Ketamine: A new chapter for clinical psychopharmacology?

Abstract

Ketamine is an N-methyl-D-aspartate antagonist which has been a major focus of research recently and is being used as a putative treatment for depression and other neuropsychiatric disorders. Along with psychedelic agents, ketamine (and the derivative esketamine) are not only the main harbingers of potentially new classes of psychiatric drugs but may also share some common features (Marguilho et al., 2023). It should be noted that other novel mechanisms, such as those related to anti-inflammatory properties (Husain et al., 2017) are also emerging. However, the evidence base for ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder is evolving particularly quickly (Borentain et al., 2023) and more work is frequently published. Thus, we have a special edition devoted to novel findings about ketamine and related agents. James et al. (2023) contribute a systematic review of the safety of repeated ketamine dosing in paediatrics. Concerns about the long-term safety of ketamine and any potential impact on the developing brain are noted to be limiting research despite the fact that a wealth of paediatric safety and dosing data exists for ketamine, given its extensive use globally as an anaesthetic, analgesic and sedative agent. The results of the review suggest that, despite methodological limitations of the studies, ketamine is well tolerated and safe for use in children, even when given repeatedly in regimens analogous to those used for treatment of depression in adults. The authors suggest that these findings support the extension of research into the use of ketamine as a novel antidepressant in children. Hartland et al. (2023) report a transdiagnostic systematic review and meta-analysis of ketamine’s anxiolytic effects. As background, they note that ketamine may be effective in treating symptoms of anxiety, although the time profile of ketamine’s anxiolytic effect is ill-defined. Thus, this systematic review and meta-analysis examined the anxiolytic effect of ketamine at different time points across a range of clinical settings. They found that ketamine appears to offer rapid and sustained anxiety symptom relief across a range of clinical settings, with anxiolytic effects occurring within the first 12 hours of administration and seemingly remaining effective for 1–2 weeks. The authors suggest that future studies with improved blinding could explore ketamine maintenance therapy for anxiety. Chisamore et al. (2023) investigated the real-world effectiveness of repeated intravenous ketamine infusions for treatmentresistant depression (TRD) in transitional age youth (TAY). They note that the efficacy and safety of ketamine in TAY (age 18–25) populations remains understudied. This was a retrospective analysis of 52 TAY patients receiving ketamine for TRD who were matched for sex, primary diagnosis, baseline depression severity and treatment resistance with a general adult sample. Patients received four ketamine infusions over 2 weeks (0.5– 0.75 mg/kg over 40 minutes). The findings show that ketamine was associated with comparable clinical benefits, safety and tolerability in a TAY sample when compared to a matched group of general adult patients. Burrows et al. (2023) examined ketamine-induced changes in resting-state connectivity, 2 hours after the drug administration in patients with remitted depression. Resting-state connectivity has been linked to ketamine’s antidepressant effects with normalisation of the brain connectivity changes that are observed in depression. The authors note that these changes, usually co-occur with improvement in depressive symptoms, making it difficult to attribute these changes to ketamine’s effects per se. Significantly decreased brain connectivity was observed at 2 hours post ketamine infusion, compared to placebo. The executive network presented with altered connectivity with different cortical and subcortical regions. Within the network, the left hippocampus and right amygdala had decreased connectivity. Their findings support a model whereby ketamine might change the connectivity of brain areas and networks that are important for cognitive processing and emotional regulation. The authors speculate that these changes could also be an indirect indicator of the plasticity changes induced by the drug. Lin et al. (2023) report on their study about baseline cognitive function, which was shown to predict full remission of suicidal symptoms among patients with TRD and strong suicidal ideation after low-dose ketamine infusion. The authors note that whether pre-treatment working memory and response inhibition function are associated with the rapid and sustained antisuicidal effect of low-dose ketamine among patients with TRD and strong suicidal ideation is unclear. Their findings suggest that Ketamine: A new chapter for clinical psychopharmacology?