Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by depressed mood or anhedonia, along with at least four additional symptoms such as cognitive and sleep disturbances or vegetative symptoms, for a minimum of 2 weeks (Diagnostic and Statistical Manual of Mental Disorders 5th edition, DSM-5). MDD is a significant contributor to global disease burden, impairs functioning [1], and elevates the risk of comorbid conditions such as diabetes mellitus, obesity, and functional gastrointestinal diseases [2,3]. The mean annual prevalence of MDD in Europe is estimated to be 6.4% [4] and 4.73% in Spain [5]. Furthermore, individuals with MDD are at a 20-fold increased risk of suicide compared to the general population [6].

Despite the growing impact of this disorder, current treatment options are suboptimal, with up to 30% of patients demonstrating inadequate response to first-line treatments [7,8]. This has led to the concept of treatment resistant depression (TRD). Although this term lacks a consensus-based definition, most authors consider it the failure to respond or achieve remission in patients treated with at least two antidepressants of different mechanisms of action [9]. While there is no established algorithm for treating TRD, the most commonly used strategies involve combining different classes of antidepressants, adding other treatments such as lithium, or physical therapies such as electroconvulsive therapy (ECT), repetitive magnetic transcranial stimulation, or deep brain stimulation. However, none of these options is specifically indicated for TRD, and evidence for their effectiveness is limited [10].

Esketamine, the S-enantiomer of racemic ketamine, is a novel antidepressant that acts as an antagonist of the N- methyl-D-aspartate (NMDA) receptor expressed in gamma-aminobutyric-acidergic inhibitory interneurons, enhancing glutamatergic neurotransmission. This mechanism of action is thought to increase synaptogenesis and modulate inflammation through mediators such as the increase in the secretion of blood-derived neurotrophic factor (BDNF) [11]. It is administered as a nasal spray, with a 7-month dosing regimen that includes an induction phase and a maintenance phase.

According to a solid body of evidence, esketamine seems to be a rapid and effective treatmenfor TRD, although there is still a lack of data regarding some relevant questions such as proper setting for administration, or long term efficacy and safety [12]. Due to its recent marketing approval, there is almost no clinical experience of its use outside research settings, which also brings questions about its proper implementation within healthcare systems and its performance in real-life and complex clinical settings [13]. Moreover, in the case of esketamine, and due to a number of reasons, most of the clinical trials assessing esketamine for TRD involved the adjunct initiation of a conventional antidepressant, which involved a serious risk of bias [14-16].

At our institution, prior to its marketing approval, expanded access to esketamine was granted between February 2020 and November 2022. The term “expanded access” refers to the provision of an investigational product for therapeutic purposes prior to receiving marketing authorization. This type of access is usually considered for patients with serious or life-threatening diseases or conditions that lack alternative treatments or have exhausted all available options. In the case of esketamine, the inclusion criteria included patients diagnosed with major depressive disorder who failed to respond to at least two oral antidepressants during the current episode, failed to respond to at least one combination/potentiation strategy, and declined or were unresponsive to at least one non- pharmacological strategy, such as ECT. These criteria were established by the Spanish Drug Agency, based on clinical consensus regarding the severity and treatment- resistance features of major depressive disorder.

Given the knowledge gaps described above, the main purpose of this study was to shed light on the effectiveness, tolerability and safety of esketamine in a real-world environment, prospectively describing the evolution of all the patients included in the expanded access program of our institution.

Objective

The aim of this study was to characterize the population receiving esketamine treatment in our Treatment Resistant Depression Program. Specifically, we sought to evaluate the response to the treatment. A secondary, exploratory objective was to identify potential clinical markers of improvement in a real-world setting, where esketamine was administered after previous treatment failures. Specifi-cally, we aimed to explore the relationship between treatment response and prior ECT use.

Study Design

We conducted a descriptive prospective study of all patients with TRD who received esketamine as expanded use between February 2020 and November 2022. Eligible participants for expanded use were those diagnosed with MDD according to the DSM-5 and fulfilled a number of inclusion criteria, including failure to respond to two or more oral antidepressants in the current episode, failure to respond to at least one combination/potentiation strategy, failure or refusal of one non-pharmacological strategy, such as ECT, no access to any clinical trial for the same indication or other expanded access program, and medical stability. There was no need to perform any change on the baseline treatment before starting treatment with esketamine.

Exclusion criteria included, among others, previous lack of response to ketamine or esketamine, previous or current diagnosis of bipolar disorder, psychotic disorder, MDD with psychotic features or cognitive disability. Also, active suicidal ideation in the last 6 months, or a suicide attempt in the last 12 months, medical instability, a number of medical diagnosis such as epilepsy, hepatic cirrhosis, or relevant cardiac alterations, as well as pregnancy, and a baseline blood pressure higher than 140/90 (systolic/diastolic) millimeters of mercury were reason for exclusion. Patients with a history of mild to severe substance use disorder were also excluded from the expanded use program. These criteria were defined by the Spanish Drug Agency in a clinical guideline for internal use that is no publically available, but isrovided as a supplement to this publicationr.

