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Suicide is 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. Suicide is always preceded by acute suicidality, i.e. a sudden increase of suicidal ideations, behaviors and attempts (1). Developing interventions for acute suicidality and understanding its pathophysiological mechanisms is the best way to prevent suicide. Though acute suicidality is co-occurrent with a wide range of mental disorders, in the current diagnostic manuals (DSM IV and 5) acute suicidality can only be diagnosed as a symptom of major depression or borderline personality disorder. Consequently, acute suicidality has hardly been investigated as a discrete and independent therapeutic target by itself, hampering research and progress regarding treatment of suicide.

Nevertheless, in recent years a few pharmacological treatment options have been examined for suicidality, such as clozapine, lithium and antidepressants (2, 3). Very recently, ketamine has been regarded as a new, potential effective drug for suicidality. Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist that is mainly used for anesthesia and pain relief (4). Subanesthetic doses of intravenous ketamine have been shown to resolve immediately depressive symptoms and suicidal ideation in depressed patients (5-7). However, the effect of ketamine has never been investigated on acute suicidality as such, and intravenous ketamine is not convenient as an administration route for treating acute suicidal patients.

Thus, with this project, we propose to examine the efficacy of ketamine in acute suicidality by itself, regardless of the underlying disorder, when applied as a single intranasal administration to suicidal patients presenting on emergency or psychiatry wards. We hypothesize that intranasal ketamine will have immediate anti-suicidal effects in the acute setting, enabling treatment of the primary, underlying disorder. To prove efficacy of ketamine for acute suicidality we propose a two-site double-blind randomized placebo controlled study. With a power level of 80% and an estimated large effect size of 0,5, based on former ketamine trials in depression (6, 8, 9), we will include 128 subjects. Patients will be included when they present with acute suicidality, defined as a rapid increase in suicidal ideation or behaviour from the patient’s baseline in the last 24 hours, with a cut-off score of 7 or above on the Beck Scale for Suicide Ideation (BSSI). Sixty-four participants will be randomly allocated to a single administration of 50mg intranasal ketamine and 64 participants to 4.5mg midazolam as active placebo. Except for minor dissociative symptoms and small changes in systolic blood pressure, 50mg intranasal ketamine was found to be safe in previous studies. Our primary endpoint will be change in suicidality scores on the BSSI between baseline and 180 minutes after the intervention. In addition, we will measure suicidality at 60 minutes and 1, 3 and 7 days after the intervention. Other secondary clinical outcomes are number of suicide attempts and suicides, and anti-depressive and psychotomimetic effects.

To detect potential biomarkers predicting anti-suicidal response to ketamine, we will measure plasma markers before and after ketamine administration. Since suicidality has been associated with low levels of Brain Derived Neurotrophic Factor (BDNF) (10, 11), and since ketamine may increase BDNF (12), we hypothesize that the anti-suicidal effect of ketamine will correlate with increased plasma BDNF. Secondly, omega-3 poly-unsaturated Fatty Acids (PUFAs) have been shown to negatively correlate with suicidality (13), hence we expect the PUFAs to be lower in subjects that are more severely suicidal. Finally, we will measure neuroimaging markers following the intervention as we expect that ketamine responders and non-responders will differ in glutamate brain levels and connectivity in frontolimbic pathways (13).

We believe that proven efficacy of intranasal ketamine will result in a readily available, easily applicable and cost-effective intervention for suicide. Based on effect-sizes of ketamine trials for suicidality in major depression, we expect that ketamine has the potential to reduce suicidality with 14%, which could amount to 240 less suicides per year in the Netherlands.

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