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

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 use 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. ClinicalTrials.gov identifier: NCT04226963

Safety and Tolerability of the Acute Ketamine Treatment in Treatment-Resistant Depression: Focus on Comorbidities Interplay with Dissociation and Psychomimetic Symptoms

“…The primary strength of this study is the report on a specific population of interest that answers the question of safety profile in subjects presenting comorbidities and generates a hypothesis for further research. Another limitation is whether it was antiepileptic medication rather than the diagnosis of epilepsy which led to the increases in BPRS in these participants—which stands in line with our previous findings [ 31 , 32 ]. Post hoc analysis from the observational registry cannot be generalized nor produce causative observations.…”

“…The sample selection for this study has been described in detail elsewhere [ 31 , 32 , 33 , 34 ]. Briefly, the study population comprises subjects enrolled in a naturalistic safety and tolerability registry protocol for ketamine infusions in TRD.…”

Comment on ‘Characteristics of poisonings involving ketamine in the United States, 2019–2021’

“…In recent years, ketamine use has become more widespread in the United States, which can be attributed, in part, to the increasing availability of ketamine in psychiatric treatment settings which subsequently could have led to increased interest in nonmedical use. Although ketamine poisoning is rare, it has increased in recent years due to polysubstance use (Włodarczyk et al, 2021).…”

“…The discussion is of prime importance as it well refers to the review findings and provides evidence for future research in the field. In our opinion, the concerns around the prolonged use of small doses of ketamine as a result of both its clinical use and as a form of self-medication and/or recreational use are also worth being analysed (Szarmach et al, 2021; Włodarczyk et al, 2021).…”

“…The paper points out that ketamine, combined with other central nervous system depressants, may increase the risk of respiratory depression (Palmar et al, 2022). It is known that adverse events during ketamine treatment were relatively common; most of them were mild or moderate (Wilkowska et al, 2021; Włodarczyk et al, 2021). It is hypothesised that adverse events are more common when ketamine is used as an add-on treatment combined with other psychopharmacological therapies (Włodarczyk et al, 2021).…”