Recruitment occurred between January 2021 and June 2022, and patients received esketamine treatment at doses ranging from 28 to 84 mg, depending on clinical response and tolerability. Participants were referred for expanded use from our Treatment Resistant Depression Program, as well as from outpatient clinics. Standard schedule was followed, implying a 4-week induction phase, when treatment was administered twice weekly, and a 6-month maintenance phase, during which the frequency of administration varied from once a week to every two weeks. Preparation visits took place before treat-ment. During these visits, we focused on psychoeducation about the expected effects during administration, as well as teaching tools for support, such as mindful breathing or therapeutic touch. Esketamine was administered in a quiet room, accompanied with music (with headphones), and under the supervision of an expert nurse. A psychiatrist was present at the beginning and end of the treatment, and remained on call at all times.

Ethics Approval

This study was approved by the Ethics Committee of Vall d’Hebron Research Institute (PR(AG)110/2021). All participants gave informed consent before participation in the study.

Measurements

Depressive symptoms were assessed weekly during the first month and monthly during the maintenance phase, using the Spanish validated version of the Montgomery- Asberg depression rating scale (MADRS) [17]. The MADRS scale was administered before the administration of esketamine in the same dosing visit, to avoid biases due to possible impairments in response immediately following the administration. The MADRS is a hetero-administered instrument designed to assess the severity of depression symptoms in adults and the efficacy of antidepressant treatment [18]. Generally accepted cut-points for the MADRS are as follows: A score of 0−6 indicates a patient free of depression; a score of 7−19 indicates mild depression, 20−34 indicates moderate depression, and 35−60 indicates severe depression [19].

In addition, we administered the Maudsley staging method (MSM) scale (Spanish version) [20] to assess treatment resistance and compliance with inclusion criteria. The MSM is a points-based staging model that incorporates three factors: previous treatments, severity of illness, and duration of current episode. A final score of 3−6 points indicates mild resistance to treatment, 7−10 points indicate moderate resistance to treatment, and 11−15 points indicate severe resistance to treatment [21].

Treatment side effects were systematically assessed and recorded in the patient’s medical record using leading and open questions in every follow-up visit. Symptom remission was defined as a MADRS score ≤ 12, and full response was defined as ≥ 50% reduction in the baseline MADRS score, following national guidelines on clinical practice in MDD [22].

Statistical Analysis

A descriptive analysis was conducted to examine clinical and demographic variables using means and standard deviations for quantitative variables, while qualitative variables were described in terms of counts and percentages.

To evaluate changes and evolution compared to baseline, a repeated analysis of variance (ANOVA) analysis and linear mixed-model were performed to assess the evolution of MADRS scores through time. The influence of each variable on MADRS scores was also tested by adding them to the mixed model.

Finally, a Kaplan–Meyer survival analysis was used to describe the time to achieve a > 50% reduction of the MADRS initial score (or full response), and the time to achieve < 12 points in the score (or remission).

All statistical analyses were performed using the STATA 15 version (StataCorp LLC).

Sixteen patients were included in the study, 9 of whom were females (56.3%) and 7 males. The patients had an age range of 27 to 71 years old, with a mean of 53.13 and a standard deviation of 10.31. Table 1 displays the primary demographic and clinical characteristics, comorbidities, and treatment.

The mean time from the first diagnosis of depression was 20.81 years (standard deviation [SD] = 11.41). Ac-cording to MSM scores, no patient had mild TRD, while 50% had moderate TRD, and 50% had severe TRD, with a mean score of 11 (SD = 1.86) indicating severe treatment-resistant depression.

Regarding treatment with intranasal esketamine, 84 mg (81.25%) was the most frequently used dose, and the transition from the 56 mg to 84 mg dose occurred between the first and second week in all patients.

Pooled reported adverse events are shown in Table 2, and all but one adverse event were mild and did not require treatment.

Included patients had a baseline mean MADRS score of 36.69 (SD = 4.44), indicating severe depression. The mean score of MADRS was 26.67 (‘moderate depression’) at T1 (in the first 48 hours after the first administration) and 19.07 (‘mild depression’) at T6 (one month after treatment), reaching a mean of 16 at the end of the follow-up. These results were statistically significant (p < 0.00001). The pooled means evolution through time is shown in Figure 1, where the MADRS level consistently fell until T3, remaining stable through time after that moment.

A linear regression analysis was performed to assess the effect of time on the evolution of the MADRS score, indicating a significant global p value using the Wald test of p < 0.001 (Table 3). A random-effects model was used to evaluate the association between MADRS score and demographic and clinical variables, and no significant association was found. Furthermore, data for patients who had received ECT was compared to those who had not, and no significant differences were found between the two groups.

