Treatment-resistant depression (TRD) poses a significant challenge in psychiatry. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a rapid-acting antidepressant, showing promise in both major depressive disorder (MDD) and bipolar disorder type I (BP). However, its clinical use is accompanied by safety concerns, primarily related to the potential for adverse events, particularly dissociative and psychomimetic symptoms. Dissociative symptoms, including memory gaps, out-of-body experiences, depersonalization, and derealization, are frequently associated with ketamine administration. While some studies suggest a link between dissociative symptoms and treatment response in TRD, others find no such relationship. The impact of comorbidities on the safety and tolerability of ketamine in TRD remains largely unclear. This study aimed to comprehensively evaluate the safety and tolerability profile of intravenous ketamine in a naturalistic setting, focusing on the potential influence of comorbidities on the occurrence of dissociative and psychomimetic effects, as measured by the Clinician-Administered Dissociative States Scale (CADSS) and the Brief Psychiatric Rating Scale (BPRS). The study's significance stems from the need to understand and mitigate potential risks associated with ketamine treatment in a diverse patient population that often presents with multiple co-occurring medical and psychiatric conditions. This knowledge is crucial for optimizing treatment strategies and ensuring patient safety.

The literature on ketamine's use in TRD reveals its potential efficacy alongside safety concerns. Studies have explored the relationship between dissociative symptoms and response, with some suggesting dissociative symptoms predict treatment response, while others contradict this finding. There's a scarcity of data on ketamine's use in TRD patients with comorbidities. Existing studies, including the authors' prior work, have examined the short-term administration of ketamine, mainly focusing on CNS adverse effects. The existing literature underscores the need for further research to clarify the complex interplay between ketamine's effects, dissociative symptoms, and the presence of comorbid conditions. This study directly addresses this gap by focusing on a population with a high prevalence of comorbidities, contributing significantly to the current understanding of ketamine's real-world safety profile.

This study employed a naturalistic observational design (NCT04226963), analyzing data from 49 inpatients with MDD or BP who met the criteria for TRD. TRD was defined as inadequate response to at least two different classes of antidepressants. Patients were medically stable and continued their baseline medications during the study. Participants received eight intravenous ketamine infusions (0.5 mg/kg) over four weeks, with safety monitoring every 15 minutes before, during, and up to 90 minutes post-infusion. Safety monitoring included vital signs and assessments using the CADSS and BPRS to measure dissociative and psychotic symptoms. The Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) were also used to assess mood symptoms. Electrocardiograms (ECGs) were performed before every other infusion and one week post-treatment. Comorbidities (hypertension, diabetes, hyperlipidemia, post-stroke, epilepsy) were recorded from medical records. Data analysis used mixed-model ANOVA to assess the interaction between comorbidities and CADSS/BPRS scores over time. The Kruskal-Wallis test and Cramer's V were used for group comparisons. A Bonferroni correction was applied to adjust for multiple comparisons. Responders, remitters, and non-remitters were defined based on MADRS scores at the one-week follow-up.

Of the 49 participants, 21 had comorbidities. Post-dose maximum CADSS and BPRS scores generally decreased after each ketamine infusion within 60 minutes, except in patients with epilepsy. At the one-week follow-up, no persistent CADSS or BPRS elevations were observed. Mixed-model ANOVA revealed a significant main effect of time for CADSS scores only in patients with hyperlipidemia, although this significance was lost after Bonferroni correction. Similarly, the main effect of time on BPRS scores was only significantly increased in the epilepsy subgroup (n=6). Specifically, significant increases in BPRS scores were observed after the 1st, 6th, and 8th infusions for patients with epilepsy, indicating potential exacerbation of psychotic symptoms in this subgroup. The analysis did not reveal significant associations between other comorbidities and changes in CADSS or BPRS scores over time after Bonferroni correction.

This study's findings suggest a generally favorable safety profile for short-term intravenous ketamine in TRD patients, even those with comorbidities. The transient nature of dissociative and psychomimetic effects, resolving within an hour post-infusion for most patients, is reassuring. However, the significant exacerbation of BPRS scores in the epilepsy subgroup warrants careful attention. This highlights the importance of individualized treatment approaches considering the patient's specific comorbidities, particularly epilepsy, and suggests the need for enhanced monitoring in patients with epilepsy receiving ketamine infusions. The study's results are consistent with findings from esketamine trials, but also point to a potential unique vulnerability in patients with epilepsy. Further studies are needed to investigate this interaction and potentially explore alternative strategies for managing ketamine-related adverse effects in this patient population.

This post-hoc analysis from a naturalistic observational study indicates a generally favorable safety and tolerability profile for short-term intravenous ketamine in TRD patients with MDD and BP, even with comorbidities. However, patients with epilepsy showed a unique vulnerability to BPRS score increases, underscoring the need for careful monitoring and consideration of comorbid conditions during ketamine administration. Larger, longer-term studies with controlled designs are needed to confirm these findings and investigate potential long-term effects, particularly in subgroups like those with epilepsy. Clinicians treating TRD patients with ketamine should carefully consider individual comorbidities, particularly epilepsy, and implement close clinical supervision during each treatment session.

This study's limitations include the relatively small sample size, single-site design, lack of blinding, and the inclusion of both unipolar and bipolar depression patients. The observational nature of the study limits causal inferences. The CADSS assessment was limited to a single post-dose measurement (30 minutes post-infusion), preventing a precise characterization of the time course of dissociative symptoms. The potential influence of anti-epileptic medication on BPRS scores in the epilepsy subgroup requires further investigation. The results should be interpreted cautiously due to potential biases inherent in observational studies.