Cost-utility analysis of esketamine and electroconvulsive therapy in adults with treatment-resistant depression

Major depressive disorder is one of the most prevalent and debilitating forms of mental illnesses and a major cause of morbidity worldwide. In the United Kingdom (UK), it is estimated that 6.4% of the population suffer from the condition [1]. Major depressive disorder is usually treated with antidepressant medication (AD), but some individuals do not respond to treatment and they are considered suffering from treatment-resistant depression (TRD). There is no universally accepted definition of TRD, although the literature has commonly defined the condition as failure to respond to at least two trials of first line AD of both adequate duration and dose [2]. It is estimated that between 10 and 30% of individuals with major depressive disorder also have TRD with a significant impact on their daily life and productivity [2‐5]. The societal impact of TRD is great due to its prevalence in the population, its impact on functioning, productivity and quality-of-life and its contribution to premature mortality [6].

Individuals with TRD can be treated with a combination of AD, mood stabilising medication, antipsychotic medication, psychological therapy and electroconvulsive therapy (ECT). ECT is often used as a “last option” when all other treatments have failed or not been tolerated. The treatment is not routinely considered for people with moderate depression unless their depression has not responded to multiple drug and psychological treatments [3]. ECT is considered highly effective in treating TRD, with remission rates between 50 and 70% [7]. Moreover, in a recent large observational study of older patients, ECT was associated with a lower one-year all-cause mortality and reduced suicide rates during three months after treatment [8]. Despite the consistent evidence that ECT is an effective treatment for patients with TRD, research suggest that it is underutilised [9‐11]. This is partly due to limited availability of ECT, patient choice, stigma and a dated perception of the treatment [9‐11]. It is also due to the fact that maintenance ECT (M-ECT) might be required, a practice that is uncommon in England [12] and not supported by UK National Institute for Health and Care Excellence (NICE) as routine treatment [13].

There has, however, been recent developments in treatments for TRD. The N-methyl-D-aspartate receptor antagonist ketamine, commonly used as a tranquiliser and pain medication, has emerged as a new treatment due to its rapid and robust antidepressant effects [14]. According to a systematic review [15], 77% of the included studies reported significant improvement in depressive symptoms among patients receiving ketamine or esketamine compared to the control group. The review concluded that ketamine is an effective treatment option for patients with major depressive disorder when administered via intravenous, intranasal and oral routes. The review included two studies where ketamine was administered intranasal with improvement in both studies. Both the Food and Drug administration (FDA) and the European Commission have approved intranasal esketamine in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) for adults with TRD [16, 17].

In an individual with TRD, ECT and esketamine are both viable treatment options. To further inform the decision regarding choice of treatment, an economic evaluation may be utilised as it compares the difference in cost and the difference in benefits between the options. In the case of an option being dominant, costing less and generating greater benefits than the alternative, it is unequivocally cost-effective. However, if an intervention generates more health to a higher cost than the option, it can still be cost-effective. In these situations, the incremental cost-effectiveness ratio (ICER) is calculated which demonstrates the additional cost per extra unit of health [18]. To our knowledge there is no cost-effectiveness analysis evaluating whether ECT or esketamine is the more cost-effective option.

To determine which option is cost-effective, the ICER is estimated by calculating the difference in cost between ECT and esketamine divided by the difference in quality-adjusted life years (QALYs) between ECT and esketamine. The ICER is subsequently compared to a threshold value which will determine if the intervention is cost-effective [18]. The analysis is done in the context of the UK, and NICE recommends a threshold in the range of £20,000 to £30,000 per QALY gained [19]. However, NICE does not reject nor approve based on cost-effectiveness alone [20].

Table 2 presents the results from the main model base case and the sensitivity analysis. The results show that from a societal perspective ECT dominates esketamine, that is, ECT generates more QALYs at a lower cost. From a healthcare perspective, the ICER, comparing ECT to esketamine is £6969 per QALY gained, i.e. ECT is more efficient and costlier. The ICER is below the lower border of the suggested threshold from NICE. The sensitivity analyses confirm these findings. In all scenarios ECT appears cost-effective compared to esketamine and in 12 scenarios ECT dominates esketamine, see Table 2.

Table 3 presents the results from the maintenance model with M-ECT. The base case from a societal perspective indicates that ECT followed by M-ECT is cost-effective compared with esketamine. The ICER is £27,070 per QALY gained. From a healthcare perspective the ICER is £38,922 and is thus above the suggested threshold from NICE ranging from £20,000 to £30,000 per QALY gained. The sensitivity analyses of the maintenance model indicates that ECT followed by M-ECT is cost-effective from a societal perspective in all sensitivity analyses but three, see Table 3. Firstly, the ICER from sensitivity analysis 1b, halving the productivity loss, is £31,138 which is above the threshold. Secondly, the ICER from sensitivity analysis 5, where the remission rate is increased the second time the individual received ECT or esketamine, is £32,059 which is above the threshold. Thirdly, the ICER from sensitivity analysis 8, where the individual received esketamine as long as they were in remission, was £41,660 also above the threshold. From a healthcare perspective the estimated ICERs of the maintenance model were above the threshold in all analysis.

This is, to our knowledge, the first study that evaluates whether ECT or esketamine is to recommend from a cost-effectiveness perspective among individuals with TRD. The base case from the main model indicated that ECT is cost-effective compared with esketamine. The results show that the absolute cost of ECT is slightly lower than the cost for esketamine and ECT generates more QALYs. Results from the sensitivity analyses demonstrate the robustness of these findings. There were some changes to the ICER, but all the sensitivity analyses resulted in ECT being cost-effective compared with esketamine. The results from the maintenance model with M-ECT somewhat supports these finding.

