Review article
The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research

https://doi.org/10.1016/j.neubiorev.2020.11.020Get rights and content

Highlights

  • Intravenous administration of ketamine is not associated with anti-cognitive effects.

  • IV ketamine in patients with TRD may have pro-cognitive effects in brain areas associated with visual learning and working memory.

  • Future studies should focus on cognition as a domain of depressive psychopathology.

  • Anxious and non-anxious TRD patients may vary in their response to intravenous ketamine treatment.

Abstract

Replicated evidence has documented cognitive deficits in populations with treatment-resistant depression (TRD). Approximately 40 % of patients with MDD present with impairment of one or more cognitive domains. As such, there is an unmet need to discover treatments that have pro-cognitive effects in TRD patients. Ketamine has demonstrated efficacy as a rapid-onset intervention for the treatment of depression. The objective of the current review was to assess the effects of ketamine on cognition in TRD patients. We systematically searched PubMed, Google Scholar and PsycINFO between database inception to March 24th, 2020.

We identified five studies that evaluated cognition in TRD populations following ketamine treatment. All studies included a 0.5 mg/kg subanesthetic intravenous (IV) administration of ketamine. One study found significant improvements in complex (p = .008) and simple (p = .027) working memory and one study found improvements in visual learning memory following IV ketamine infusions (p = .014). Improvements in speed of processing and verbal learning memory were observed in anxious TRD participants only. Importantly, a subanesthetic dose of IV ketamine does not worsen cognitive function.

Introduction

Major depressive disorder (MDD) is characterized by significant cognitive and psychosocial impairments, compared to healthy subjects (Association and American Psychiatric Association, 2013). For example, nearly 40 % of patients with MDD present with impairment of one or more cognitive domains, including executive function, attention, memory, psychomotor speed and cognitive flexibility (Bortolato et al., 2015; Gualtieri and Morgan, 2008; Roger S. McIntyre et al., 2013; Motter et al., 2016). However, it is important to note that a dissociation exists between patient reports and objective assessments of cognitive deficits. Notwithstanding, persistent cognitive dysfunction contributes to occupational and psychosocial impairments, as well as diminished workplace productivity and functioning (i.e., presenteeism) or missed days at work (i.e., absenteeism) (Baune and Air, 2016; Lagerveld et al., 2010). Fewer than half of MDD patients achieve full symptom remission following first-line treatment options, with cognitive difficulties, sleep problems and low energy being the most common residual symptoms (Baune et al., 2010; Rush, 2007). Indeed, there is an ongoing debate on whether these deficits are an epiphenomenon of depression, with their own symptom progression, or a dimension of MDD. As such, this underscores the need for treatments that specifically improve cognitive functioning in patients with treatment-resistant depression (TRD; Knight and Baune, 2018).

Currently, antidepressants targeting the monoamine system provide modest improvements in depressive symptomatology for many individuals with MDD (Gaynes et al., 2009; Gitlin, 2006). Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study indicated that approximately 35 % of individuals with depression experience complete remission, while 65 % remain symptomatic following multiple antidepressant medication trials (Rush et al., 2006). Individuals suffering from TRD experience substantially longer depressive episodes, and greater work-related impairment (Rizvi et al., 2014). As such, current first-line antidepressants offer only modest improvements in neurocognition, with significant positive effects observed with only psychomotor speed and delayed recall in a subset of antidepressants, such as vortioxetine, with most antidepressants having no evidence for improving cognitive function (Rosenblat et al., 2015). The foregoing unmet needs underscore the need for a fast-acting, effective treatment for TRD with robust pro-cognitive effects (McIntyre et al., 2014).

