The Effects of Multidose Ketamine Treatment on Cognitive Performance Over Time in Patients With TRD

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Ketamine, a dissociative anesthetic, has been found to have rapid antidepressant and anti-suicidal effects at low doses in individuals with treatment-resistant major depressive disorder (MDD).¹ Although the effects of a single dose on mood are experienced quickly, in contrast to most antidepressants, the effects are generally short lived. This has prompted the development of multidose treatment regimens for individuals with treatment-resistant depression (TRD) to extend the effect.

As more treatments have become available, interest has grown in monitoring how greater instances of exposure to ketamine, even in the low doses used in clinical applications, may positively or negatively affect neurocognition beyond the acute effects following treatment administration.

Although single therapeutic doses of ketamine have been shown to induce acute negative effects on cognitive performance on tasks of attention, executive function, and verbal memory in patients with depression, and multi-domain cognitive impairments in healthy individuals, performance returns to baseline within 24 hours.^2,3

However, as multiple-dose treatment schedules become increasingly common, clinicians and researchers have begun to pay closer attention to the serious neurocognitive deficits associated with higher-dose recreational ketamine abuse, as well as the detrimental changes to brain structure that have been seen in some animal models.^4,5

Moreover, as both the isolated S-enantiomer esketamine (which was approved for use in adult TRD in 2019) and intravenous (IV) racemic ketamine (which is offered off-label for TRD) are increasingly being used in clinical/non-research settings, the need to characterize ketamine’s impact on patient cognition as it is used in real-world, clinical applications is vital.^6,7

In the context of these emerging questions regarding the long-term effects of therapeutic applications of ketamine for TRD, we aim to characterize how the number of treatments over time correlate with changes in cognitive performance on a standardized, multidomain battery in patients treated in a real-world, clinical setting. We thus present a retrospective analysis of 25 patients who received IV ketamine for TRD over a timeframe of up to 2 years.

Methods

Participants

The present analysis included the data from 25 patients receiving ketamine as a clinical treatment for MDD from Yale Interventional Psychiatric Services (IPS). Data represent 587 total ketamine treatments, with the median number of treatments received equaling 21.5. Included participants ranged in age from 16 to 66 years of age at the time of first ketamine treatment. The sample included 8 males and 17 females.

All participants had a diagnosis of MDD, verified via the Mini International Neuropsychiatric Interview, and were considered treatment resistant, having failed to respond to at least 1 antidepressant at time of intake. Patients with a diagnosis of schizophrenia or schizoaffective disorder, or a recent (within 6 months of intake) diagnosis of substance use disorder were not included in the analysis.

All participants, and legal guardians for participants under the age of 18 years, provided signed, informed consent. As this study constitutes secondary data analysis, it was judged exempt from full IRB approval.

Procedure

Prior to ketamine treatment, all patients completed a physical exam, chemistry and hematological bloodwork, and an EKG. The clinical protocol consisted of IV ketamine infusions twice per week at a dose of 0.5mg/kg of body weight over 40 minutes. Dosing was based on ideal body weight if a patient’s BMI was greater than or equal to 30. During each ketamine infusion, patients were monitored via pulse oximetry, heart rate, and 3-lead EKG continuously as well as via blood pressure measurement every 5 minutes.

As this study aimed to reflect a real-world clinical setting, subsequent treatments were gradually tapered in frequency based on the clinical status of the participant. Patients included in this sample received between 5 and 45 infusions over a timeframe of up to 2 years.

Cognitive performance was assessed using the CogState Battery, a series of standardized neuropsychological tasks that have been used in other psychopharmacological studies to effectively characterize various aspects of cognition.⁸ The CogState Battery has shown acceptable test-retest reliability and offers multiple parallel versions of each task in order to minimize practice effects.^9,10

The subtests utilized in our analysis were the immediate and delayed recall portions of the International Shopping List (ISLT; verbal learning), the Detection Test (DET; processing speed), the Identification Test (IDN; attention), the One Card Learning Test (OCL; visual learning), the One Back Test (OBT; working memory), and the Two Back Test (TWB; working memory). The OBT was scored to produce measurements of both task accuracy and the patient’s reaction time.

Patients completed the assessment battery at baseline, 2 weeks following their first infusion, and during their 3-, 6-, 12-, 18-, and 24-month follow-up appointments, during which many participants continued to receive maintenance dosing. On days in which participants received treatment, assessments were completed prior to infusions. As the present sample reflects real-world clinical data, patients may have been unable to complete the full cognitive testing battery at every follow-up time point due to timing and resource constraints.

Statistical Analysis

Random effects regression models were used to test for associations with cognitive performance. In the models, each cognitive measure represented the dependent variable; the time and number of ketamine infusions were included as continuous predictors; and random intercepts and/or slopes were included to account for the correlation between measurements within the same subject. Each regression coefficient was estimated at a 95% confidence interval (CI), and the best-fitting model was determined using information criteria.

