Social learning is important for societal functioning, and adolescence is a critical period for the development and maintenance of social behaviors. Specifically, the ability to establish and maintain beneficial social interactions while avoiding or withdrawing from detrimental or harmful ones is crucial for healthy interpersonal functioning. Beyond self-report measures, the multi-round trust game, a commonly used behavioral economics paradigm, can help elucidate differences in social decision-making between healthy and clinical populations. To more specifically probe the role of social learning and generosity sensitivity during social exchange in young people, we have designed a new task: the Social Learning-Generosity (SL-Gen) Task. Using versions of the multi-round trust game as a basis for the design, we have incorporated more environmentally realistic task components, including controlled gain, loss, and variable gain-loss generosity conditions. In a single-session online study, the present research investigated task behavior and task acceptability in individuals aged 18–24 from a United Kingdom census-based sample, as well as exploring task differences by self-reported trust and gender. While this task is sensitive to differences in self-reported trust and gender and behaves similarly to existing versions of the trust game with respect to these effects, it has added utility within mental health research and treatment contexts for characterizing social decision-making behavior in more detail using set generosity conditions.

The ability to form and sustain interpersonal relationships relies on the capacity to interpret social signals and update understanding of others’ behavior in dynamic contexts. Young adulthood is a critical period for refining these skills. Social learning and social reward responsivity have been implicated in depression, yet findings from social exchange studies remain mixed. Specifically, it remains unclear whether overall depressive symptom severity or specific symptoms such as anhedonia are most relevant to disrupted social decision-making. In a single-session online study, we examined social learning and generosity sensitivity in a UK population sample of young adults (18–24 years; n=553). Participants completed the Social Learning–Generosity (SL-Gen) task, a multi-round trust game paradigm designed to probe feedback-driven updating and behavioral adaptation to structured generosity conditions, alongside questionnaire measures of depression (PHQ-9) and social anhedonia (ACIPS). Depressive symptom severity was minimally associated with task performance; in contrast, greater social anhedonia and higher PHQ-9 anhedonia item scores were associated with differences in both evaluative updating and investment behavior. Specifically, individuals with greater social anhedonia showed lower initial investments, lower investments in higher generosity conditions, and smaller reductions in generosity ratings following unfair (loss-condition) interactions. Anhedonia was also associated with slightly flatter investment slopes in certain conditions. These findings suggest that anhedonia, rather than global depressive symptom severity, is linked to reduced sensitivity to negative social feedback. Task-based social learning measures may therefore help identify mechanistic subgroups within depression characterized by blunted social reward processing which may have utility for pinpointing treatment targets.

Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT4 receptor (5-HT4R) agonists rapidly improve learning and memory, consistent with this receptor's role in hippocampal neuroplasticity. However, their effects in clinically depressed patients, remain unexplored. In this double-blind, randomised study, 52 right-handed, unmedicated individuals with MDD received 6-9 days of the 5-HT4R agonist PF-04995274 (15mg, once daily) or placebo. Participants subsequently underwent fMRI scanning during a memory encoding task and completed behavioural measures of auditory verbal learning and spatial working memory. Compared to placebo, PF-04995274 significantly increased activity in the hippocampus (ROI analysis) in response to novel versus familiar images, particularly in the left hemisphere. Whole brain analysis also revealed greater activation in the left inferior parietal lobule, a key region for memory processing. In contrast with previous studies using the 5-HT4R agonist prucalopride, PF-04995274 had limited effects on behavioural measures of memory. The results demonstrate that short term 5-HT4R agonism enhances hippocampal and parietal activity during memory encoding in patients with depression. This replicates and extends previous findings in healthy volunteers using prucalopride, and is consistent with preclinical evidence establishing a key role for 5-HT4Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT4R activation in modulating memory-related brain circuits in MDD and highlights its therapeutic potential for treating cognitive symptoms of depression.

The discovery of ketamine’s rapid antidepressant properties in the past two decades put the glutamate system in the spotlight as a neurobiological treatment target for depression. One neurocognitive mechanistic model of ketamine’s antidepressant effect focusses on its impact on negative affective memories, namely making negatively valenced memories less salient. Here, we synthesise translational evidence from human and rodent studies which suggests that affective memory recall engages a distributed network areas including the amygdala, hippocampus and prefrontal cortical regions, with subgenual cingulate cortex potentially playing a key role in how NMDA receptor antagonists modulate the connectivity across this cognitive pathway. We discuss how experimental studies based on reinforcement-learning and value-based recall could be used to probe these systems and build mechanistic models of affective memory recall and fast-acting antidepressant action.

