More new research on the psychopharmacology of old drugs

Abstract

This edition of the Journal of Psychopharmacology has papers on two of the most venerable agents in central nervous system pharmacology. Ketamine was first synthesised in the USA in 1962 by Professor Calvin L. Stevens, and repurposing this dissociative anaesthetic has been one of the most interesting psychopharmacological tales of the 21st century to date. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. From the early studies, which showed a rapid onset of antidepressant action, the intravenous infusion of the racemic mixture of ketamine is now a recommended treatment in some countries (Swainson et al., 2020). Janssen have developed a nasally administered formulation of (S)-ketamine, which has been approved as a medicine for treatment-resistant depression in the USA and more recently in Europe (Mahase, 2019). Despite this, important questions remain to be answered. Foremost amongst these relate to the mechanism of action of ketamine and the relative roles of (S)-ketamine, (R)-ketamine and the racemic mixture. Jelen et al. (2020) outline these questions in detail and signpost what is needed in future research. Similarly, Bevilacqua et al. (2021) report a randomised controlled trial which examines a putative role of nitric oxide signalling in the antidepressant mechanism of action of ketamine. Work of this nature, which seeks to understand the molecular mechanisms underlying ketamine’s clinical benefits, will likely be the springboard to the development of further generations of treatment. Once an effective drug treatment is identified in psychiatry, clinicians and researchers almost inevitably investigate that treatment’s benefits in (trans)diagnostic categories or symptom domains related to the original indication. In this tradition are papers by McIntyre et al. (2021), who report on the effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder who present with prominent anxiety; Lattie et al. (2021) who report on the anxiolytic effects of acute and maintenance ketamine, and Lucchese et al. (2021) who report the impact of the degree of treatment resistance and anxiety co-morbidity on the effects of repeated subcutaneous esketamine for treatment-resistant depression. Alcohol misuse is a common feature of treatment-resistant depression, and Rothberg et al. (2021) report results from a randomised controlled trial which show that mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking. Our final two ketamine papers report more physiological aspects of this ‘new’ treatment. Zhou et al. (2021) report on a topic of clear interest, namely the cardiovascular effects of repeated sub-anaesthetic ketamine infusion in depression. Finally, Roy et al. (2021) report preliminary evidence from adolescents with treatmentresistant depression of brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine. Clearly, if these markers stand the test of replication, they will greatly advance the field. If ketamine is an old drug being repurposed, lithium is an element almost as old as our universe. Lithium’s entry to our pantheon of medicines was heralded by John Cade’s seminal paper in 1949 and, over the subsequent decades, lithium has become accepted as the gold standard ‘mood stabiliser’. Nevertheless, important concerns remain about the clinical benefits and harms of lithium, and three of these are the subject of papers in this edition. Poels et al. (2021) report data from The Netherlands which show that lithium exposure during pregnancy increases foetal growth – a most useful addition to the scientific literature concerning lithium’s role in perinatal psychiatry. Scandinavia continues its fine tradition of research into the monovalent cation. Falhammar et al. (2021) report a reduced risk for hospitalisation due to hyponatremia in lithium-treated patients in a Swedish population-based case-control study. Lithium’s effects on the kidney remain a great clinical concern, and thus Golic et al.’s report (2021) about starting lithium in patients with compromised renal function – asking is it wise – is timely. These will hopefully not be the last papers we see on lithium, especially as we now recognise environmental lithium’s significant benefits on suicide and potentially other aspects of health (Memon et al., 2020). These findings open the prospects of future basic and clinical studies on the effects of lithium on brain development and health. These papers will very likely not be the end of new research on the psychopharmacology of old drugs. We look forwards to future studies on ketamine and derivatives, psychedelics (old agents currently being rapidly rehabilitated and brought into the pharmacopoeia) and of course the everfascinating element, lithium. More new research on the psychopharmacology of old drugs