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.     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
Common symptoms include persistent low mood, loss of interest and enjoyment, sleep and appetite changes, guilt or self-criticism, poor concentration, and reduced energy.
Affects 5% to 10% of patients in the primary care setting.
Risk factors include prior depression and a family history of depression. Recent bereavement, stress, or medical illness may contribute.
For screening and diagnosis, self-rating forms are helpful, but clinical diagnosis is essential. Positive screening should trigger full history, mental status examination, treatment, and follow-up.
Most patients respond well to treatment with medication, talk therapy, or a combination of both.
Suicidal ideation can occur before and peak during treatment, so early and careful follow-up is advised.
Depressive disorders are typically characterised by persistent low mood, loss of interest and enjoyment, neurovegetative disturbance, and reduced energy, causing varying levels of social and occupational dysfunction. Depressive symptoms include depressed mood, anhedonia, weight changes, libido changes, sleep disturbance, psychomotor problems, low energy, excessive guilt, poor concentration, and suicidal ideation. In some cases the mood is not sad, but anxious or irritable or flat. 
Major depressive disorder is characterised by the presence of at least five symptoms and can be classified along a spectrum of mild to severe. Severe episodes may include psychotic symptoms such as paranoia, hallucinations, or functional incapacitation.
Subthreshold (minor) depression is characterised by the presence of two to four depressive symptoms, including depressed mood or anhedonia, lasting longer than 2 weeks.
Persistent depressive disorder (dysthymic disorder) is characterised by at least 2 years of three or four dysthymic symptoms for more days than not. Dysthymic symptoms include depressed mood, appetite change, sleep disturbance, low energy, low self-esteem, poor concentration, and hopelessness.
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.
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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