Depression in adults: treatment and management

  • NICE guideline
  • NG222
  • Published: 

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January 2026 exceptional surveillance of depression in adults: treatment and management (NICE guideline NG222)

Context

Depression is characterised by low mood, loss of interest and enjoyment in life, and a range of associated emotional, cognitive, physical and behavioural symptoms.

Standard treatment for depression includes antidepressants or psychological therapies (including cognitive behavioural therapies) or a combination of both. NICE's guideline on depression recommends considering electroconvulsive therapy (ECT) for severe depression when preferred by the patient, when a rapid response is needed, or other treatments have failed.

Depression is treatment-resistant when symptoms have not improved after at least 2 standard treatments.

NICE has not reviewed evidence on ketamine in depression before but it carried out a technology appraisal (TA) of esketamine nasal spray in 2022, which was reviewed again in 2024. NICE did not recommend esketamine for treatment-resistant depression due to limitations in the clinical evidence and economic model. Further research was recommended to address some of these uncertainties.

Triggers for the surveillance review

The review was suggested following an application from the Royal College of Psychiatrists in association with other bodies to the Medicines Repurposing Committee, a programme which was suspended in April 2025. The application concerned the use of intravenous racemic ketamine for the acute treatment of severe or treatment resistance unipolar depression in adults and acknowledged its current off-label use in the private sector.

Methods

The surveillance process consisted of:

  • Literature searches to identify relevant evidence.

  • Considering the new evidence and intelligence that triggered the review.

  • Considering the evidence used to develop the guidance.

  • Examining related NICE guidance and quality standards.

  • Examining the NICE event tracker for relevant ongoing and published events.

  • A search for ongoing research.

For further details about the process and the possible update decisions that are available, see processes and methods for NICE-wide guidance surveillance.

Search and selection strategy

Searches were carried out across Medline, CDSR and Epistemonikos to identify systematic reviews of ketamine in depression published since the publication of the esketamine TA in 2022, when treatment-resistant depression was last reviewed.

A search for ongoing trials was conducted in clinicaltrials.gov.

Other relevant external guidance

The Royal College of Psychiatrists position statement on psychedelic and related substances for medical use PSO2/25, September 2025, acknowledges increasing interest in these compounds to treat a range of mental illnesses, including in pharmacologically assisted psychotherapy. The publication highlights that high-quality evidence on efficacy remains limited. Specifically on ketamine, they acknowledge methodological limitations in much of the relevant literature, as well as potential side effects and lack of longer-term data.

International guidelines have recommended intravenous ketamine, including the Royal Australian and New Zealand College of Psychiatrists guidelines for the use of ketamine in psychiatric practice (2025), the Canadian Network for Mood and Anxiety Treatments (CANMAT, 2023 update), and the Norwegian Medical Products Agency TA: Intravenous ketamine for treatment-resistant depression (2025). The guidelines have acknowledged that there is limited guidance translating research findings into clinical practice, particularly evidence for repeated IV ketamine infusions, risk of bias or moderate to very low confidence in reviewed studies. Many guidelines draw on evidence from the Anand (2023) study, discussed below.

Evidence considered when developing the existing guidance recommendations

NICE's guideline on depression includes several different types of treatment for people with treatment-resistant depression. These include oral treatments, augmentation therapy (when an antidepressant is used with a non-antidepressant), combination therapy (an antidepressant with another antidepressant), and ECT. The guideline also includes psychological therapies as options to use in combination with pharmacological agents.

Ketamine is currently approved as an anaesthetic drug by the MHRA. It is not currently approved for treating depression and it has not previously been considered by NICE.

NICE's technology appraisal guidance on esketamine nasal spray for treatment-resistant depression (TA854) was published in December 2022. This did not recommend esketamine in combination with selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). The committee made this recommendation due to:

  • treatment positioning and clinical pathway

  • choice of comparator treatments

  • internal and external validity of the clinical evidence

  • long-term effects of treatment

  • natural history of the condition

  • resource use

  • implementation.

Due to these limitations, there was uncertainty around economic modelling, and it was not possible to determine a reliable cost-effectiveness estimate.

NICE published a review decision in June 2024, which states that the evidence received in consultation did not support the need for an update of the existing recommendation.

There are none related to intravenous ketamine in treatment-resistant depression.

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