Depression, identified by the World Health Organization as one of the leading causes of disability worldwide, affects approximately 280 million people, accounting for about 3.8% of the global population(World Health Organization, 2023a). The complexity of this mental disorder, characterized by a broad spectrum of psychological and physical symptoms, profoundly impacts individuals' quality of life, as well as poses significant challenges to health systems(Juruena et al., 2015). Concerns about depression are compounded when accompanied by suicidal ideation (SI), a condition that dramatically increases the risk of suicide. It is estimated that a significant proportion of patients with depression are at risk for suicide. In fact, of these between 30% to 70%, report suicidal thoughts during their mood episodes (World Health Organization, 2023b). However, almost all available interventions were studied using depressive symptoms scores as a primary outcome, which may include suicide ideation but the efficacy on suicide behavior would be a secondary analysis or post-hoc. In addition, suicide is highly associated with depression but the correlation is not always linear with depression severity, in particular when taking into account those patients with comorbidities. In this context, the search for clinical interventions that address not only the symptoms of depression but also the risk of suicidal ideation and behavior are highly needed. Ideally, these interventions should fulfill the requirements of rapid onset of action, accessible implementation and tolerability. Current treatments, while effective in mitigating symptoms to some extent, often fall short in achieving complete remission or restoring full functional capacity. A notable limitation of these existing therapies is their delayed onset of clinical efficacy, typically manifesting several weeks post-initiation. Ketamine stands out as a medication with potential anti-suicide effects, and investigating alternative and more accessible ways of administration are critical needs in the field.

Given the complexity and urgency in addressing depression accompanied by SI, the pursuit of innovative therapeutic strategies is critically important. Current treatments, while effective in mitigating symptoms to some extent, often fall short in achieving complete remission or restoring full functional capacity. A notable limitation of these existing therapies is their delayed onset of clinical efficacy, typically manifesting several weeks post-initiation.

In this context, ketamine (an N-methyl-d-aspartate (NMDA) receptor antagonist), has emerged as a promising therapeutic intervention in the field of psychiatry over recent years, notably in the management of treatment-resistant depression (TRD) and SI (Monteggia and Zarate, 2015). Currently, evidence suggests that its antidepressant properties are predominantly facilitated through the modulation of glutamate neurotransmission, thereby promoting enhanced synaptic plasticity and bolstering neurotrophic signaling(Duman et al., 2016). The rapid onset of ketamine's action (occurring within a matter of hours) and the established efficacy in treating TRD may be particularly tailored to treat patients with SI(Del Sant et al., 2022; Smith-Apeldoorn et al., 2022; Surjan et al., 2022). However, the dissociative side effects, the potential for abuse and the necessity for supervised administration, restrict its broad-scale use in the medical practice(Sanacora et al., 2017). Thus, scientific investigations are increasingly focused on refining ketamine administration routes in order to reduce adverse effects.

One possible alternative that has proven favorable initial results is subcutaneous ketamine, enhancing therapeutic benefits while simultaneously mitigating associated adverse outcomes (Cavenaghi et al., 2021), such as psychotomimetic side effects (Domany et al., 2020). Despite studies showing that subcutaneous ketamine may exhibit an antidepressant and anti-suicidal effect, they have assessed reduction in suicidal ideation as a secondary analysis and without well validated scales(George et al., 2017; Ionescu et al., 2019; Loo et al., 2016; Surjan et al., 2022; Tham et al., 2022). A recently published case series showed that repeated ketamine subcutaneous administration in individuals with TRD resulted in significant improvements in depressive symptoms and SI, accompanied by a rapid onset of clinical improvement(Pereira et al., 2023). However, the impact on SI was evaluated by items of Montgomery-Asberg Depression Rating Scale (MADRS)(Montgomery and Åsberg, 1979) and Hamilton Depression Rating Scale (HAM-D)(Hamilton, 1960). The classical scales show an item about SI, however they are limited in detecting the dimensional aspect of suicide ideation and behavior, and its central ambivalence. For this purpose, scales designed to measure SI and correlates such as the Columbia-Suicide Severity Rating Scale (C-SSRS)(Posner et al., 2011) can provide better insights into the anti-suicidal effects of a treatment. The C-SSRS dimensional scale measures the intensity and severity of suicidal thoughts and behaviors, providing differentiated insights into treatment response. Its application allows a more targeted therapeutic approach, reflecting the multifaceted nature of suicidal risks(Posner et al., 2011; Syndergaard et al., 2023). Currently, there are no studies addressing the subcutaneous administration of ketamine with a 6-month follow-up.

The primary aim of our study is to evaluate the effect of subcutaneous ketamine in reducing depressive symptoms, suicidal ideation, and suicidal behavior among individuals in a current depressive episode. We also investigated the impact of subcutaneous ketamine on other psychiatric symptoms. This trial was registered in the U.S. National Library of Medicine–Clinical Trial Registry (NCT05249309) and the study protocol was previously published (Anzolin et al., 2023).