Spravato (esketamine) a novel treatment for major depressive disorder (MDD)

 In Conditions, Feature article, Mental Health, Pharmacy Information


In December 2019 Janssen-Cilag launched Spravato 28mg nasal spray onto the UK and European markets with the indication to treat adults with treatment-resistant major depressive disorder (MDD). It was restricted to use in combination with an SSRI or SNRI, where patients had failed to respond to at least two different antidepressant treatments within the current moderate or severe depressive episode.

It was launched through a restricted access and risk-minimisation program because of its pharmacological profile and subsequent risks of sedation, dissociation, and abuse. This has limited its use in general practice.

How does it work?

Esketamine is a glutamate receptor modulator which works on the N-methyl-D-aspartate (NMDA) and is thought to increase signalling between cells. This may contribute to the restoration of synaptic function in the brain regions involved with the regulation of mood and emotional behaviour.

Whilst esketamine can provide relief to some sufferers of treatment-resistant depression (TRD) in a matter of hours (as opposed to weeks or months), these benefits are not prolonged and repeat sessions are needed before these patients can progress towards remission and relapse prevention. However, some patients only respond partially and therefore will not improve further despite repeated treatments.

NICE appraisal

At the end of January 2020, Nice issued their draft guidance which stated that esketamine nasal spray should not be used for the management of TRD.(1)

This was primarily down to the high costs of setting up specialist clinics, the drug, and the need for long-term repeat dosing. NICE also felt that the clinical trials had not been against ECT or other comparable adjunctive or psychological treatments.

Clinical trials have indicated efficacy but some experts in the field were concerned that these had been downplayed by NICE and that social costs such as quality of life and suicide prevention had not been adequately considered. To that end the manufacturer appealed with new evidence. Due to COVID-19 delays, the final publication is expected in September 2020.(2)

Health Improvement Scotland is meeting in September to decide whether to give the drug its full approval.

The future
Janssen have since applied to the EMA to extend the use of esketamine to a short-term treatment for the rapid reduction of depressive symptoms in adults with MDD who are suicidal with the intent.

What is required to set up a Spravato clinic?

A Spravato ‘ketamine clinic’ is a dedicated clinical space with resuscitation equipment. Currently clinics have used existing ECT spaces to reduce set-up costs.

Facilities need to provide a safe, calm environment with low stimulus for patients who are either in a sedated or dissociated state.

Patients should be provided with either a comfortable chair or couch to rest in during treatment.

Patients must be supervised by suitably qualified healthcare professionals who are trained in blood pressure monitoring.

Practitioners are required to have undergone risk minimisation training delivered by Janssen-Cilag.

How is the drug administered?(3)

One spray device delivers two sprays (one spray per nostril) to be administered by the patient with head tilted back at a 45-degree angle, under the supervision of a healthcare professional.

Spravato® is usually used twice a week for the first four weeks before decreasing to once weekly.

After the first eight weeks, Spravato® is usually used either once a week or once every two weeks. Typically, a standard treatment course would be six months.

What are the risks?(4)

Effects are short lived, peaking generally at 40 minutes and wearing off after one-and-a-half to two hours.

Transient dissociative states or perception disorders

  • Patients should be counselled on the likely effects of dissociation symptoms (both positive and negative). Typically, 26% of all patients experience only mild to moderate effects, with the severity reducing over time with repeated treatments.
  • In the Phase 3 clinical trials only 4% of respondents were described as having a severe level of dissociation.
  • Patients who are more likely to dissociate fall into the following patient groups: those who have a history of trauma, PTSD, childhood abuse, substance abuse (including alcohol), anxiety and mood disorders, eating disorders, suicidality, and alexithymia.

Disturbance in consciousness

  • Caution should be exercised when treating patients who are co-prescribed either sedative or CNS-depressant medications. The patient must also be alcohol free for at least 24 hours.
  • A ready-to-leave checklist has been prepared by Janssen-Cilag to ensure that outpatients are safe to leave the clinic. Driving is not permitted for 24 hours.

Increased blood pressure

  • In clinical trials, older patients (over 65 years) were more likely to experience transient elevations in blood pressure (systolic increases up to 40mm Hg and diastolic increase up to 25mm Hg). Less than 3% of patients experienced a rise in systolic pressure that equalled 180mm Hg and only 4% experienced a rise in diastolic pressure that equalled 110mm Hg. The patient’s blood pressure should always be back within the normal range before leaving the clinic.
  • Any patient who is hypertensive on arrival (150/90) should be declined treatment.

Drug abuse

  • Patients should be monitored for signs of drug-seeking behaviour (requesting higher doses or more frequent appointments). Nasal sprays are unsuitable for prescription and should only be used within the clinic. Practitioners are warned to look for patients presenting with interstitial cystitis, as this may be a sign that the patient has used street ketamine.
  • Tolerance will be unlikely to develop if the dosing schedule is adhered to.



  1. https://www.nice.org.uk/news/article/nasal-spray-medicine-for-treatment-resistant-depression-not-recommended-by-nice
  2. https://www.nice.org.uk/guidance/GID-TA10371/documents/committee-papers
  3. https://www.medicines.org.uk/emc/product/10977/smpc
  4. https://www.medicines.org.uk/emc/rmm/1718/Document
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