A Kaplan–Mayer survival test was conducted to evaluate the response and remission rate through time.

Figure 2 shows the Kaplan-Mayer survival test assessing the time to achieve response (< 50% of the initial MADRS score). After the induction phase (one month after the initial dose), 50.53% of patients had reached response.

Figure 3 displays the Kaplan-Mayer survival test assessing the time to achieve remission (< 12 in the MADRS score), where five patients (31.25%) achieved remission at the end of the follow-up period.

The present study investigated the effectiveness and tolerability of nasal esketamine treatment in patients with TRD. As far as we know, this is the study with the largest number of patients with TRD treated with nasal esketamine in our country.

The results described in this study show that esketamine is a fast an effective treatment for TRD patients, allowing for a consistent improvement in their MADRS scores from a mean baseline of 36.69 (severe depression) to a mean of 19.07 (moderate depression) after one month of treatment, although the onset of response can already be observed in the first 48 hours after the first administration (mean MADRS score 26.67). Most of the patients maintained the improvement after two months, even when the dose schedule was changed to once weekly, or every two weeks, keeping a mean of 16 points in the MADRS score after this period. However, it is relevant to mention that a longer follow-up would be needed to assess how this improvement evolves through time after the discontinuation of the treatment, as esketamine is considered a short-term treatment that precisely aims at avoiding chronicity.

The reported results are consistent with previous clinical trials that show a response rate of 50.2% and a remission rate of 35.8% in TRD patients [23], which is relevant given that the criteria to access these trials involved only the failure to respond to two or more antidepressants, while all the participants in our sample tried at least 3 antidepressants, and were using an augmentation treatment.

It is also worthy of note that most of the patients enrolled in the study had been diagnosed a mean of 20 years before they started treatment with esketamine and had been treated with at least 3 different therapies without responding. Six of them (37.5%) had also received ECT in the same episode without improvement, but no significant difference was found between this group of patients and the rest of the sample, who didn’t receive ECT in that episode, or refused to do so.

This data means that our sample included very severe and difficult to treat depressive patients. The delay in diagnosis and treatment has been related to a lack of response with conventional treatments [24], but the requirements needed to access the expanded use program prevented the inclusion of patients with a more recent diagnosis or who had tried less treatments. Further studies should assess if esketamine might be more efficacious in a more “naïve” population. Chronic, or long-term MDD, has been associated with more mental and non-mental comorbidities, worse clinical features [25] and higher mortality [26]. An early access to this treatment might lead to a gain in functionality, an economic save of resources, and a decrease in comorbidities and poorer prognosis. The fact that we found no difference between patients that previously received ECT and those that didn’t, could point to the possibility of using esketamine, with a better profile of adverse effects, before resolving to ECT. A recent clinical trial showed ketamine to be non-inferior to ECT when treating severe depression, which is in line with our findings [27], taking also into account that esketamine has been found to be non-inferior to ketamine [28].

The fact that our patients responded to esketamine when they had failed to respond to other, more conventional treatments, is also consistent with the novel mechanisms of action through which esketamine is thought to act, involving glutamatergic neurotransmission and modulation of inflammation [29].

In our study, we observed that esketamine was generally well tolerated among the patients enrolled. Notably, no serious adverse events were reported during the study period. However, we did observe a higher-than-expected rate of dissociation, which was present in almost one third of the patients, but no specific medical intervention was required in any case. Of note, we did encounter one moderate adverse event in our study, which involved hypertension with a blood pressure reading of up to 180 mmHg and headache. This adverse event was effectively managed with the administration of captopril 25 mg, resulting in full remission, with no recurrence during subsequent administration sessions. The use of captopril instead of benzodiazepines was motivated by the fact that benzodiazepines might hinder the therapeutic effect of ketamine and esketamine [30]. We did observe some transient increases in blood pressure that were not registered as adverse events as they were mild (less than 10 mmHg), transient and self-limited, and asymptomatic (no headache, or any other symptom that can be caused by sudden increases in blood pressure). These changes were mainly observed 40 minutes after administration, as expected, since the maximum plasmatic concentration of esketamine is reached at this moment. Blood pressure was measured before administering esketamine, and 15, 40, and 90 minutes after administration. There was not any case of observed elevation of blood pressure that lasted between measure times.

We also observed that two patients discontinued treatment before the end of the follow-up period due to a worsening of depressive symptoms. During the administration sessions, both patients presented with anxiety, which was managed with non-pharmacological techniques such as verbal support and therapeutic touch. These techniques were effective in managing their symptoms, and no pharmacological intervention was required. This adverse event was not considered the reason for discontinuing treatment, but might grant consideration as a possible proxy for poor prognosis.

