Ketamine for refractory depression: Save the best for last?

Per current prescribing guidelines, patients are considered eligible to receive ketamine for treatment-refractory depression, generally defined as having failed two or more oral antidepressant therapies (Bahr et al., 2019; Daly et al., 2018). Based on algorithmic prescribing guidelines for depression, ketamine is often listed as an alternative to electroconvulsive therapy (ECT), with recent studies suggesting that it is non-inferior to ECT (Anand et al., 2023). As such, guidelines often suggest that before turning to ketamine, patients should have failed at least one first-line monoamine reuptake inhibitor, one monoamine reuptake inhibitor in a different class or other medication for depression, and augmentation with medications targeting psychosis and/or relapse prevention of mania or bipolar depression (Giakoumatos and Osser, 2019; Trivedi and Kleiber, 2001). To reach this point with adequate trials of each regimen takes upwards of 1 year (6–8 weeks to titrate, 6–8 weeks to assess effect after changing dosage, 4 weeks to cross-taper, equating to a minimum of 4–5 months to adequately trial a single treatment).

For disorders like bipolar disorder and schizophrenia, evidence suggests using the most effective treatments as first- or second-line interventions may lead to superior long-term outcomes (Lähteenvuo et al., 2018; Remington et al., 2013). While this is likely also true for depression given evidence regarding neuroplasticity, prolonged stress, and treatment outcomes, this has often failed to impact clinical practice for depression treatment for understandable historical reasons (Levinstein and Samuels, 2014). Older pharmacological treatments with higher relative efficacy for depression have long been associated with higher rates of adverse effects, which, since the discovery of selective monoamine reuptake inhibitors with statistical effectiveness and a lower risk and side effect profile, have been deemed to outweigh any potential benefit as first-line agents (Thase, 2003). However, the emergence of ketamine offers a rapid-acting intervention that may be non-inferior to ECT and with a generally low side-effect burden (Anand et al., 2023). Furthermore, a recent review looking into the response of specific domains of depression to ketamine treatment showed strong evidence for treatment of suicidality and, to a lesser extent, anhedonia, two domains with limited current treatment options, and emerging data suggest intranasal esketamine may be effective as monotherapy for treatment-refractory depression (Jawad et al., 2023; Use of SPRAVATO as Monotherapy, n.d.). This begs the question: where should ketamine be placed in the hierarchy of interventions for treatment-refractory depression?

Given the novelty of ketamine as a treatment for depression, much remains to be determined regarding safety. Acute side effects are well known and are limited to the immediate timeframe during and following treatment. This is largely due to the “interventional” nature of delivery. In contrast to daily medication administration to achieve therapeutic steady-state levels in the system, current validated protocols using ketamine often utilize a schedule of approximately six treatments during the first two weeks of treatment followed by monthly “boosters.” As such, while patients may experience some side effects during and immediately after the treatment, side effects are uncommon in the days between treatments once the medication has left the system (Nikayin et al., 2022). What remains unknown are the potential long-term side effects of ketamine treatment, particularly over repeated clinical exposures; further evidence is necessary to fully determine where to place ketamine in the treatment hierarchy for refractory depression.

Importantly, ketamine produces a potent psychoactive effect with rapid onset and offset, predisposing it to risk of abuse. Studies of habitual users of illicit ketamine have shown the main side effects of concern are cognitive decline and interstitial cystitis. However, it should be noted that these are seen with use in quantities significantly greater than those used for depression treatment. While some evidence suggests no long-term risk of interstitial cystitis or cognitive decline if administered in adherence with evidence-based protocols, others have called attention to insufficient longitudinal data that make it impossible draw conclusions regarding long-term risks (Nikayin et al., 2022; Zhang et al., 2016). Ethical concerns have emerged with off-label prescribing of ketamine due to its potential abuse liability and lack of standardized protocols that may predispose patients to unforeseen harm. In addition, insufficient long-term data limit the ability of physicians to adequately inform patients of the risks and benefits of treatment, and case reports of interstitial cystitis are beginning to emerge in community medical settings that utilize experimental regimens not supported by current data (Chang et al., 2024; Zhang et al., 2016).