The model allowed for using all available data on each participant even in the presence of missing data at a given timepoint. Based on the small sample size and exploratory nature of the study, power was limited. However, results are informative in providing preliminary examination of associations and estimates of effect sizes to guide future studies. All tests were tested at the 2-side 0.05 alpha threshold and conducted using SAS, version 9.4 (Cary, NC).

Results

No deleterious effects of multidose ketamine regimens on patient cognition were observed (Figure).

Figure. Effects of Multidose Ketamine Regimens on Patient Cognition

A modest positive association was identified between the number of ketamine treatments and the delayed recall portion of the ISLT (β = 0.104, 95% CI: 0.022 – 0.186, p = 0.013), such that for every 10 additional infusions, an additional item was recalled from the initial list after a 20-minute time delay.

A signal of worsened performance with increased numbers of treatments was observed for DET (β = 0.004, 95% CI: -0.0001 – 0.008), such that for each additional treatment, the mean time to detect the card had turned over increased by 0.4%. However, this effect did not reach significance (p=0.052). None of cognitive tasks considered were associated with time.

Discussion

The present study represented a retrospective analysis of neurocognitive data collected from a real-world clinical sample of patients receiving IV ketamine over a period of up to 2 years. Using a sample of 25 participants who received between 5 and 45 treatments over the course of the assessment period (median 21.5), we aimed to explore whether time or number of treatments correlated with changes in a range of cognitive functioning as measured by the CogState Battery.

Our analysis found small but significant performance gains in verbal learning, as measured by the delayed recall portion of the ISLT, and no indication of significant neurocognitive performance changes on the other included subtests.

The lack of significant impairment is consistent with existing randomized controlled trails of ketamine and open-label studies of ketamine for TRD.¹¹ Notably, most studies evaluating the neurocognitive effects of ketamine for TRD assess cognition only at the conclusion of a fixed number of doses, delivered over the course of several weeks, and generally find a neutral or positive effect of treatment on cognitive performance across the majority of assessed domains.

Dai and colleagues’ 2022 retrospective chart review of cognitive changes in 25 patients with TRD following 8 to 10 doses of IV ketamine similarly found no significant difference in cognitive performance from baseline. Similarly, findings from the long-term follow-up data on esketamine similarly showed stable cognitive performance over time in a large sample (N=1,148), although some indications of slowed reaction time, as measured by the DET, were found among older participants.¹²

Though the reduction in performance on DET in our sample did not reach statistical significance, the indication toward a reduction in processing speed with additional treatments would be consistent with previous research in multidose treatment schedules.^13,14

Since our study was not powered to detect significant changes, research focusing on ketamine’s long-term effects on processing speed in particular may be beneficial for providing a more robust and accurate profile of ketamine’s adverse effect profile.

Findings of performance improvements in verbal learning, as was observed in our sample, have been variable, with some reporting similar modest improvements^12,15,16 and others finding no effect of treatment on verbal memory¹³ or a reduction in performance.¹⁴ Considering the high variability of findings in this area, as well as the range of tasks used to assess performance, more research is needed to understand how long-term ketamine treatment may affect verbal learning, particularly with the flexible dosing schedules used in clinical contexts.

Strengths, Limitations, and Future Directions

Our findings contribute to the body of research on the safety and efficacy of ketamine for TRD, with our analysis finding no significant impairment of performance as a function of time or number of ketamine treatments. The lack of neurocognitive impairment observed when more ketamine treatments are administered than would generally occur over the course of a trial, and over a longer time course, offers valuable data in support of ketamine’s safety as it is administered in typical clinical use.

However, there are several notable limitations to the present analysis. Firstly, the small sample size of only 25 patients means that the present study was not sufficiently powered to detect small or moderate changes in cognitive performance resulting from treatment.

Secondly, this constitutes secondary analysis without adjustment for multiple comparisons. Thus, the aim of our analysis was to offer preliminary data from a real-world clinical setting and offer an estimation of the presence or absence of a signal of cognitive change in order to guide future studies.

Similarly, the uncontrolled nature of the treatment leaves a high likelihood that non-specific effects may play a role in the reported findings. Future studies with larger samples are needed to fully characterize how ketamine treatment affects cognition in MDD and TRD, particularly in typical clinical use.

Ms Kumpf is a postgraduate associate in the Child Study Center at Yale University School of Medicine in New Haven, Connecticut. Mr Pittman is a psychiatry statistician at Yale University School of Medicine. Dr Wilkinson is an associate professor of psychiatry and associate director of the Depression Research Program, Psychiatry, at Yale University School of Medicine. He is the author of the new book Purpose: What Evolution and Human Nature Imply About the Meaning of Our Existence.

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