Depression in adults
Esketamine approved in the US as the first ever monotherapy for treatment-resistant depression in adults
For the first time, the Food and Drug Administration (FDA) has approved a ketamine-related drug as a standalone treatment for adults with major depressive disorder (MDD). Esketamine nasal spray is approved for patients who have treatment-resistant depression (TRD) - defined as an inadequate response to at least two oral antidepressants.
The approval follows a multicentre randomised controlled trial which demonstrated the rapid efficacy of esketamine monotherapy. Within the first 24 hours of the initial dose, participants experienced significant improvements in their Montgomery-Asberg Depression Rating Scale (MADRS) total score, with the effects persisting for at least 4 weeks. By the fourth week, 22.5% of patients receiving esketamine had achieved remission (MADRS total score ≤12), compared to 7.6% in the placebo group.
Until now, esketamine had been approved in the US exclusively as an adjunctive therapy alongside an oral antidepressant for two indications in adults: as a treatment for TRD, and for those with MDD experiencing suicidal ideation or behaviour.
This expanded indication makes esketamine accessible to individuals with TRD who are not on an antidepressant or who wish to discontinue their current one, which may help to overcome treatment barriers owing to negative experiences with oral antidepressants, such as poor tolerability.
Despite growing clinical adoption of esketamine, several questions remain. The optimal patient profile for treatment response, how long therapeutical effects might persist, and the appropriate duration of therapy all require further investigation. While no longer considered a last-resort treatment, esketamine is not a first- or second-line treatment.
Esketamine is approved only for use in an appropriate certified clinical setting under the supervision of a health care provider; typically this will mean referring to a designated treatment facility offering esketamine. A key practical consideration is the logistical and occupational commitments required of patients; for example, the need to take time away from work and to arrange necessary transport and support. The drug must be self-administered by the patient, who is supervised by a health care provider in a certified medical office, and the patient monitored for at least 2 hours because of the risk of sedation, respiratory depression, difficulty with attention, judgement and thinking (dissociation), suicidal thoughts and behaviours, and the potential for drug misuse. For these reasons, esketamine is only available via a restricted distribution programme in the US.
People with poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or intracerebral haemorrhage.
Esketamine is available in Europe; however, it is not currently approved for monotherapy. Availability of esketamine varies according to the country of practice and relevant regulatory approval.
Summary
Definition
History and exam
Key diagnostic factors
- presence of risk factors
- depressed mood
- anhedonia
- functional impairment
Other diagnostic factors
- weight change
- libido changes
- sleep disturbance
- changes in movement
- low energy
- excessive guilt
- poor concentration
- suicidal ideation
- somatic symptoms
- bipolar disorder excluded
- substance abuse/medication side effects excluded
- medical illness excluded
- schizophrenia excluded
Risk factors
- postnatal status
- personal or family history of depressive disorder or suicide
- history of an anxiety disorder, or anxiety symptoms
- adverse childhood experiences
- dementia
- corticosteroid use
- interferon use
- oral contraceptive use
- co-existing medical conditions
- female sex
- comorbid substance use
- personality disorders
- history of violent victimisation
- obesity
- older age (≥65 years)
- separated/divorced marital status
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
Investigations to consider
- 24-hour free cortisol
- vitamin B12
- folic acid
Treatment algorithm
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): pregnant
more severe depression (PHQ score ≥16): non-pregnant
less severe depression (PHQ <16): non-pregnant
treatment-resistant/refractory depression
pregnant
treatment responsive
recurrent episode
Contributors
Authors
Dean F. MacKinnon, MD
Associate Professor
Psychiatry and Behavioral Sciences
The Johns Hopkins Hospital
Baltimore
MD
Disclosures
DFM declares that he has no competing interests.
Acknowledgements
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.
Disclosures
RSM has received research funds from Stanley Medical Research Institute and National Alliance for Research on Schizophrenia and Depression (NARSAD). RSM is on the advisory board for AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen-Ortho, Solvay/Wyeth, Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, Shire, and Schering-Plough. RSM is on the Speakers Bureau for Janssen-Ortho, AstraZeneca, Eli Lilly, Lundbeck, Biovail, and Wyeth. RSM has received research grants from Eli Lilly, Janssen-Ortho, Shire, and AstraZeneca. RSM has received travel funds from Bristol-Myers Squibb. TF declares that she has no competing interests. RK has received research grants from Pfizer on non-depression-related topics.
Peer reviewers
Christopher Dowrick, BA MBChB MSc MD
Emeritus Professor
University of Liverpool
UK
Disclosures
CD has been reimbursed by Novartis for participating in an educational event.
Erin K. Ferenchick, MD
Center for Family and Community Medicine
Columbia University Medical Center
Upper Manhattan
NY
Disclosures
EKF declares that she has no competing interests.
References
Key articles
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed., text revision (DSM-5-TR). Washington, DC: American Psychiatric Publishing; 2022.
National Institute for Health and Care Excellence. Depression in adults: treatment and management. Jun 2022 [internet publication].Full text
American College of Physicians. Nonpharmacologic and pharmacologic treatments of adults in the acute phase of major depressive disorder: a living clinical guideline from the American College of Physicians. Feb 2023 [internet publication]..Full text
Reference articles
A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.
Differentials
- Adjustment disorder with depressed mood
- Substance-/medication- or medical illness-associated and other depressive disorders
- Bipolar disorder
More DifferentialsGuidelines
- WHO Clinical descriptions and diagnostic requirements for ICD-11 mental, behavioral and neurodevelopmental disorders (CDDR)
- Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders
More GuidelinesPatient information
Depression in adults: what is it?
Depression in adults: what treatments work?
More Patient informationCalculators
Geriatric Depression Scale
Depression (any) Screening by a Two Item PHQ-2
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