Positioning of Esketamine Treatment in the Real-world Management of Depression

Inclusion Criteria:

1. Adults aged 18-65 years old
2. Diagnosis of Major Depressive Disorder (MDD)
3. Currently depressed
4. Had an inadequate response to 2 or more courses of antidepressants (of adequate dose and duration)
5. Be maintained on their current antidepressant medication or psychological therapy at the time of enmrolment
6. Able to understand and provide informed consent

Exclusion Criteria:

1. Concurrent diagnoses:

   * Participants with other 'Diagnostic and Statistical Manual of Mental Disorders' (DSM-5) e.g., current substance misuse disorder, bipolar disorder, schizophrenia
   * Participants who are unable to understand the study and therefore unable to provide informed consent
2. Pregnancy:

   * Participants who are pregnant and/or breastfeeding
   * Participants who are not willing to avoid pregnancy for themselves or their partners during the study by using effective birth control methods
3. Current medications:

   * Participants taking a total daily dose of benzodiazepines greater than the equivalent of 6mg/day of lorazepam
   * Participants on complementary and alternative medicine therapies i.e., St John's wort, Chinese medicines, and various herbal and homeopathic treatments
4. Stimulants

   * Participants taking stimulants such as methylphenidate, amphetamine, and dextroamphetamine for a diagnosis such as ADHD can still have Esketamine provided they do not continue taking stimulants concurrently for the duration of the study.
   * Concurrent use is excluded due to the synergistic effect with Esketamine that can cause increased blood pressure.
5. Medical history:

   * Participants with current or past history of seizures (uncomplicated childhood febrile seizures with no sequelae are not exclusionary)
   * Participants with a history of uncontrolled hypertension
   * Participants with uncontrolled diabetes mellitus
   * Participants with aneurysmal vascular disease including thoracic and abdominal aorta, intracranial and peripheral arterial vessels, or arteriovenous malformation, intracerebral haemorrhage
   * Participants with untreated glaucoma, current penetrating or perforating eye injury, brain injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other condition associated with increased intracranial pressure or increased intraocular pressure or planned eye surgery
   * Participants who are currently receiving electroconvulsive therapy (ECT) or have received ECT in the past month.
6. Substance Misuse History:

   * Participants who have ever had a substance misuse disorder involving any of the following over their lifetime: ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3,4-methylenedioxy-methamphetamine (MDMA), or other hallucinogen use history
   * Participants with hypersensitivity to Esketamine, Ketamine, or any of the excipients