Frontiers in Psychiatry, 2022 | Volume 13 | Article 865466

Conclusion: This study reports the outcomes of 11 severely ill patients with comorbid TRD and PTSD after IN Esketamine treatment. Esketamine significantly improved depression symptoms, suggesting that it is likely to be a treatment of choice in this specific population.

Keywords: Esketamine, treatment-resistant depression, post-traumatic stress disorder, assisted-therapy, trauma-focused psychotherapy

INTRODUCTION

Major depressive disorder (MDD) is a common psychiatric disorder and is considered as one of the leading causes of disability worldwide (1). More than one third of depressed patients fail to fully respond to antidepressant treatments at adequate doses and duration, and are regarded as treatment- resistant depression (TRD) patients (2). Treatment resistance is characterized by an absence of symptomatic remission after the use of two successive trials of antidepressants of different pharmacological classes, well conducted in terms of dosage and duration while ensuring quality compliance (3, 4). A wide range of socio-demographic (female sex, age, financial insecurity, low level of education, etc.) and clinical factors, such as psychiatric and somatic comorbidities, are associated with treatment resistance (3). Post-traumatic Stress Disorder (PTSD) is one of those comorbidities (5, 6). It is a chronic and disabling condition arising after exposure to a severe traumatic event, characterized by persistent reexperiencing, avoidance, and hyperarousal symptoms. Risk for PTSD depends on trauma exposure severity, cumulative number of traumas, and trauma type; interpersonal traumas (physical and sexual assault in the context of relationship) carrying the highest risk (7). Patients with comorbid depression and PTSD have greater functional impairment (8) and their likelihood of suicidality is increased by more than three times compared to individuals with only one of these disorders (9).

Treatment strategies for TRD include antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin- norepinephrine reuptake inhibitors (SNRIs), tricyclics and monoamine oxidase inhibitors], psychotherapy and brain stimulation techniques [e.g., electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS)] (10). Because some patients do not respond to those treatments, additional therapeutic strategies are strongly needed (11). In recent years, a growing body of evidence has implicated the glutamatergic system in the pathogenesis of depression, N -methyl-D-aspartate (NMDA) glutamate receptors being identified as a potential pharmacotherapeutic target for MDD, including TRD (12–14). Intravenous ketamine, a non- competitive receptor antagonist of NMDA glutamate receptors, was found to exhibit a robust and rapid onset of efficacy in patients with TRD when administered at subanesthetic doses (0.5 mg/kg) (15–19). Glutamate is also involved in stress responsivity, the formation of traumatic memories, and the pathophysiology of PTSD (20). So ketamine was proposed as a potential treatment for chronic PTSD (21–23) or for comorbid PTSD with TRD (24), although the results regarding ketamine efficacy in this indication are contradictory (25).

Nevertheless, ketamine is known for its abuse potential and profound adverse effects, such as psychotomimetic symptoms, neurotoxicity, cognitive impairment, and hypertension. These effects appear to be less frequent with its S-enantiomer or Esketamine, making it preferable to use (26). Oral Esketamine administration yields a low bioavailability of around 20%, which stimulated the development of its intranasal (IN) form (27). Indeed, the bioavailability and the kinetics of effects of ketamine vary considerably according to the route of administration (e.g., bioavailability: oral: 20%; intramuscular: 90%; rectal: 25%; intranasal: 50%; epidural: 77%; kinetics of effects: oral: delay 15– 30 min, duration: 60–90 min; intramuscular: delay: 10–15 min, duration: 30–120 min; intravenous: delay: 1–2 min, duration: 20– 60 min) (28). Granted marketing authorization by the European Medicines Agency (EMA) for the treatment of TRD in December 2019 (29), Esketamine nasal spray is used as an antidepressant for TRD. It delivers a 28 mg Esketamine dose via two sprays (one per nostril) (29, 30). Phase-3 short-term trials of Esketamine nasal spray (28, 56, or 84 mg) plus an oral antidepressant have demonstrated a statistically significant reduction in depressive symptoms [reduction from baseline Montgomery– Åsberg Depression Rating Scale (MADRS) total score] in patients with TRD compared with an oral antidepressant plus placebo nasal spray (31), and a sustained decreased risk of relapse among stable remitters and responders in long-term trials (29, 32, 33). Long-term safety data showed that most treatment-emergent adverse events (AEs) were mild or moderate in intensity, and resolved on the same day (33). However, the optimum dose, duration, and frequency of use are not fully understood yet (34) and potential indications still need to be clarified. There is no head-to-head data to compare ketamine or Esketamine formulation in terms of tolerance or efficacy. Nevertheless, a recent case series demonstrated that 10 consecutive patients who had responded to IV racemic ketamine for TRD successfully maintained their antidepressant response when switched to IN Esketamine (35).

On the basis of the reported efficacy of intravenous ketamine on PTSD and TRD, we hypothesized that IN Esketamine could be effective in TRD patients with comorbid PTSD. This study is the first one to examine the efficacy and the safety of repeated IN Esketamine administration over a 6-month period on symptoms of depression in this specific population. We further discuss the possible mechanisms of action and the potential synergistic effect with psychotherapeutic intervention.

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