Extant literature has evaluated the efficacy of ketamine, an N-methyl D-aspartate receptor antagonist, across numerous routes of administration, such as intravenous (IV), intranasal (IN), and oral routes (Coyle and Laws, 2015b; Fond et al., 2014; Rosenblat et al., 2019). The efficacy and safety of different ketamine formulations has also been assessed, such as racemic ketamine and the enantiomer esketamine and arketamine (Daly et al., 2018; Fava et al., 2018; Leal et al., 2020). For TRD, IV racemic ketamine and IN esketamine provide rapid onset antidepressant and anti-suicidal effects within 24 h following administration (Mathew and Zarate, 2016, Singh et al., 2016, Singh et al., 2017, van de Loo et al., 2017). The rapid efficacy of IV ketamine for patients with TRD has been further established through numerous randomized, double-blind, placebo-controlled trials, and large case-series from clinics providing off-label repeat-dose ketamine treatment for unipolar and bipolar TRD (aan het Rot et al., 2010; Berman et al., 2000; Coyle and Laws, 2015a; Daly et al., 2019; Kraus et al., 2017; Newport et al., 2016; Phillips et al., 2019). Our study assesses the effects of IV ketamine only, as the IN administration of esketamine lowers absorption predictability (Quintana et al., 2018).

Preliminary findings suggest that recreational abuse of ketamine may be associated with cognitive impairments in working memory, episodic memory and executive functioning (Morgan et al., 2009, 2014). The efficacy of ketamine in TRD patients provides the impetus to evaluate whether ketamine treatment can improve measures of cognition or limit anti-cognitive effects, as observed in the recreational use of ketamine. Notwithstanding the effects of typical monoamine-based antidepressants and recreational abuse of ketamine on cognition (Morgan et al., 2014; Rosenblat et al., 2015), the neurocognitive effects of ketamine in treatment-resistant depression is less clearly understood. Herein, we aim to systematically evaluate the effects of IV ketamine on cognition in TRD.

Section snippets

Literature search and study selection

Two independent reviewers (HG and BG) searched the literature for studies that evaluated cognition in TRD patients following ketamine treatment across all forms of administration (IV, IN and oral). We conducted a search on PubMed, Google Scholar and PsycINFO for English-language articles published between database inception to March 24th, 2020 using the following medical search heading (MeSH) terms and search strings: (Ketamine OR Esketamine OR S-Ketamine OR Arketamine OR R-ketamine) AND

Search results and study characteristics

After removal of duplicates, our database search returned 543 unique articles. An additional 3 articles were found through a manual search of the references. Subsequently, 546 titles and abstracts were independently reviewed for eligibility. The full text of 16 articles were screened for eligibility.

Following full-text review, 11 articles were excluded for not meeting the outlined inclusion criteria and primary study outcomes. The reasons for exclusion are as follows: seven articles were

Discussion

Our review explored the effects of ketamine on neurocognition in TRD populations. The primary cognitive measures amongst the included studies were WM, SOP, VBM and VSM. Improvements were observed in complex and simple WM (Shiroma et al., 2014). Similarly, improvements in SOP (one day and two weeks) and VBM (one day) were observed in anxious TRD patients following ketamine treatment (Liu et al., 2019). Meanwhile, only one study found improvements in VSM following IV ketamine infusions. However,

Limitations and future directions

Current findings suggest that IV ketamine may have positive effects in working memory, anxious depression (the negative valence systems) and anhedonia (the positive valence system). Future studies should aim to expand on the effects of IV ketamine with these specific domains of cognition, as well as a transdiagnostic approach of evaluating cognition in accordance with the RDoc criteria. Moreover, due to the limited number of studies that have evaluated the effects of IV ketamine on cognition in

Conclusion

In conclusion, our review emphasizes the need for further research regarding ketamine and its impact on cognition in TRD patients. While few procognitive effects are observed, all studies report no cognitive impairments following subanesthetic administration of ketamine. This differs from current findings evaluating prolonged recreational use of ketamine, which demonstrate anti-cognitive effects. However, current research is limited and studies are primarily conducted in experimental settings

Contributors and funding source

Authors HG and RSM developed the research hypothesis and study design. Author HG and BG conducted the data extraction, data analysis and wrote the final draft of the manuscript. All authors contributed to the final manuscript proofreading, edits and approval for submission. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

We want to extend our appreciation to all team members and co-authors for their contributions to this manuscript.

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