Package advice esketamine nasal spray (Spravato®) for the treatment of adults with treatment-resistant major depressive disorder

Zorginstituut Nederland has completed its assessment whether esketamine nasal spray (Spravato®) can be included in the insured package. The treatment is indicated for the treatment of adults with treatment-resistant major depressive disorder. Due to its expected high costs the Minister of Medical Care and Sports has placed the treatment in the so-called ‘package lock’ or ‘sluice’ for expensive drugs. These products can only be accepted into the insured package after the Zorginstituut has advised on their inclusion in the insured package and, where applicable, subject to Ministry negotiations to arrive at a financial arrangement with the supplier.

Zorginstituut Nederland has concluded that esketamine nasal spray should be included in the basic health care package, but as the 4th step of the treatment algorithm, after successful price negotiations, preferably in the form of pay for performance or pay for proof agreements.

Criteria for including treatments in the insured package

The Zorginstituut assessed esketamine nasal spray  based on the four package criteria:

  • effectiveness;
  • cost-effectiveness;
  • necessity;
  • feasibility.

Assessing from the perspective of the basic package which is paid from collective premiums, the Zorginstituut looks at whether new care is better than what is currently available. In doing this we look not only at the degree of certainty that has been achieved, from a scientific perspective and from the perspective of societal support, but also at efficiency aspects. The Zorginstituut was advised by two independent committees:

  • the Scientific Advisory Board (WAR) which examines data on established medical science and medical practice and determines the cost-effectiveness;
  • the Insured Package Advisory Committee (ACP) which considers the societal assessment. Stakeholders are also consulted during the process.

Integral package criteria weighting

  • In the 1st step of the pharmacotherapeutic treatment of depression, the patient can be started on various types of antidepressants.
  • In the 2nd step, it is recommended to switch to another antidepressant mentioned in the 1st step.
  • In the 3rd step, a second product is added to the antidepressant that proved to be insufficiently effective in the 2nd step (augmentation). At this point, esketamine nasal spray has a value comparable with that of the existing augmentation strategies.
  • Prior to the assessment, the occupational group indicated it foresaw a place later on in the treatment algorithm for esketamine nasal spray, namely in the 4th step, after non-response to at least 3 consecutive medical management steps with antidepressants and augmentation. Esketamine nasal spray has added value in this place in the treatment algorithm, compared to tranylcypromine.

The results of studies for esketamine nasal spray show various uncertainties, as do many other studies on medicinal products for depression. Nevertheless, esketamine nasal spray meets the established medical science and medical practice.


In the case of esketamine nasal spray, a regular cost-effectiveness analysis is either not considered (in case of equal value compared to augmentation strategies) or not possible. The study results are not representative of the 4th step in the treatment algorithm for which added value has been established. In addition, there are very limited published data about tranylcypromine. In a very exceptional move, the Zorginstituut has created a cost-effectiveness signal. This enables the Zorginstituut to use the limited data to make a cautious assessment of the expected cost-effectiveness of the medicinal product, taking into account various assumptions. This cost-effectiveness signal has shown that esketamine is unlikely to be cost-effective in comparison to tranylcypromine.

Zorginstituut's advice

For the first time in a long while, a new medicinal product has been registered for this group of patients. Esketamine nasal spray is innovative because it uses a new mechanism of action, which may also make it work faster than the existing medicinal products. However, there are many uncertainties about the place of the product, its effectiveness, budget impact and cost-effectiveness.

The Zorginstituut sees an added value for esketamine nasal spray when the product is used in the 4th step of the treatment algorithm. This is in line with the advice of the occupational group. The Zorginstituut takes into consideration that the 3rd step of the treatment algorithm already has adequate treatment options. By legally limiting the use of this product to the 4th step, the risk of an extremely large budget impact (as described above for the use in the 3rd step) is greatly reduced. 

The Zorginstituut's advice is to proceed to price negotiations and inclusion in the insured package at this time, but only in the 4th step of the treatment algorithm. The Zorginstituut advices the Minister to consider making pay for performance or pay for proof agreements. The pay for performance agreements can ensure that reimbursement only takes place when esketamine nasal spray has the desired effect. A pay for proof agreement means that a lower price is reimbursed initially, but if more evidence is provided for the (cost) effectiveness of the treatment, a higher amount will be reimbursed.

This report is a summary of recommendations by Zorginstituut Nederland. The original text of this excerpt is in Dutch.