Background
About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.

Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).

Objectives:To provide advice and guidance regarding the management of mood disorders, derived from scientific evidence and supplemented by expert clinical consensus to formulate s that maximise cli

The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders

Objective To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). Methods This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. Results Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Asberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). Conclusions Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. Trial registration ClinicalTrials.gov identifier: NCT02497287.

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Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

https://eprints.ncl.ac.uk/file_store/production/264279/A380D7B6-131B-4594-A3DA-D31408941FD0.pdf

The identification, assessment and management of difficult-to-treat depression: an international consensus statement

The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.

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Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders.

Importance Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rankP = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rankP  Conclusions and Relevance For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. Trial Registration ClinicalTrials.gov identifier:NCT02493868

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Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

The present invention provides methods of maintaining stable remission or stable response achieved by a patient with depression following administration of a therapeutically effective amount of esketamine during an initial administration phase, comprising continuing administration of a therapeutically effective amount of esketamine for at least five months during a subsequent administration phase. The present invention also provides methods for the long term treatment of depression in a patient, comprising administering to the patient in need of the treatment a clinically proven safe and clinically proven effective therapeutically effective amount of esketamine for at least six months. In some embodiments, the depression is major depressive disorder or treatment resistant depression.

Honglan Li

Papers

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Esketamine for the treatment of depression