Safety and effectiveness of intranasal esketamine for treatment-resistant depression: a real-world retrospective study

Major depressive disorder (MDD) is one of the most common mental health disorders in the US and is a major cause of disability [1]. In 2017, an estimated 17.3 million adults in the US had at least one major depressive episode, representing over 7% of all US adults [2]. Treatment-resistant depression (TRD) is broadly defined as failure to achieve response or remission to at least two antidepressant medications with adequate dosing and duration [1,3]. TRD patients account for approximately one third of MDD patients and this population disproportionally accounts for the burden of disease caused by depression [1,3–5].

Current pharmacotherapy strategies for TRD include switching antidepressants, combining antidepressants, using second-generation antipsychotics and augmentation with lithium [2,6]. However, most antidepressants take several weeks for patients to note symptom improvement, which is when TRD patients may be at imminent risk of suicidal ideation or suicide attempt [7–9]. Non-pharmacological treatments for TRD include somatic therapies such as transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), vagal nerve stimulation (VNS) and deep brain stimulation (DBS) [10]. The clinical efficacy of ECT is well established, but this treatment is costly and is associated with acute cognitive impairment and amnesia. TMS is not fully supported by clinical trials for TRD, with small sample sizes, variable treatment schedules and high drop-out rates [10]. TMS is also time consuming, as TMS sessions, usually 30–60 min each, are given five-times a week for a period of 4 to 5 weeks for a total of 20 to 30 sessions [10]. Furthermore, TMS is costly and insurance companies are reluctant to reimburse for this treatment [10]. In 2005, VNS was approved by the FDA as an adjunctive treatment for TRD in patients who had failed four or more antidepressant medications [11,12]. However, there are perioperative risks involved with device implantation and response is not seen until 3 to 12 months after implantation, thus VNS is not recommended for acute treatment of TRD [12,13]. Furthermore, there is a lack of reimbursement by US insurance providers for VNS, namely Medicare/Medicaid [10]. DBS is an experimental surgical treatment for TRD with high cost and substantial risk associated with the surgical procedure [10]. Moreover, the effects of the stimulation can take weeks to months to begin working [10]. Thus, there is a significant unmet need for rapid acting treatment for patients with TRD.

Ketamine was approved by the US FDA in 1970 as an anesthetic, but also has been observed to improve symptoms of depression and other mood disorders [9,14]. Hypothesized mechanism of actions of ketamine for depression include direct synaptic or extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, selective inhibition of NMDARs localized on GABAergic interneurons and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation [15]. Downstream mechanisms regulating synaptic plasticity have also been hypothesized to affect the antidepressant response to ketamine, which include an increase in brain-derived neurotrophic factor (BDNF) protein levels, a decrease in eukaryotic elongation factor 2 kinase (eEF2k) activation, activation of mechanistic target of rapamycin (mTOR) and inhibition of glycogen synthase kinase-3 (GSK-3) [15,16]. These hypothesized mechanisms of action of ketamine are not mutually exclusive and may act harmoniously to produce an antidepressant response [15].

Ketamine is a racemic mixture of two stereoisomers, the S- and R-enantiomer [14,17]. Compared with the R-enantiomer, the S-enantiomer binds to the NMDA receptor with greater affinity and has stronger anesthetic and analgesic action, producing less lethargy and cognitive impairment [17]. Racemic ketamine can be administered via intravenous (IV), intranasal (IN), oral, sublingual (SL), anal, subcutaneous (SQ) and IM routes; however, the majority of research to date has been on IV administration with dose ranges of 0.5–0.75 mg/kg [18–20]. A meta-analysis of IV ketamine infusion for TRD found that patients experienced rapid reduction in depressive symptoms during the first 24 h after one infusion, and the effects decreased at 7 days post-infusion, showing how ketamine is promising for short-term treatment of TRD [19]. Sustained benefit from ketamine typically requires multiple infusions at a high-frequency during an induction period, typically six sessions over 2–3 weeks, followed by lower-frequency treatment during maintenance treatment [18,21]. While racemic ketamine is only prescribed for psychiatric disorders as an off-label indication, the S-enantiomer, esketamine (Spravato™), was approved by the FDA in March of 2019 as a rapid-acting treatment for TRD [9,17]. With its novel mechanism of action and rapid reduction of depressive symptoms as early as 24 h post-administration, esketamine has garnered interest for the treatment of TRD [1,9,17,22].