A few estimates in the sensitivity analysis from the main model are particularly noteworthy. Analysis number 7 (lowering QALYs for ECT, increasing QALYs for remission with esketamine and AD) still generated more QALYs for ECT than esketamine. This is due to the higher remission from ECT resulting in more QALYs despite reducing QALYs during ECT treatment. This is an important finding as studies have reported lower QALYs from ECT than from other treatments. QALYs from ECT treatment have been reported as low as 0.3 and 0.56 [22, 43] while QALYs in remission after AD has been reported as high as 0.85 [44, 45]. Nguyen and Gordon [46] have reported a higher disutility from ECT at 0.104 compared with AD at 0.066. Alike, research regarding QALYs in schizophrenia has suggested different utility scores depending on side effects from the medication [47]. For individuals experiencing difficult side effects or stigma from ECT [48], it is possible that the QALYs would differ between ECT and esketamine. Our sensitivity analysis from both models supports the fact that ECT would still be cost-effective.

Sensitivity analysis 6a (five-year time horizon) and 8a (esketamine in remission) are interesting findings. In the main model, ECT dominates esketamine in both scenarios, indicating that the time horizon which esketamine is administered does not change the cost-effectiveness. This in combination with sensitivity analysis number 5a and b (increasing the remission rate the second time the individual received esketamine to 0.9) suggests that administrating more esketamine, makes it less cost-effective. However, the maintenance model with M-ECT yields slightly different results. In this model the ICER falls above the threshold in sensitivity analysis 5 and 8.

The model included loss of productivity by accounting for unemployment and part-time work in the depression state and unemployment in the remission state, similarly to another cost-effectiveness analysis [23]. However, the loss of productivity did not include part-time employment in the remission state. As indicated by the sensitivity analysis, halving and doubling the productivity loss still results in ECT being cost-effective in the main model and the ICER falls just above the threshold in the maintenance model.

Other cost-effectiveness studies have assessed esketamine compared with AD and have concluded that esketamine is not cost-effective. Ross and Soeteman [49] compared esketamine to AD by using a decision-analytic model. They concluded that esketamine was likely not cost-effective and their sensitivity analysis did not find any realistic cost-effective scenarios. Agboola et al. [50] likewise evaluated the cost-effectiveness of esketamine plus background AD compared with AD alone in patients with TRD and reached similar conclusions. The current study is a valuable complement to these studies, as we now have evidence regarding ECT being cost-effective compared with esketamine.

ECT is cost-effective due to its higher remission rate, compared to esketamine, at a slightly lower cost in the main model. The remission rate for ECT was 69.6 and 50% in the sensitivity analysis while the study used for esketamine remission rate reported between 36 and 38.8%. Critique towards a relaxed inclusion of participants and a relaxed definition of TRD in the esketamine trials have been voiced [51]. The trials only required individuals to have two failed treatments of any two AD, enabling inclusion of patients in whom only SSRIs had failed. In the study by Fedgchin et al. [27] only 30.1 and 48.2% had three or more previous AD and in the study by Daly, et al. [26] 21.1 and 26.2% had tried more than two AD. Thus, clinicians might find that esketamine demonstrates less efficacy among real-world patients with higher levels of treatment resistance. The trial also included a new AD that the individual had not tried before, making it a possibility that part of the treatment effect came from the AD. The treatment protocol used for the maintenance phase has been evaluated and Nijs et al. [52], suggests that altering the dose of esketamine might optimise the treatment. The treatment protocol stipulates that during the maintenance phase individuals receive esketamine once a week following a further reduction to every other week. Researchers adjusted the dose for individuals relapsing during the reduction and saw that 47% improved by increasing the dose from bimonthly to weekly. These finding suggest that an individualised treatment plan of esketamine might optimise treatment response in the real world. However, with an increased dose comes an increased cost and potentially a higher risk for drug abuse.

The study by Eranti et al. [28] used for the transition probabilities for remission and relapse from ECT, only included 22 participants in the first phase and 16 participants in the follow-up phase. The most common reason for exclusion was not consenting to ECT and there was no statistically significant difference in mean age or sex ratio between the eligible patients who consented and those who declined to participate. Moreover, ECT was not administered for a fixed schedule, rather it was given until treatment response was evident but the mean duration was similar to the control group which was three weeks. This invites to some uncertainty regarding the transition probabilities. However, similar transition probabilities have been reported from another study [53], and the sensitivity analysis with a lower remission rate did not result in any noteworthy changes to the ICER. On the other hand, the strength of the study by Eranti et al. [28] and the study by Rush et al. [30], used for the relapse and remission rates for standard treatment, was that the same patients who remitted were followed-up for relapse, mimicking real-world conditions. Moreover, the studies used to populate the model had similar definitions of TRD. As mentioned previously, the esketamine studies had a more relaxed criteria, while the other studies applied the definition of two failed AD.

This study found that, from a cost-effectiveness point of view, ECT should be the first-hand option for individuals with TRD, when other first line treatments have failed. The time horizon did not change the estimates noteworthy and there was no scenario in the main model where esketamine was cost-effective. Nonetheless, esketamine could potentially be an option for individuals not able to undergo ECT. Further research regarding potential subgroups of individuals where esketamine treatment could be cost-effective is warranted. Considering the lack of economic evaluation of ECT and esketamine, this study is of great value to decision makers.