Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression

This open-label trial (n=49) assessed the safety and tolerability of intravenous ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BP) who were already using standard antidepressant medication. No antidepressants were associated with psychomimetic symptomatology except for citalopram. The use of classic mood stabilizers was significantly associated with an increase in psychomimetic symptomatology.

Abstract

“Background: There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine’s safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP).

Methods: A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol.

Results: No antidepressants were associated with psychomimetic symptomatology except for citalopram (p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The uise of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed.

Conclusions: Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients.”

Authors: Adam Wlodarczyk, Wieslaw J. Cubala, Maria Galuszko Wegielnik & Joanna Szarmach

Summary

This study aimed to investigate the safety and tolerability of ketamine in treatment-resistant depression and bipolar disorder and the relationship between dissociative symptomology and psychometric outcomes.

49 patients with MDD and BP were administered ketamine and observed.

No antidepressants were associated with psychomimetic symptomatology except citalopram (p = 0.019). Patients treated with classic mood-stabilizers showed an increased intensity of psychomimetic symptomatology.

Conclusions: Ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients.

ClinicalTrials.gov identifier: NCT04226963

Keywords: dissociation, ketamine, psychosis, safety, tolerability, treatment-resistant depression

Revisions accepted.

Introduction

Ketamine is effective for treating treatment-resistant depression in both major depressive disorder and bipolar disorder type I, but there are concerns regarding its safety and tolerability. In particular, dissociative symptoms may be associated with treatment response.

Methods and population

The sample selection methods for this study have been described in detail elsewhere. Briefly, patients diagnosed with TRD-MDD and TRD-BP were included in the study, and the CADSS was used to assess the acute psychoactive effects of ketamine.

Physicians use the BPRS and BPRS+ to assess treatment-emergent psychotic symptoms. The BPRS and BPRS+ are 18-item rating scales that consider the positive symptoms of suspiciousness, hallucinations, unusual thought content, and conceptual disorganization.

All patients enrolled in this study were medically stable and able to communicate and provide consent. They received antidepressants or mood stabilizers in monotherapy or in combination with an evidence-based strategy to treat bipolar depression.

This study was approved by the Independent Bioethics Committee for Scientific Research at Medical University of Gdask, Poland, and was prospectively registered at ClinicalTrials.gov.

Study design: ketamine infusions

This study followed an observational design, with patients continuing baseline psychotropic standards of care and treatment of chronic somatic diseases during ketamine infusions. Safety monitoring was performed every 15 min before, during, and after infusion, and until 90 min after the infusion.

A subject was a responder if their MADRS score improved by 50% or more from the baseline, or if their MADRS score decreased by 10 points.

Statistical analysis

All analyses were conducted using IBM SPSS Statistics 25.0. Fisher’s exact test, Mann-Whitney U test, Kruskal-Wallis H test, and mixed-model analysis were used to determine the differences between groups, and a level of significance of 0.05 was adopted for all tests.

Results

The use of classic mood stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the BPRS, except for risperidone, which was not associated with dissociative symptomatology.

A significant increase in CADSS was observed for the patient receiving risperidone between the fifth and seventh infusions, and between the sixth and seventh infusions. Among patients not receiving risperidone, the CADSS score was significantly lower following the eighth infusion. The scores in the BPRS were significantly higher in patients taking citalopram than in those who were not. The scores were also significantly higher between the second and fifth infusions and between the second and eighth infusions.

Patients being treated with lithium showed higher BPRS scores than those not taking lithium, and patients being treated with valproate showed higher BPRS scores than those not taking valproate. A simple effects analysis showed no significant differences within the group receiving lithium and the group not receiving valproate.

Patients who were treated with lamotrigine had a higher BPRS score after the eighth infusion compared with those who were not. The differences between the remaining measurements were not significant.

The post ketamine effects were observed without sequelae. There were no significant associations observed within the bipolar/depressive groups regarding psychomimetic or dissociative symptoms according to MADRS scores.

Discussion

The current literature suggests that central nervous system side effects related to intravenous infusion of ketamine occur relatively frequently. However, the current study suggests that the safety and tolerability of ketamine may be negatively affected when it is administered as an add-on to certain other psychopharmacological treatments.

Risperidone significantly increased dissociative symptoms over time, and four different concomitant antidepressant medications were associated with increased psychotic symptoms over time. These changes might be explained by increased dopamine neurotransmission and enhanced glutamate release.

Our results are in agreement with those of other studies that have reported no association between intensity of dissociative and psychomimetic symptomatology and antidepressive treatment by ketamine. However, some studies have reported an association.

The current study demonstrates that ketamine has an overall good safety profile for patients receiving antipsychotics and antidepressants, but that patients receiving mood stabilizers may be more prone to psychotic symptomatology.

Strengths

This study adds to the body of knowledge regarding the tolerability and general safety of ketamine administration, and supports the results of several previous studies.

Limitations

This study has several limitations, including the small sample size, observational design, lack of treatment blinding and control group, and short follow-up time. Future studies should investigate the role of ketamine-related CNS symptomology in treatment-resistant depression.

Conclusion

In patients with TRD, intravenous ketamine produces clinically relevant and measurable CNS-related adverse events. These adverse events seem to be related to concomitant psychotropic medication type, and symptom improvement following ketamine infusion does not appear to be related to either dissociative or psychomimetic symptomatology.

Conflict of interest statement

W, J, C, and MG have received research support from a number of companies, including Actavis, Eli Lilly, Minerva Neurosciences, Sunovion Pharmaceuticals, KCR, Janssen, Otsuka, Apodemus, Cortexyme, Acadia, and GW Pharmaceuticals.

Funding

The authors disclosed receiving financial support from the Medical University of Gdansk, Poland for the research described in this article.