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…
ID
Source
Brief title
Condition
- Suicidal and self-injurious behaviours NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in suicidality scores on the BSSI between baseline and 180 minutes after
75 mg intranasal ketamine administration compared to 4.0 mg intranasal
midazolam (placebo).
Secondary outcome
1. Suicidality from baseline to 60 minutes, 180 minutes, 1 and 3 days and 1, 2
and 4 days after one intranasal ketamine administration as measured with:
a. Beck Scale for Suicide Ideation (BSSI) (Dutch version)
b. Suicidality item on the Montgomery Asberg Depression Rating Scale. (MADRS)
(Dutch version) (57).
2. Actual number of suicides and suicidal acts at 60 and 180 minutes, 1 and 3
days and 1, 2 and 4 weeks after ketamine/midazolam administration.
3. Number of subjects that are admitted at
4. Depressive symptoms as measured with the MADRS from baseline to 60 and 180
minutes, 1, 3 and 7 days and after one intranasal ketamine administration
compared to placebo (57).
5. Clinical severity and improvement as measured with the CGI.
6. Somatic symptoms, as measured with the SAFTEE (Dutch version) from baseline
to 60 and 180 minutes (58).
7. Establishing the DSM 5 diagnosis with the Mini International
Neuropsychiatric Interview.
8. Establishing the presence of Childhood Trauma with the Childhood Trauma
Questionnaire (CTQ).
9.. Change in BDNF concentration, genetics and other biomarkers, and the
correlation pattern between change in BDNF concentration and suicidality. Three
blood samples will be taken by venepuncture at baseline: two samples into a
vacuum tube containing ethylene diamine tetra-acetic acid (EDTA) that will be
transferred into a heparinised tube, and one directly into a serum gel tube. At
180 minutes also three blood samples will be taken to measure the BDNF
concentration. Two in an EDTA tube and one into a serum gel tube (59).
Furthermore, at baseline one 10ml EDTA sample will be taken in order to study
genetics. (See table 1)
10. Plasma ketamine concentration at 180 minutes.
11. Structural MRI, functional MRI (fMRI), diffusion tensor imaging (DTI),
H-MRS-analysis of glutamate in hippocampus and prefrontal cortex. Subjects that
were administered ketamine will be compared to subjects that were administered
midazolam, at one day after administration (This only applies for patients
included in the UMCG).
12. A responder/non responder analysis. (Response is defined as a 50% reduction
in BSSI-score) for the total study period.
13. Correlation patterns for the total study period between changes in BSSI-
and MADRS-scores.
14. Correlation patterns for the total study period between sex and changes in
BSSI scores.
Background summary
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 100 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.
Study objective
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 of 75 mg
intranasal ketamine will diminish suicidality more than 4.0 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 7 days 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, which is comparable
to a dose of 0,5mg/kg intravenous ketamine, as safe.
Study design
The study will be performed in two centers: the University Medical Center
Groningen (UMCG) and GGz Centraal in Almere. 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 12 patients will be
performed. In this study we will follow the same procedure as in the main
study, except for the fact that these subjects will be administered ketamine in
an open-label fashion. 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.
Intervention
Subjects will be randomly allocated to either 75 mg of i.n. ketamine or the
active placebo midazolam (4.0mg i.n.). The patients will be treated on the
psychiatric ward of the UMCG or GGz Centraal. 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.
Study burden and risks
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.
There exists a risk of ketamine abuse. Therefore we extended the follow up to 4
weeks after the intervention, in order to observe this, might this occur,
offering the opportunity to act upon this adequately.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
Acute suicidality: suicidal thoughts and/or behaviour have increased within the
last 96 hours of the hypothetical administration of ketamine/midazolam.
A Beck Scale for Suicide Ideation (BSSI)-score of 7 or above
Subjects are in the age of 18-70
Exclusion criteria
1. Earlier participation in this study
2. Psychosis (as a primary diagnosis) (depression with psychotic features will
not be an exclusion criterion per se).
3. A diagnosis of schizophrenia or another primary psychotic disorder.
4. A history of PCP- or ketamine addiction.
5. Being under influence of GHB (Substance abuse in the (recent) history is not
an exclusion criterion per se (with the exception of GHB and a high blood
alcohol concentration, and intoxications leading to medical unstable
conditions).
6. A blood alcohol concentration (BAC)of >0.05%
7. A clinically significant and unstable infectious, immunological,
cardiovascular, gastro-intestinal, pulmonal, renal, hepatic, endocrine or
haematological disorder, a myocardial infarction, miction problems or a complex
surgical problem that needs immediate attention.
8. Presence of any contra-indication for ketamine use, such as severe high
blood pressure, a recent myocardial infarction or relevant cardiac problems,
severe thyroid problems, severe liver problems, severe kidney problems,
epilepsy and increased intracranial pressure.
9. A known hypersensitivity for ketamine.
10. Concomitant use of a MAO-inhibitor.
11. Concomitant use of a potent CYP3A4 inhibitor, such as clarithromycin,
erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil,
goldenseal and grapefruit.
12. Concomitant use of a potent CYP3A4 inducer such as phenytoin, rifampicin,
St. John*s Wort and glucocorticoids.
13. Severe nose congestion or nasal polyps.
14. Pregnancy or giving breastfeeding
15. Women of reproductive age, who are heterosexually active, using unreliable
contraception.
16. Being unable to answer the questionnaires
17. Legal incompetency with regard to participation in this study
18. No informed consent
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002905-24-NL |
| Other | NL7215/NTR7414 |
| CCMO | NL74304.042.20 |
| OMON | NL-OMON20015 |