Major depressive disorder (MDD) is estimated to afflict one out of every five individuals at some stage. Depressive symptoms cast a pervasive shadow over various aspects of life, encompassing a spectrum from suicidal ideation to changes in weight, disrupted sleep patterns, impaired work performance, and diminished interest in social interactions. The financial strain resulting from absenteeism, isolation from friends and colleagues, and the stigma associated with MDD are all significant repercussions that often lead many individuals to delay seeking treatment (Otte et al., 2016).

Pharmacological therapy often involves one of the following antidepressant drug classes: Tri-Cyclic Antidepressants (TCA), Selective Serotonin Reuptake Inhibitors (SSRI), and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), which are frequently used as first-line treatments for MDD (Guideline Development Panel for the Treatment of Depressive Disorders, 2019).

Recent data indicates that only about 50%–66% of patients will achieve clinical remission after two to four trials of pharmaceutical interventions. Consequently, approximately one-third of individuals with MDD will not respond positively to four consecutive treatment trials. Treatment-resistant depression (TRD) is extensively studied in clinical and research contexts (McAllister-Williams et al., 2020; Rush et al., 2019). It is defined as the lack of response to two appropriately administered trials of antidepressants. TRD is characterized by a significant burden despite conventional treatment efforts. This reframing shifts the therapeutic focus from achieving remission to achieving the best possible control of symptoms and to improving the patient's quality of life. This therapeutic approach necessitates a comprehensive optimization of all available treatment modalities, including medications, psychotherapy, and neuro-stimulation, to enhance the overall quality of life for patients (McAllister-Williams et al., 2020; Rush et al., 2019).

In the past three decades, a focused and accelerated effort has been made to find more individualized treatment modalities for TRD. These include cutting-edge biological therapies and neuro-stimulation techniques (such as transcranial magnetic stimulation [TMS] and vagus nerve stimulation [VNS]), with additional treatments in development.

An essential concept in biological research concerning antidepressants revolves around the aberrant activity of the glutaminergic system (Vutskits, 2018). The widely recognized anesthetic ketamine exerts multifaceted effects on several regions of the cortex, influencing various systems, including the glutaminergic and opioid systems (Abdallah et al., 2016; Laruelle et al., 2005). The clinical effectiveness of ketamine in its racemic form to treat MDD has been investigated in numerous trials over the last ten years. Intranasal S-enantiomer-based - Esketamine development was prompted by promising but inconsistent results. The American Food and Drug Administration (FDA) approved the use of Esketamine in 2019 after it demonstrated a rapid antidepressant activity during phase II and III studies (Hashimoto, 2019; Popova et al., 2019; Reardon, 2019). Ketamine is administered through a nasal spray, rendering it a convenient and well-tolerated treatment choice. The trials conducted to assess its efficacy, funded by pharmaceutical companies, (Popova et al., 2019; Daly et al., 2019) involved a meticulously selected cohort of patients, adhering to stringent study criteria. In contrast, post-marketing real-world studies encompass a broader spectrum of clinical conditions and comorbidities, including personality, substance use and dependence, and anxiety disorders (Saturni, et al., 2014).

In recent years several cohort studies evaluating the efficiency and safety of Esketamine have been published. Results showed a 37–40% remission rate and a 48–60% response rate after the first month of treatment. Sedation, somnolence, lightheadedness, hypertension, and dissociation were found to be the most frequent side effects (10%) (Brendle et al., 2022; Chen et al., 2023; Martinotti et al., 2022; Samalin et al., 2022). However, these trials did not investigate long-term or comorbid effects, and focused primarily on short-term efficacy and side effects.

This study's primary goal was to evaluate the treatment effectiveness of Esketamine in individuals with TRD in a clinical setting representative of “real-world" practice.