The FDA's approval of esketamine was based on the efficacy and safety results of four phase III clinical trials [23,24]. Three trials were short-term parallel-group designs (TRANSFORM-1 and TRANSFORM-2 with patients ages 18 to 64 years; TRANSFORM-3 with patients ages 65+ years) and one trial was a longer-term randomized withdrawal maintenance-of-effect design (SUSTAIN-1) [23]. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary outcome measure to assess change in depressive symptoms in all trials. Patients enrolled were diagnosed with MDD and had failed two or more prior treatment lines. To assess esketamine efficacy, patients were randomly assigned to receive esketamine nasal spray (56 or 84 mg for TRANFORM-1 and TRANSFORM-2; 28, 56, or 84 mg for TRANSFORM-3) versus placebo. Additionally, all patients received a new oral antidepressant. Of the 421 patients randomly assigned to receive esketamine in the three short-term trials, 142 (34%) achieved remission and 199 (47%) responded. Of the 289 patients randomly assigned to receive placebo in the three short-term trials, 68 (24%) achieved remission and 102 (35%) responded. In the long-term SUSTAIN-1 trial, patients who had initially achieved remission or response while receiving esketamine in the short-term trials were randomly assigned to continue esketamine or replace with a placebo [23]. Two of the studies (TRANSFORM-2 and SUSTAIN-1) showed a statistically superior effect of esketamine versus placebo on the study's primary efficacy end point (i.e., MADRS total score change from baseline at day 28) [23]. In TRANSFORM-2, the treatment effect was apparent at day 2, which is an unusually rapid onset of effect for antidepressant medication [23]. In SUSTAIN-1, time to depressive relapse was significantly longer in patients who continued esketamine treatment than patients who switched to placebo, demonstrating evidence that esketamine is effective beyond one month for patients who initially responded [9,23]. Additionally, based on the safety data of these trials, the FDA approved esketamine with a Risk Evaluation and Mitigation Strategies (REMS) program to mitigate the risk associated with serious adverse outcomes and the potential for abuse and misuse [9,25,26]. The REMS program specifies that esketamine only be dispensed and administered to patients under direct observation of a healthcare provider where they can be monitored for at least 2 h post-administration [26].

Having a new treatment for TRD is important given the substantial burden of the disease coupled with the unmet clinical need. However, the efficacy, safety, patient profile and use of esketamine in the real world may differ from that reported in the clinical trial data for esketamine. For instance, patients treated in real-world settings may have more severe depressive symptoms, a less rigorous or regular treatment schedule than observed dose-frequency data in the RCTs, or other co-occurring psychiatric conditions that were excluded from the RCTs; therefore, the efficacy and safety of treating these populations with esketamine is unknown [17].

Given the limited real-world and long-term data for patients with TRD receiving esketamine treatment, the aim of our study is to better understand the demographic and clinical characteristics, treatment patterns, clinical outcomes and adverse events of patients with TRD receiving esketamine therapy in a private outpatient psychiatric clinic setting.

This retrospective analysis was conducted in accordance with International Society for Pharmacoepidemiology (ISPE) Guidelines for Good Pharmacoepidemiology Practices (GPP) and received approval from the University of Utah human subject protection review board.

We evaluated patients receiving esketamine treatment at a private integrative psychiatric clinic that provides outpatient mental health treatment, specializing in ketamine and esketamine treatment. The services provided include diagnostic evaluations, medication management, psychotherapy, TMS, and esketamine and ketamine treatment. This clinic is a certified esketamine treatment center and has been administering esketamine since 2019 when the FDA approved the medication for treatment of TRD.

