Last reviewed: July 2019
Last updated: March  2019
27 Mar 2019

US FDA approves eskatamine nasal spray for treatment-resistant depression in adults

Esketamine (the s-enantiomer of ketamine) is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist. A nasal spray formulation has been approved and is to be used in conjunction with an oral antidepressant for treatment-resistant depression (TRD). TRD is defined as a lack of response in the current episode to at least two antidepressant treatments given at adequate doses for an adequate duration.

The efficacy and safety of esketamine nasal spray were evaluated in several short-term (4-week) and longer-term maintenance-of-effect trials. [232] [233] [234] [235] The most common side effects experienced in the clinical trials were disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoaesthesia), anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.

Esketamine nasal spray is only available under a Risk Evaluation and Mitigation Strategy (REMS), meaning the patient will have to attend a certified medical office to take the nasal spray; both prescriber and patient must sign a Patient Enrollment Form and after administration, the patient must be monitored for at least 2 hours for sedation, dissociation, suicidal thoughts and behaviours, and because of the potential for drug misuse.

How this approval will affect daily practice remains to be seen. With the logistical challenges of its administration and its side effect profile, trials of combinations of antidepressants and augmentation with lithium or antipsychotics may remain preferred first- and second-line options for TRD.

When prescribing esketamine nasal spray, be aware that patients with poorly controlled hypertension or aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects.

See Management: emerging

Original source of update



History and exam

Key diagnostic factors

  • presence of risk factors
  • depressed mood
  • anhedonia
  • functional impairment

Other diagnostic factors

  • weight change
  • libido changes
  • sleep disturbance
  • psychomotor problems
  • low energy
  • excessive guilt
  • poor concentration
  • suicidal ideation
  • bipolar disorder excluded
  • substance abuse/medication side effects excluded
  • medical illness excluded
  • schizophrenia excluded

Risk factors

  • age >65 years
  • postnatal status
  • personal or family history of depressive disorder or suicide
  • corticosteroids
  • interferon
  • propranolol
  • oral contraceptives
  • isotretinoin
  • co-existing medical conditions¬†
  • comorbid substance use
  • personality disorders
  • gene-environment interaction

Diagnostic investigations

1st investigations to order

  • clinical diagnosis
  • metabolic panel
  • FBC
  • thyroid function tests
  • Patient Health Questionnaire-2 (PHQ-2)
  • Patient Health Questionnaire-9 (PHQ-9)
  • Edinburgh Postnatal Depression Scale
  • Geriatric Depression Scale
  • Cornell Scale for Depression in Dementia
Full details

Investigations to consider

  • 24-hour free cortisol
  • vitamin B12
  • folic acid
Full details

Treatment algorithm


Authors VIEW ALL

Associate Professor

Psychiatry and Behavioral Sciences

The Johns Hopkins Hospital




DFM declares that he has no competing interests.

Dr Dean F. MacKinnon would like to gratefully acknowledge Dr Roger S. McIntyre, Dr Tonya Fancher, and Dr Richard Kravitz, the previous contributors to this topic.

Peer reviewers VIEW ALL


Residency Training

St Vincent's Hospital




SM declares that he has no competing interests.

Department of Psychiatry and Psychotherapy

Medical University of Vienna




DW has received lecture fees from CSC Pharmaceuticals, GlaxoSmithKline, and Pfizer, and has served as a consultant for GlaxoSmithKline.

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