Major depressive disorder (MDD) is a common and disabling mental condition that affects up to one in five adults in the United States during their lifetime, and more than 300 million people worldwide at any given time, according to the World Health Organization (Hasin et al., 2018; World Health Organization, 2017). Furthermore, up to one-third of patients are considered to have treatment-resistant depression (TRD), defined as an insufficient response to two more adequate trials of antidepressant medications .
Ketamine, an N-methyl-D-aspartate receptor antagonist, was demonstrated to have a rapid antidepressant action in a randomized double-blind trial for the first time in 2000 . Since then, emerging studies have indicated rapid and robust antidepressant effects of ketamine in adults with TRD (Andrade, 2019; Domany et al., 2019; Fava et al., 2020b; Marcantoni et al., 2020; Wilkinson and Sanacora, 2016). A single subanesthetic (0.5 mg/kg) dose infusion of intravenous (IV) ketamine has rapid-acting and robust antidepressant effects in at least 50% of patients, however, the effects dissipate by day 10 to day 14 [10–14]. Patients not responsive to a single infusion of ketamine may improve with subsequent infusions, and improvement following a single infusion can be sustained by subsequent infusions [15–17].
Cognition plays a key role in recovery and functional outcomes in MDD . Given known harmful effects of ketamine in cognition when used in cohorts struggling with ketamine use disorders, there has remained concern that serial administration of low dose ketamine could have the potential to negatively affect cognition. Human results of acute ketamine use on memory are mixed . Results of studies on chronic ketamine use have suggested that individuals who had taken high doses of ketamine frequently or abused it for a long period of time could be more prone to experiencing serious neurocognitive impairment [20–22]. Furthermore, a single infusion of ketamine (0.4 or 0.8 mg/kg) induced dose-dependently impaired episodic and working memory and slowed semantic processing, recognition memory, and procedural learning, and infusion of analgesic doses (8–20 mg/h) in healthy volunteers was shown to produce significant deficits in cognition [23, 24]. On the other hand, Ning’s group noted no deterioration in cognitive function from six ketamine infusions at 0.5mg/kg over 12 days [25, 26]. Instead, a single infusion of 0.5 mg/kg in TRD patients was seen to be slightly beneficial in attention and response control .
As concerns regarding ketamine and cognition have evolved, concomitant curiosity regarding the predictive value of baseline neurocognitive function has emerged [26, 28, 29]. Murrough et al (2014) have suggested individuals with TRD performing with lower neurocognitive function at baseline were more likely to obtain a positive antidepressant response from a single ketamine infusion. On the other hand, a study conducted be Bönke’s group indicated no significant correlation between baseline cognitive performance and a change in symptom severity, nor a correlation between a change in cognitive performance and antidepressant responses from six series ketamine infusion treatments .
In 2018, we began to treat patients with TRD by ketamine infusion in the translational Ketamine Service at McLean Hospital. Over the years, we have refined a serial infusion ketamine protocol based on the evolving literature and our clinical experience. The protocol includes an induction phase and either a booster or maintenance phase. The induction phase consists of 8-10 treatments on a twice-weekly schedule with the IV ketamine does initiated at 0.5 mg/kg over 40 minutes; thereafter, titration to response was permitted in a conservative fashion at the discretion of the ketamine team with the maximum dose up to 1.0 mg/kg. After the induction phase, if the patient achieved a substantial response, patients had the option of completing the phase with a brief taper series. Thereafter, patients were instructed to return for booster infusions (generally between 1 and 3 infusions) if depression symptoms returned.
In this real-world context, the investigation below seeks to 1) report the neurocognitive effects of repeated ketamine infusions in patients with TRD who have finished the induction phase through a retrospective chart review and 2) examine whether there is an association between cognition at baseline and antidepressant effects induced by repeated ketamine infusion.