A total of 171 patients were treated with esketamine therapy from July 2019–June 2021 and met all inclusion/exclusion criteria. The patient population had an average age of 36 (±12) years, included a higher proportion of females (60%) and were predominantly white (92%) (Table 1).

Several common psychiatric diagnoses were generalized anxiety disorder (GAD) (39%; n = 67), attention-deficit hyperactivity disorder (ADHD) (25%; n = 43), insomnia (25%; n = 43) and post-traumatic stress disorder (PTSD) (12%; n = 20) (Table 1). There were 168 (98%) patients with recorded use of other psychiatric medications besides esketamine, with an average of 5.8 (SD: 4.0) psychiatric medications per patient. There were 160 (94%) patients with a recorded prescription for an oral antidepressant and each of these patients were taking on average 2.3 (SD: 1.4) oral antidepressants (Table 1). For all other psychiatric medication classes listed, patients were taking one to two medications each.

The patient self-reported medical, social and family history questionnaires are summarized in Tables 2 & 3. The number for each question changes based on whether the patient completed the questionnaire and/or the individual question. The number of respondents is shown for each question and percentages are based on available data. The majority of patients reported a history of acute or chronic pain (55% [38/69]) and high blood pressure (32% [17/53]). Regarding mental health history, 45% of respondents reported one or more prior psychiatric hospitalizations (35/78), 48% of respondents reported self-harm behavior (31/64) and 46% of respondents reported one or more prior suicide attempts (28/61). Most patients with available data did not have a history of heavy alcohol use (5% [5/107]), daily tobacco use (6% [9/146]), recreational cocaine/amphetamine use (18% [24/134]), or psychedelic/entheogenic drug use (19% [25/134]). Several patients had a history of opiate use (including prescription opiates and/or heroin) but denied current use (78% [105/137]). Of the 135 respondents with data on family history of mental illness, 70% (n = 120) reported a family history of mental illness. The majority of patients reported having one or more family members with a history of depressive disorder (71% [96/135]) or anxiety disorder (57% [77/135]).

Using data from a real-world setting, this study demonstrates esketamine therapy was efficacious in relieving depressive and anxious symptoms without major safety concerns. We observed clinically meaningful improvements in depressive symptoms in this population. In this study, patients receiving between 6–10 treatments had an average reduction of 4.1 points in PHQ-9 score from baseline to last treatment session. For patients with 11–15, 16–30 and 31–71 treatments, reduction in PHQ-9 score ranged from 5.5 to 6.9 points from baseline to last treatment session. These clinically meaningful improvements in PHQ-9 scores suggest a reduction in the risk of relapse and recurrence of depressive symptoms [29,31]. Furthermore, the change in PHQ-9 scores observed in this population are larger than what was observed in the esketamine short-term RCTs, which ranged from -2.2 to -2.8 per study [23]. Thus, the results of this study support esketamine's consistent benefit and clinically meaningful efficacy in real-world practice [23,32].

In terms of potential relapse risk, decreasing dose frequency to once weekly does not seem to be problematic because average depression, anxiety and SI scores did not increase to levels above those measured at session 14. This finding aligns with data from the long-term SUSTAIN-1 trial [23]. The results of SUSTAIN-1 showed that continuation of esketamine significantly reduced the risk of relapse by 51% for patients who achieved stable remission and 70% for patients who achieved stable response compared with patients that switched to a placebo [23]. However, these relapse prevention results should be considered in the context of relapse rates for oral antidepressants, because these results do not indicate that patients who respond to esketamine had lower relapse risk than patients who respond to oral antidepressants. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a randomized trial where outpatients with MDD were followed across 4 treatment steps [4]. The STAR*D trial reported relapse rates of 65% for patients at treatment step 3 and 71% for step 4 [4]. These relapse rates were much higher than rates in the esketamine continuation group in the SUSTAIN-1 trial – 27% of remitters relapsed and 26% of responders relapsed [4,23]. Thus, our study and the SUSTAIN-1 trial provide important evidence that esketamine is effective beyond the first month of treatment for patients who initially experience improvement in depressive symptoms [9,23].

