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Introduction: Major depression is a common, disabling mental health condition associated with the highest disease burden for any neuropsychiatric disorder worldwide, according to the WHO. Due to the imperfect efficacy and tolerability profiles of existing treatments, investigational compounds in novel treatment classes are needed. Opioid-receptor antagonists are a potential new class of treatments currently under investigation. Areas covered: Major depressive disorder is first overviewed. Existing treatments, both their mechanisms of action and their place within the antidepressant space, are discussed herein. Then, the profile of Aticaprant and the wider context of kappa-opioid antagonism for depression are discussed in focus. Expert opinion: Early evidence indicates that Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant. [ABSTRACT FROM AUTHOR]

Background: Psychosis-relevant preclinical studies have demonstrated GABAergic drugs such as benzodiazepines can downregulate hippocampal hyperactivity and prevent the emergence of psychosis- like phenotypes. However, whether benzodiazepines can reduce and normalise increased hippocampal resting cerebral blood flow (rCBF) observed in individuals at clinical high-risk for psychosis (CHR-P) remains unknown. Aims: To determine whether an acute dose of diazepam can reduce and normalise hippocampal and subfield rCBF in CHR-P individuals. Methods: We conducted a within-subject, double-blind, placebocontrolled, randomised, cross-over design study in 24 CHR-P individuals (mean [± SD] age: 24.1 [±4.8] years, 15F). Participants underwent two MRI sessions, three weeks apart; once under a single dose of diazepam (5 mg) and once under placebo (50 mg ascorbic acid). A previously collected dataset of 21 healthy controls (HC) was used for comparison. rCBF was measured using pseudocontinuous arterial spin labelling and sampled in each participant' s native space using participant-specific hippocampus/subfield masks generated with the MAGeT Brain toolbox. Individual Mixed ANCOVAs (covarying for global rCBF, age, and sex) and linear mixed-effects models (participant ID as random effect) investigated the effect of group (CHR-P placebo vs. HC and CHR-P diazepam vs. HC) and drug (CHR-P placebo vs. diazepam), respectively, on hippocampal/subfield rCBF per ROI. These models were repeated voxel-wise in study-specific template space to investigate whole-brain effects. Significance was set at pFDR<0.05. Pearson' s correlations assessed whether baseline clinical characteristics could predict diazepam-induced changes in hippocampal rCBF. Results: CHR-P individuals under placebo showed significantly increased rCBF compared to HC in the hippocampus (F(1,41)=24.7, pFDR<0.001), and this was significantly reduced by diazepam (t(69)=-5.1, pFDR <0.001) to the extent that it no longer differed from HC (F(1,41)=0.4, pFDR=0.204). This effect of hyperactivity and normalisation under diazepam was seen across all subfields studied and in several psychosisrelevant cortical and subcortical regions connected to the hippocampus, including medial/dorsolateral prefrontal cortex, nucleus accumbens, and amygdala. Smallest reductions in diazepaminduced bilateral hippocampal rCBF change were observed in CHR-P individuals with highest attenuated psychotic symptom severity (r= 0.494, p=0.014) and poorest social functioning (r=- 0.416, p=0.043) at baseline, which appeared to be driven by the left CA4/DG (positive symptom severity: r=0.528, p=0.008; social functioning: r=-0.503, p=0.012). increased rCBF in the hippocampus and subfields of CHR-P individuals, providing proof-of-concept of the efficacy of GABAenhancing drugs to modulate hippocampal hyperactivity in this clinical group. Our results that CHR-P individuals who were clinically most unwell showed the smallest changes in rCBF suggest the development of more hippocampal-selective GABAergic pharmacological agents (e.g., those targeting a5-GABAA receptors) as a promising strategy for regulating hippocampal hyperactivity and preventing psychosis development. [ABSTRACT FROM AUTHOR]

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies. [ABSTRACT FROM AUTHOR]