Efficacy of ketamine on acute suicidality, a multicenter double blind randomized placebo-controlled trial
(Ketamine Trial Amsterdam, KETA)

Suicide is currently one of the three leading causes of death in the
Netherlands in people aged 15-44 and has a substantial impact on families and
society. Nevertheless, to date no evidence based pharmacological intervention
for acute suicidality exists. Subanaesthetic doses of intravenous ketamine have
been shown to immediately resolve depressive symptoms and suicidal ideation in
depressed patients. However, this effect was never investigated for suicidality
per se. Herewith, we propose a double blind randomized placebo controlled trial
in 144 patients presenting with acute suicidality regardless of the underlying
diagnosis, to test the hypothesis that a single dose of 75mg intranasal
ketamine is able to diminish acute suicidal ideation. Additionally, we will
examine ketamine*s anti-suicidal mechanism of action by measuring plasma and
neuroimaging markers. This study may result into a readily available and easily
applicable intervention for the treatment of acute suicidality.

The aim of this study is to find a directly applicable intervention for acutely
suicidal patients, so that the risk of these patients committing suicide is
substantially lowered, leading to fewer actual suicides. To this end we propose
a randomized placebo controlled trial in 144 subjects presenting with acute
suicidality in two university hospitals, regardless of the underlying
diagnoses. Subjects will be randomized to receive either intranasal (i.n.)
racemic ketamine or midazolam as an active placebo with comparable dissociative
and sedating effects.

Our primary objective is to investigate if a single administration of75 mg
intranasal ketamine will diminish suicidality more than 3.8 mg intranasal
midazolam, as measured on the Beck Scale for Suicide Ideation (BSSI) after 180
minutes. We hypothesize that intranasal ketamine will lower suicidality as
measured on the BSSI significantly more than intranasal midazolam.
Our secondary objective is to investigate the mechanism via which ketamine may
exert its anti-suicidal effects. We will determine changes in serum Brain
Derived Neurotrophic Factor (BDNF) from baseline to 180 minutes after the
intervention. In addition, we will explore anti-suicidal neuroimaging markers
after administration of ketamine or placebo, such as hippocampal volume,
hippocampal-frontolimbic connectivity and glutamate levels.
Finally, we will investigate if ketamine exerts an antidepressant effect in
acutely suicidal patients and if the anti-suicidal effect is associated with
the antidepressant effect. We hypothesize that ketamine will indeed exert an
antidepressant effect, but that the antisuicidal effect is not entirely
mediated by this. Also, we will determine the actual number of suicides in both
groups until 1 year follow up.
In nearly 595 patients that were treated with i.v. ketamine doses of 0.5mg/kg
for chronic pain or depression, no serious adverse events were observed.
Therefore, we consider a dose of 75mg intranasal ketamine as safe, which is
comparable to a dose of 0,5mg/kg intravenous ketamine.

The study will be performed in two centers: the Academic Medical Center (AMC)
in Amsterdam and the University Medical Center Groningen (UMCG). The
coordinating investigators (one in each center) will be supported by a research
nurse (one for each center) and medical students. We choose for a double blind
randomized active-placebo controlled trial because this design is the gold
standard for studying the efficacy of a pharmacological intervention. In order
to better understand ketamine*s mechanism of action and to determine a
responder/non-responder profile, we will determine genetic polymorphisms for
genes involved in the presumed mechanism of action of ketamine and we will
conduct functional and structural magnetic resonance imaging (MRI)-scans one
day after administration of either ketamine or midazolam.

Before the actual study, a pilot-feasibility study with 16 patients will be
performed. In this study we will follow the same procedure as in the main
study. Only after evaluation of both the efficacy and the safety of this pilot
study, we will start the main study. Depending on the pilot study we might want
to make changes to the design of the main study.

Subjects will be randomly allocated to either 75 mg of i.n. ketamine or the
active placebo midazolam (3.8mg i.n.). The patients will be treated on the
emergency ward of the general hospital of the AMC or the UMCG, or if they are
recruited form the psychiatric department, they will be treated at the
Psychiatric Medial Unit (PMU) where sufficient somatic support is available.
Vital parameters will be measured every 30 minutes until 180 minutes after
administration. In case of a significant abnormality in any of the vital
parameters, the subject will receive adequate medical care. Patients will
remain hospitalized for 8-24 hours after ketamine/midazolam administration.
They will have to be accompanied by someone when leaving the hospital.
Racemic ketamine is associated with less side-effects than S-ketamine,
therefore we choose to administer racemic ketamine. The intranasal ketamine and
midazolam containers will be manufactured by Tiofarma. The dosage that has been
used in the only previous randomized controlled trial with i.n. ketamine was
50mg. We consider this dose as conservative. A dose of 75mg intranasal ketamine
is comparable to a a dose of 0,5mg of intravenous ketamine, which is a usual
ketamine dose for research in psychiatry.

The side-effect profile of a single low dose of racemic ketamine seems to be
relatively favourable. The most serious events that have been observed are
brief periods of dissociation and an elevated blood pressure. Since in this
study only a single dose will be administered, long-term side effects of
ketamine, such as cognitive or urologic problems are very unlikely to occur.
Subjects are hospitalized for 8-24 hours after ketamine administration, so in
case SAE or a SUSAR occurs, this can be immediately treated. Although we assess
the risk of our study as low, we are aware that suicidality is a sensitive
subject, and that there is a significant chance, given the characteristics of
our target group, that an actual suicide might occur. For this reason, an
independent Data and Safety Monitoring Board (DSMB) will be established to
examine safety parameters when 50% of the subjects are included.