The population received esketamine treatment in accordance with the manufacturer's recommended dosing – twice per week for weeks 1–4 (i.e., the induction phase), weekly for weeks 5–8 (i.e., maintenance phase) and weekly or every other week for weeks 9+ [33]. At session 9 we observed a transient increase and variability thereafter in PHQ-9 and GAD-7 scores. This is the instance where the time between sessions began to increase substantially – a median of 4 days since the last treatment at session 8, a median of 6 days at session 9 and a median of 7 days thereafter. The increase in days between treatment is one possible explanation for the plateau in depression score improvement since esketamine is a rapid acting medication with transient effects. The rapid reduction of depression and anxiety symptoms is a key benefit of esketamine and continued administration may be necessary to relieve depressive symptoms. Additionally, it is important to note that clinical contact is frequent for esketamine therapy compared with oral antidepressant treatment because of the delivery model of esketamine, which likely aids in patients' improvement in depression/anxiety symptoms [34].

The results of this study must be interpreted in the context of its limitations. First, this is a descriptive, real-world observational cohort study. Thus, the findings from this study represent routine clinical practice and support other studies that have examined the use of these agents for TRD. Second, data in medical charts is subject to missing data and coding errors. Third, the outcome measures utilized have limitations that must be considered. We did not have data on outcome measurements (PHQ-9, GAD-7 and SI score) between treatments. Thus, our conclusions on the trends in outcome measurements should be interpreted in the context of not knowing fluctuations between esketamine treatment sessions. Additionally, the PHQ-9 and GAD-7 survey instruments asked respondent about the preceding two weeks to assess depression and anxiety symptom criteria. Thus, these tools are limited in measuring rapid reduction of depression and anxiety symptomatology as well as measuring changes in symptoms when treatment visits are frequent. Also, clinical trials of esketamine used the MADRS as the primary outcome for measuring severity of depression [23]. Thus, comparisons between clinical trial data and the results presented in this study need to consider the differences and limitations of these two instruments for measuring depression severity. Fourth, patients were encouraged to seek psychotherapy in addition to esketamine treatment. However, it was not feasible to report the number of patients receiving psychotherapy since some patients sought psychotherapy from other clinics, and patients that did receive psychotherapy from the same clinic they received esketamine treatment received varying number of visits and modalities of psychotherapy dependent upon their provider. Finally, because the study was conducted in an outpatient psychiatric clinic setting, the population studied may not be representative of TRD patients in other healthcare settings or other areas of the US.

Using novel data, this study demonstrates the significant disease burden of TRD and the effectiveness esketamine therapy has in relieving depressive and anxious symptoms without major safety concerns. Esketamine and ketamine are fundamentally changing how researchers and clinicians study and treat depression, and this study provides new evidence for esketamine use in clinical practice. Further research is warranted to continue studying the long-term and real-world benefits of esketamine therapy for TRD.

All the authors have equal contribution towards conceptualizing and designing the study. M Brendle extracted and analyzed data and completed the manuscript writeup. S Ahuja and M Della Valle extracted and formatted data. P Thielking, R Robison and DC Malone reviewed the data analysis and critically reviewed/revised the manuscript writeup. All authors have read and approved the final article.

R Robison and P Thielking are employed by Numinus and have stock ownership in Numinus. R Robison is on the Janssen Speakers Bureau for esketamine. Janssen Pharmaceuticals did not financially support this research. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

This paper is received approval from the University of Utah institutional review board on 14 July 2021 as non-human subject research (IRB 00145104). These data do not contain any information that could identify subjects. Informed consent was not required for this study.

The data that support the findings of this study are available on request from the corresponding author, M Brendle. The data are not publicly available due to their containing information that could compromise the privacy of research participants.