There is an ongoing need to identify novel pharmacological agents for the effective treatment of depression. One emerging candidate, which has demonstrated rapid-acting antidepressant effects in treatment-resistant groups, is nitrous oxide (N2O)—a gas commonly used for sedation and pain management in clinical settings and with a range of pharmacological effects, including antagonism of NMDA glutamate receptors. A growing body of evidence suggests that subanaesthetic doses of N2O (50%) can interfere with the reconsolidation of maladaptive memories in healthy participants and across a range of disorders. Negative biases in memory play a key role in the onset, maintenance, and recurrence of depressive episodes, and the disruption of affective memory reconsolidation is one plausible mechanism through which N2O exerts its therapeutic effects. Understanding N2O’s mechanisms of action may facilitate future treatment development in depression. In this narrative review, we introduce the evidence supporting an antidepressant profile of N2O and evaluate its clinical use compared to other treatments. With a focus on the specific memory processes that are thought to be disrupted in depression, we consider the effects of N2O on memory reconsolidation and propose a memory-based mechanism of N2O antidepressant action.

Abstract Background Depression is common and costly. First-line antidepressants are ineffective for many and have little impact against cognitive deficits. Stimulating 5-HT4 receptors (5-HT4R) rapidly improves learning and has antidepressant-like effects in rodents 1,2. The highly-selective 5-HT4R agonist, prucalopride (licensed for constipation), had a facilitatory effect on behavioural learning/memory in healthy humans after a single 3 and 6 days' treatment 4,5. Neurally, it also increased hippocampal activity 4 and reduced activation within the default mode network 5, findings supported at a network level by resting state analyses 6. Aims & Objectives Here, we present results from 2 further translational studies, examining 5-HT4R agonists in the context of mental illness. In study 1, we hypothesised that 5-HT4R agonism in participants with un-medicated depression would also increase hippocampal activation during a memory encoding task. In study 2, using a live electronic health record database, we investigated whether a prescription of prucalopride for constipation compared to alternative anti-constipation agents would reduce the future risk of depression. Method For study 1, 57 right-handed un-medicated depressed patients were randomised to a 5-HT4R agonist PF-04995274 (15mg) or placebo in a double-blind design. 53 participants received a 3T scan and fMRI memory task eliciting hippocampal activation 7 on day 6-9. Emotionally-neutral “familiar” pictures were viewed before the scan, and again in the scanner with similar “novel” images. Imaging data were analysed with FSL and corrected for multiple comparisons/sex/perfusion/grey matter. Study 2 was an emulated target trial using anonymised routinely collected data from TriNetX Analytics. We included adults without prior mental illness who received either a prescription of prucalopride (primary cohort) or linaclotide/lubiprostone (comparator cohorts). Cohorts were matched for 118 covariates capturing sociodemographics, comorbidities, and concurrent medications. The primary outcome was a first diagnosis of depressive disorder (ICD-10 F32) within two years of prescription date. Results 5-HT4 versus placebo participants had significantly lower HAM-D scores after study 1 [HAM-D 17: F(1,56)=7.6; p<0.01]. In hippocampal analyses, while processing scenes, the 5-HT4 group had significantly increased activity to novel compared to familiar images, particularly in the left hemisphere [condition*hemisphere*group: F(1,49)=3.56, p=0.04, ηρ2=0.08); novel vs familiar (i) prucalopride L (p=0.035) &R hemisphere (p=0.050); (ii) placebo L (p=0.789) &R hemisphere (p=0.053)]. In study 2, treatment with prucalopride was associated with reduced incidence of depression compared to both lubiprostone [HR 0.84, 95% CI 0.73-0.96, p=0.01, n=7101) and linaclotide (HR 0.85, 95% CI 0.75-0.97, p=0.016, n=6460]. Secondary analyses indicated robustness and specificity of the results. Discussion & Conclusion In participants with un-medicated depression, the 5-HT4R agonist PF-04995274 increased hippocampal activation during a memory task; a replication of previous results in healthy volunteers using another 5-HT4R agonist. The pharmaco-epidemiological findings also suggest 5-HT4R agonists may be novel agents in the prevention of depression. Results from both studies are consistent with preclinical evidence establishing a key role for 5-HT4Rs in mood disorders and cognitive deficits. References 1) Lucas G, Rymar VV, Du J, et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 2007; 55(5): 712-25. 2) Murphy SE, de Cates AN, Gillespie AL, et al. Translating the promise of 5HT4 receptor agonists for the treatment of depression. Psychol Med 2021; 51(7): 1111-20. 3) Murphy S, Wright L, Browning M, Cowen P, Harmer C. A role for 5-HT4 receptors in human learning and memory. Psychol Med 2020; 50(16): 2722-30. 4)de Cates AN, Wright LC, Martens MAG, et al. Deja-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task. Trans Psychiatry 2021; 11: 497. 5) de Cates AN, Martens MAG, Wright LC, et al. The effect of the 5-HT4 agonist, prucalopride, on an fMRI faces task in the healthy human brain. Frontiers in Psychiatry 2022; 13(859123). 6) de Cates AN, Martens MAG, Wright LC, et al. 5-HT4 receptor agonist effects on functional connectivity in the human brain; Implications for pro-cognitive action. Biol Psychiatry Cogn Neurosci Neuroimaging 2023. 7) Filippini N, MacIntosh BJ, Hough MG, et al. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 2009; 106(17): 7209-14.

