Ketamine as an Effective Therapy for Treatment-resistant Depression
Major Depressive Disorder (MDD), colloquially known as depression, has plagued millions of people over the course of time, and research suggests that between 30-35% of depression cases meet the criteria to be deemed treatment-resistant depression (TRD) (Voineskos, Daskalakis, and Blumberger 2020; Olin et. al 2012). Despite the relatively low figure representing treatment resistance, a lot of the population experiencing depression maintains a low response rate to treatment in general. The ambiguity resulting from those statements is due in part to the absence of a universal definition of treatment resistance as a result of a lack of concurrence by professionals on a suitable definition; however, many researchers agree that depression can be deemed treatment-resistant after a paucity of symptomatic responses to two trials of antidepressant pharmacotherapy (Voineskos, Daskalakis, and Blumberger 2020). This common occurrence of poor responses to first-line antidepressant therapy presents a massive risk to patients as depression, especially the treatment-resistant subtype, introduces an exorbitant risk of suicide attempt and completion. The established difficulty in treating so many cases of depression has created room for masses of research to be done regarding effective second-line remedies, and recently, the FDA has allowed depression treatment and research with drugs such as ketamine.
Traditionally, TRD has been met with a switch from single-drug pharmacotherapy to adjunctive treatment with a second drug that is not technically an antidepressant alone. In these cases, lithium and second-generation antipsychotics are commonly used in conjunction with an antidepressant. In 2006, “The STAR*D trial reported a 16% remission in the group of patients taking citalopram augmented by lithium. However, in this large-scale study, lithium levels were kept quite low, which may have contributed to the low-response rate” (Voineskos et al, 2020). Conversely, in a comparison of 17 studies investigating the use of doses of lithium ranging from 300 mg to 1500 mg daily when used as adjunctive therapy, 10 of them found a response rate of at least 50% (Bauer et. al 2003). Similarly, several studies found that “Quetiapine [an antipsychotic] at a dose of 300mg per day demonstrated up to 48% response and 24.5% remission in combination with SSRIs [selective serotonin reuptake inhibitors] and has since been approved for adjunctive treatment of MDD by the FDA” (Voineskos, Daskalakis, and Blumberger, 2020). These results are encouraging, and for some people, they result in effective treatment of their ailment. Statistically, however, nearly most people with TRD who are treated with adjunctive lithium and antipsychotic pharmacotherapy do not experience any response. Although a response is not the same as remission, a response to treatment is still a desirable outcome. However, the low response rate and remission to these traditional treatments leave physicians, researchers, and patients wanting more.
There was little literature on TRD until the 1990s, and surprisingly enough, it was only a decade later when ketamine’s antidepressive qualities were first investigated in a randomized controlled trial. Historically, ketamine has been used in humans and animals since the mid-20th century, beginning around the 1960s in humans. Over time, ketamine’s anesthetic qualities have been championed by doctors and patients. After meticulous research and product development, in 2019 the FDA approved the use of a ketamine derivative, esketamine, (brand name Spravato) to treat TRD. Although, it was not a decision taken without careful consideration, as it took nearly decades for enough evidence surrounding ketamine’s antidepressive qualities to come to light for the FDA to deem it an appropriate alternative treatment. In a study judging the effects ketamine had on suicidality in patients with TRD, assessed as two failed trials of antidepressant pharmacotherapy, 81% of patients scored either a 0 or 1 on the Mongomery-Asberg Depression Rating Scale Suicidality Item (MADRS-SI), scored 0-6, only 24 hours after a subanesthetic dose (0.5mg/kg) of intravenous racemic ketamine (Price et. al 2009). Other studies comparing ketamine therapy to electroconvulsive therapy (ECT), a historically somewhat effective last-line treatment for TRD, found that although ketamine and ECT have similar outcomes in the context of remission and response, ECT has been associated with more damaging side effects, such as memory loss. Although the antidepressant effects of ketamine are known to last only up to a week after a single infusion, one study found that ongoing ketamine treatments resulted in relapse a total of 19 days after the sixth infusion in 8 out of 9 patients (Rot et. al 2010). Despite this, ketamine has been found to work more quickly than ECT, with most patients experiencing rapid remission and response hours after a single infusion, while ECT patients generally require 6-12 treatments to achieve the same results.
Despite the short-lived benefits of using ketamine as an antidepressant, it works faster than other alternative treatments, and it seems to elicit a higher response rate than ECT and polypharmacotherapy. Taking into account the overwhelming research that supports the use of clinically administered ketamine, as well as the FDA’s approval of esketamine, it can be suggested that for patients experiencing TRD, there may be relief in ketamine treatments.
*Edited by Samuel Jaffe
References
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Voineskos, Daphne, Zafiris J Daskalakis, and Daniel M. Blumberger. “<p>Management of Treatment-Resistant Depression: Challenges and Strategies</p>.” Neuropsychiatric Disease and Treatment Volume 16 (January 21, 2020): 221–34. https://doi.org/10.2147/ndt.s198774.