While there is a need for long-term safety data, current evidence utilizing validated protocols of ketamine administration suggests that psychiatry must critically consider where ketamine should be placed within the treatment hierarchy for refractory depression. As noted above, if the short-term side-effect burden of ketamine is compared to conventional depression treatments, it appears that ketamine may be a more tolerable intervention. Additionally, recent data shows that esketamine augmentation is more effective than quetiapine for treatment-resistant depression. Along with evidence suggesting ketamine’s non-inferiority to ECT, it may be reasonable to infer that ketamine is at least as effective, if not more so, than many conventional strategies for refractory depression (Folkerts et al., 1997).

We submit that given ketamine’s position as a treatment of last resort, the next logical research question should be to compare ketamine against other second-line treatments for depression, such as augmentation strategies for first-line monoamine reuptake inhibitors. While clinical trials show augmentation can be efficacious when prior treatments have failed, many strategies come with significant side effects. It is well established that mirtazapine and serotonin/dopamine receptor antagonists, while effective, increase the risk for metabolic-related disorders like diabetes and hyperlipidemia (Laimer et al., 2006; Reynolds and Kirk, 2010). While the doses of aripiprazole used for depression augmentation may carry less metabolic risk, short-term side effects can be significant, with the most commonly reported side effects being akathisia and parkinsonism (Hsu et al., 2018). Serotonin/dopamine receptor antagonists and certain types of monoamine reuptake inhibitors often produce significant anticholinergic effects, which may be associated with an increased risk of dementia (Coupland et al., 2019). Medications for bipolar disorder, like lithium, while generally safe, require frequent monitoring and risk end-organ damage if levels are too high. While we are still determining the long-term effects of ketamine treatment, evidence suggests ketamine may be more effective than the above augmentation strategies and carries a more tolerable short-term side-effect profile with minimal known long-term side effects if used appropriately.

While the price of generic ketamine is low, the interventional nature of treatment results in additional costs. If ketamine were to be escalated up the depression treatment hierarchy, the field must either develop new models of delivery that conserve resources while expanding availability or show that treating depression with ketamine as a second-line augmentation strategy results in reductions in overall healthcare expenditures. Currently, providers using ketamine off-label have started to utilize group-based models to lower out-of-pocket expenses; however, no data exist showing whether this approach has comparable efficacy to individual treatment models. Similarly, providers have also started using ketamine to assist psychotherapy. While more data are needed to assess ketamine’s efficacy as a psychotherapy adjunct, this model may provide a way to minimize the need for recurrent ketamine treatment by relying upon the facilitation of the psychotherapeutic process rather than ketamine itself. Regarding overall healthcare costs, while there is no data evaluating the long-term cost-effectiveness of early intervention with ketamine for depression, there are comparable data in schizophrenia that suggest early intervention with clozapine reduces overall healthcare costs due to a reduction in the cumulative burden of disease (Butler et al., 2022). Given the substantial impact of depression, particularly treatment-refractory depression, on healthcare expenditures, lost productivity, and unemployment, determining the overall cost-effectiveness of ketamine in comparison to the existing standard of care should be a matter of pressing concern (Zhdanava et al., 2021).

Ketamine has recently been shown to be non-inferior to ECT, one of psychiatry’s most effective treatments for severe depression, and has a low side-effect burden given the schedule inherent to its interventional nature (Anand et al., 2023; Nikayin et al., 2022). Compared to other second- and third-line augmentation strategies for refractory depression, ketamine appears to be more effective, better tolerated, and safer. While more data are needed on long-term side effects, current data suggest that using ketamine as a second-line augmentation strategy for refractory depression may be indicated, and doing so may reduce the overall burden of disease, thereby decreasing healthcare costs and improving the quality of life for patients suffering from refractory depression (Lam et al., 2024).