Neuroscience & Biobehavioral Reviews
May 10, 2021
Laith Alexander, Luke A. Jelen, Mitul A. Mehta et al.
79 citations
The anterior cingulate cortex (ACC), including its subgenual, perigenual, and dorsal zones, plays a key role in major depression and its treatment. Ketamine, a rapidly acting antidepressant, induces acute (over minutes) and post-acute (over hours to days) changes in subgenual and perigenual ACC activity, and these changes can correlate with antidepressant efficacy. The subgenual and dorsal ACC zones are specifically linked to ketamine's anti-anhedonic effects. The review emphasizes combining human neuroimaging with animal brain manipulations to understand causal relationships between brain activity and therapeutic outcomes. Circuit-based perspectives highlight ACC function in a central network mediating affective pain and its role as the anterior node of the default mode network.
Translational Psychiatry
December 3, 2023
Laith Alexander, Peter C. T. Hawkins, Jennifer W. Evans et al.
26 citations
Ketamine's antidepressant effects involve changes in brain connectivity that depend on which part of the anterior cingulate cortex (ACC) is examined. In a double-blind, placebo-controlled crossover trial, patients with treatment-resistant depression and healthy volunteers received intravenous ketamine or placebo. Two days later, resting-state functional connectivity between ACC subregions and other brain areas differed between groups. Changes in perigenual ACC connectivity to the insula correlated with improved depression scores. Subgenual ACC connectivity was most altered by ketamine compared to placebo, and changes in its connectivity to other ACC subregions and the ventral striatum correlated with reduced anhedonia. Accurate ACC segmentation is needed to understand ketamine's effects.
medRxiv
December 11, 2022
Hannah Hartland, Kimia Mahdavi, L. Jelen et al.
22 citations
Ketamine reduces anxiety symptoms within 12 hours of administration, and the effect lasts for 1 to 2 weeks. A systematic review and meta-analysis of 14 randomized controlled trials found significant reductions in anxiety scores compared to placebo at acute (less than 12 hours), subacute (24 hours), and sustained (7–14 days) time points. Improvements in anxiety and depression symptoms were correlated at 24 hours and at 7–14 days. The relationship between peak dissociation and anxiety improvement was not significant. Most studies had a high risk of bias.
Irish Journal of Psychological Medicine
August 19, 2020
John R. Kelly, Matthew Crockett, Laith Alexander et al.
16 citations
The medium- to long-term mental health consequences of COVID-19 are predicted to increase, requiring multidisciplinary strategies. Psilocybin therapy shows promise as a transdiagnostic treatment for disorders with maladaptive habitual patterns, such as depression, addiction, and obsessive compulsive disorder. The COMPASS Pathways phase 2b double-blind trial is testing psilocybin therapy in antidepressant-free treatment-resistant depression (TRD) to determine safety, efficacy, and optimal dose. Results from the Imperial College London Psilodep-RCT comparing psilocybin therapy to the SSRI escitalopram will soon be published. The efficacy and safety of psilocybin therapy with SSRIs in TRD is not yet known; a COMPASS study in Dublin will address this. Psilocybin therapy may play an important role in post-COVID-19 psychiatry, though it is at an early clinical stage.
British journal of pharmacology
October 28, 2024
Laith Alexander, Dasha Anderson, Luke Baxter et al.
11 citations
Psychedelic drugs are being investigated as a new class of rapid-acting antidepressants, but their mechanisms remain unclear—specifically whether antidepressant and psychedelic effects arise from related or independent processes. This review examines behavioral methods used in animal studies to measure both the psychedelic and antidepressant effects of these drugs. It highlights conceptual and methodological challenges, stresses the importance of using doses comparable to those in human clinical use, and calls for attention to potential sex differences in preclinical research. Understanding these mechanisms could help identify new drug targets and improve treatments.
Translational psychiatry
May 12, 2026
Linda Bryant, Laith Alexander, Sergio Mena et al.
A machine-learning model using structural brain scans predicted which adults with treatment-resistant depression would respond to a single ketamine infusion. The model, trained on 99 participants, achieved 72% balanced accuracy in the discovery sample and 60% in two independent groups, with performance dropping to chance in a saline-treated control group. Greater gray matter volume in frontal regions predicted response, while greater cerebellar volume predicted non-response. The findings suggest that pre-treatment brain structure may help guide personalized treatment decisions for ketamine therapy.