Traditional paradigms for studying the unconscious processing of threatening facial expressions face methodological limitations and have predominantly focused on fear, leaving gaps in our understanding of anger. Additionally, it is unclear how the unconscious perception of anger influences subjective anger experiences. To address this, the current study employed Continuous Flash Suppression (CFS), a robust method for studying unconscious processing, to assess suppression times for angry, fearful and happy facial expressions. Following the administration of CFS, participants underwent an anger induction paradigm, and state anger symptoms were assessed at multiple timepoints. Suppression times for angry faces were compared to those for happy and fearful faces, and their relationship with state anger symptoms post-induction was examined. Results revealed that fearful faces broke suppression significantly faster than happy faces. Anger was slower to break suppression compared to fear, but no significant differences emerged between anger and happiness. In addition, the faster emergence into awareness of fear compared to anger was linked to an increased state anger after the induction, indicating that differences in the unconscious processing of these two emotions can potentially influence symptoms of subjective anger. These findings provide new insights into how angry and fearful faces are processed unconsciously, with implications for understanding the cognitive mechanisms underlying subjective anger.

The 5-HT1A receptor is expressed widely across the brain and is implicated in the mechanism of action of several therapeutics for mood disorders. However, there is limited and contradictory evidence about the role of this receptor in emotional processing and cognition. The current study tested the acute effects of a single dose of the 5-HT1A agonist buspirone (20 mg), on a range of emotional processing (Emotional Test Battery) and cognitive (Auditory Verbal Learning Task (AVLT) and N-back) tasks in healthy, male and female volunteers (N = 62). The study was a randomised, double-blind, placebo controlled, parallel group design. Buspirone reduced accuracy for detection of facial expressions of disgust and increased misclassification of negative facial emotions. It had no significant effects on categorisation or recall of emotionally-valanced words. Buspirone also reduced recall accuracy in the AVLT but had no significant effect in the N-back task. Participants receiving buspirone were more likely to experience nausea, light-headedness and sleepiness. Acute buspirone administration produced a mild impairment in verbal memory and a subtle negative bias in emotional processing in healthy volunteers. These effects are consistent with the mixed effects of buspirone on pre- and post-synaptic 5-HT1A receptors.

Ketamine's potential as a rapid-acting antidepressant was first identified in 2000, despite its long-standing use as an anaesthetic agent. Clinically, ketamine alleviates depressive symptoms, including the difficult-to-treat symptom of anhedonia, within hours, with the effects of a single dose lasting for days. Since then, research has focused on uncovering the mechanisms underlying its rapid antidepressant effects in both humans and animal models. While its molecular and cellular effects have been extensively characterized, its impact on cognitive and neuropsychological mechanisms-potential mediators of its clinical efficacy-remains an area of ongoing investigation. Preclinical studies suggest that ketamine rapidly influences the lateral habenula (involved in punishment processing) and fronto-striatal (reward) systems, reverses negative affective biases in established memories, and promotes long-term stress resilience. Translating these findings to human models is crucial, and emerging evidence suggests that ketamine engages similar mechanisms in healthy volunteer and patient groups. However, its clinical application is constrained by acute side effects and an unknown long-term safety profile. Further research into ketamine's mechanisms of action will be essential to inform the development of novel, safer and more accessible rapid-acting antidepressants.

BACKGROUND:Statins are among the most prescribed medications worldwide. Both beneficial (e.g. antidepressant and pro-cognitive) and adverse (e.g. depressogenic and cognitive-impairing) mental health outcomes have been described in clinical studies. The underlying neuropsychological mechanisms, whether positive or negative, are, however, not established. Clarifying such activities has implications for the safe prescribing and repurposing potential of these drugs, especially in people with depression. METHODS:In this double-blind, randomized, placebo-controlled experimental medicine study, we investigated the effects of simvastatin on emotional processing, reward learning, working memory, and waking salivary cortisol (WSC) in 101 people at-risk for depression due to reported high loneliness scores (mean 7.3 ± 1.2 on the UCLA scale). This trial was largely conducted during periods of social distancing due to the COVID-19 pandemic (July 2021-February 2023), and we employed a fully remote design within a UK-wide sample. RESULTS:High retention rates, minimal outlier data, and typical main effects of task condition (e.g. emotion) were seen in all cognitive tasks, indicating this approach was comparable to in-person testing. After 28 days, we found no statistically significant differences (F's < 3.0, p's > 0.20) for any of the measures of emotional processing, reward learning, working memory, and WSC. CONCLUSIONS:Study results do not substantiate concerns regarding adverse neuropsychiatric events due to statins and support the safety of their prescribing in at-risk populations. Although other unmeasured cognitive processes may be involved, our null findings are also in line with more recent clinical evidence suggesting statins do not show antidepressant or pro-cognitive efficacy.

The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function.