received repeated ketamine infusions
three times a week in a period of 12 days for up to six infusions. Their
average MADRS-SI score was 3.0 at baseline. Nine patients scored 0 on the
MADRS-SI scale after every repeated infusion. One patient had a score of 2
after the first infusion (baseline score 4). The patient was dropped from
further infusion because of lack of response in overall depressive symptoms,
defined as at least 50 percent reduction in MADRS total score.
The effect of ketamine on suicidal ideation was likely an indirect result
of the antidepressant effect of the drug, the authors concluded after they
analyzed the correlation between the total score of the nonsuicide-related
items in the MADRS and the suicide-related item score. The 26 patients in the
single-dose study had an average preinfusion MADRS total score of 37 (scale
range 0-60), which decreased to 15 at 24 hours after the infusion. Seventeen
of these patients had a 50 percent reduction in MADRS total score.
All study participants had moderate to severe depression as indicated by an
Inventory of Depression Symptomatology score of 32 or above at baseline and
had failed at least two adequate antidepressant trials in the current
depressive episode. They had been suffering from major depressive disorder for
a mean of 29 years. All had been in the current depressive episode for at
least two years and failed an average of six antidepressants in the current
episode. Five of the 26 participants had a history of suicide attempts.
No patient experienced hallucinations during the studies, Rebecca Price,
M.S., a Ph.D. candidate in psychology at Rutgers University and the lead
author of the article, told Psychiatric News. The psychotomimetic
side effects observed in the studies were "minimal" at this low
dose of ketamine, she said, and additional results and analyses are pending
publication.
The rapid antidepressant effect of ketamine infusion has previously been
reported in small clinical trials conducted by researchers at the Mood and
Anxiety Disorders Program at the National Institute of Mental Health (NIMH).
The NIMH researchers also demonstrated that ketamine's mechanism of action may
lie in its antagonism of the NMDA (N-methyl d-aspartate) receptors and
subsequent activation of the AMPA (amino-3-hydroxy-5
methylisoxazole-4-propionic acid) receptors; both are biologically activated
by the neurotransmitter glutamate (Psychiatric News, September 7,
2007).
An abstract of "Effects of Intravenous Ketamine on Explicit
and Implicit Measures of Suicidality in Treatment-Resistant Depression"
is posted at<www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223(09)00519-8/abstract>.▪