In our clinical experience, the administration of esketamine in a supportive environment, with trained clinicians that were able to manage acute distress, and the use of music and minimization of sensory stimuli, were very useful in improving tolerability and allowing the patient to ease into the experience. Also, agreeing on a care plan, especially during the induction phase, can increase safety and reduce anxiety; this generally involves including a significant person of the patient to pick them up after treatment and to be available, as well as learning to identify signs of distress and ways of coping with it.

None of the reported adverse effects was significantly correlated with differences in the clinical outcomes. This fact grants consideration, given the current debate between authors that consider esketamine and ketamine to exert their effect only through their pharmacological action, while others suggest that dissociation could be a marker associated with improvement [31]. Our results, showing no relationship between dissociation and improvement, are consistent with recent findings [32]. No specific psychotherapy was combined with the treatment in our patients, and we found no difference in improvement between patients already receiving psychotherapy, and those that didn’t. Nonetheless, the different proposed mechanisms of esketamine and ketamine, including the altered states of consciousness that they can cause, and the window of neuroplasticity that they seem to open, could prove beneficial for a synergy with certain types of psychotherapy [33]. We believe that further studies comparing the combination of esketamine with psychotherapy, versus the sole use of esketamine, could shed light on this question, and maybe allow for the development of structured treatment programs that could enhance its effectiveness and prevent relapses. Also, recent studies show that some clinical factors can predict the chances of remission and response to treatment [34]. We suggest that developing prospective studies testing possible endophenotypes and biomarkers of depression as well as a thorough stratification based on these factors could contribute to a better prediction of response to esketamine.

Although our results can shed some light onto real-life experience on esketamine response in severe and complex patients, the main limitation of our study rests in its low sample size, which could have hindered the possibility of finding relevant correlations that could inform prognosis. In the case of the survival model, the number of events are few, so the variability and the interval of the estimation is not precise; hence, conclusions in this regard must be taken with care. Given its observational nature, there was also no specific control for possible bias such as confounding factors.

In conclusion, esketamine appears to be a promising treatment for individuals with TRD, demonstrating fast and effective results and good tolerance. However, further studies are necessary to fully understand its potential, such as longer-term follow-up periods and the assessment of its combination with other pharmacological and psychotherapeutic treatments. Additionally, incorporating new endophenotypes, biomarkers, and a highly detailed clinical phenotype based on novel discoveries related to the etiologic pathways of depression would greatly improve our knowledge of this novel treatment and aid in better stratifying patients.

Over the course of this investigation, Óscar Soto- Angona was a recipient of a Río Hortega contract from the Carlos III National Health Institute.

We thank and acknowledge Santiago Pérez Hoyos (Vall d’Hebron Research Institute – Biostatistics Unit) for his expert supervision of the statistical results reported.

J.A.R.Q was on the speakers’ bureau and/or acted as a consultant for Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medicine, Rubió, Uriach, Technofarma, and Raffo in the last three years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogi, Bial, and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last three years: Janssen- Cilag, Shire, Oryzon, Roche, Psious, and Rubió.

A.R.U has received travel awards (air tickets + hotel) for taking part in annual psychiatric meetings from Lundbeck and has acted as a speaker at various training courses financed by Organon, Janssen-Cilag, Lundbeck.

O.S.A has received travel awards (air tickets + hotel) for taking part in annual psychiatric meetings from Lundbeck and Janssen-Cilag. He also has acted as a speaker for Lundbeck, and as a consultant for MAPS Foundation.

J.V.S has received travel awards (air tickets + hotel) for taking part in annual psychiatric meetings from Lundbeck and Janssen-Cilag and was on the speakers’ bureau and acted as consultant for Janssen Cilag.

B.I. has no conflict of interest to report.

A.L.G. has no conflict of interest to report.

Conceptualization: Júlia Vendrell-Serres, Óscar Soto- Angona, Amanda Rodríguez-Urrutia and Josep Antoni Ramos-Quiroga designed the study and obtained the ethics approval. Data acquisition: Júlia Vendrell-Serres, Antonia López González and Óscar Soto-Angona gathered the clinical data and collaborated in the creation of the dataset used for the study. Formal analysis: Júlia Vendrell-Serres, Amanda Rodríguez-Urrutia and Óscar Soto-Angona performed the statistical analysis of the results obtained. Funding: no funding was provided or used for the development of this publication. Supervision: Josep Antoni Ramos-Quiroga supervised the development of the study. Writing of original draft: Óscar Soto-Angona, Benedetta Inzoli and Amanda Rodríguez-Urrutia conducted the bibliographic search, and wrote the different versions of the manuscript. Writing review & editing: All authors provided key suggestions and contributed to the discussion, proofreading and correction of the final version of this work. All authors meet all four criteria for authorship included in the ICMJE recommendations