Angharad Natalie de Cates

Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT ₄ receptor (5-HT ₄ R) 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 experimental medicine study, 52 right-handed, unmedicated individuals with MDD received 6–9 days of the 5-HT ₄ R agonist PF-04995274 (15 mg, 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-HT ₄ R agonist prucalopride, PF-04995274 had notably limited effects on behavioural measures of memory. The results demonstrate that short term 5-HT ₄ R 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-HT ₄ Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT ₄ R activation in modulating memory-related brain circuits in MDD and previously identified beneficial effects of another 5-HT4 receptor agonist, prucalopride, on cognitive performance.

Background: Cognitive impairment is a common and persistent feature of depression, yet it remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT ₄ receptors (5-HT ₄ R) enhances neuroplasticity and improves cognition. This novel study examines the cognitive effects of 5-HT ₄ R agonism in adults with a history of recurrent depression. Methods: Fifty participants who were not currently depressed but had experienced at least two previous episodes of depression were randomized in a double-blind design either to prucalopride (2 mg daily, titrated from 1 mg) or to placebo for 7–10 days. Participants completed self-report questionnaires and a task battery at baseline and post-intervention assessing declarative memory, working memory, emotional processing, and executive function. Results: Compared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task and was associated with faster response times on a complex working memory task without loss of accuracy. It also improved the accurate recognition of rapidly presented facial expressions. Composite analysis of non-emotional tasks identified that the prucalopride group participants post-intervention were faster and more accurate than at baseline compared to those receiving placebo. Prucalopride had minimal effects on affective cognition, consistent with previous findings. Cognitive improvements were independent of baseline mood symptoms or self-reported cognitive difficulties. Conclusions: Short-term 5-HT ₄ R agonism improved performance on multiple objective cognitive measures in individuals with remitted depression. These findings replicate our previous results in healthy volunteers showing a pro-cognitive effect of prucalopride and support a role for 5-HT ₄ Rs as a promising target for cognitive enhancement in mood disorders.

Background: Selective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant proportion of patients, slow onset, minimal cognitive benefit and side-effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT ₄ R) agonists may produce faster antidepressant effects via distinct mechanisms; however, there has been no experimental research in clinical populations to date. Aims: To test whether the novel 5-HT ₄ R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD). Method: In a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg) or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and functional magnetic resonance imaging (fMRI) of implicit emotional face processing (days 6–9). Observer- and self-reported symptoms of depression were also measured at baseline and study end. Results: As anticipated, citalopram reduced relative accuracy and increased relative reaction time to identify negative faces, with corresponding changes in neural activity (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments demonstrated an early treatment response with reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety and negative affect. Conclusions: PF-04995274 did not show the typical antidepressant profile of negative bias reductions observed with citalopram. Instead, it was associated with distinct increased medial-frontal activation during an emotional faces task, coupled with preliminary evidence of early clinical improvement, suggesting a potential alternative pathway for antidepressant effects. Findings support further clinical trials of 5-HT ₄ R agonists and investigation of pro-cognitive and mood effects. Clinical trials registration number: NCT03516604.

Background: Cognitive impairments are common in depression and often persist beyond mood resolution. However, the relationship between cognitive performance, its neurological underpinnings, and future depression risk is unclear, limiting strategies for primary and secondary prevention. Objective: Our objective was to determine whether cognition associates with subsequent depression, both relapse and first-episode occurrences. Methods: 1862 UK Biobank participants with a history of International Classification of Diseases (ICD)-10-defined depression in remission (RD) (mean (SD) age: 52.7 (7.13) years) were age-matched and sex-matched to 1862 participants without depression history or current antidepressant use. Cognitive scores were compared between groups at the composite (z-score), domain and task levels. MRI-derived phenotypes assessed brain network structure and functional connectivity. Longitudinal associations with future depression were assessed using logistic regression models and a Cox proportional hazards model controlling for key confounders. Findings: Participants with RD had a higher risk of future depression (33%) than controls (13%), including when we accounted for temporal differences in longitudinal assessment (HR=3.16 (95% CI 2.71 to 3.67), global proportional hazard assumption p=0.07). Composite cognitive performance in controls was inversely associated with future depression risk (risk estimated marginal means: 0.25% at −1SD, 0.20% at mean, 0.15% at +1 SD). In RD, this relationship was reversed (0.74% at −1SD, 0.90% at mean, 1.10% at +1 SD). Executive functioning, processing speed and reasoning task scores all contributed. Higher grey matter in default mode network regions was associated with better concurrent cognitive performance across all participants, but not with future depression risk. Other MRI findings were limited. Conclusions: RD carried a threefold higher risk of future depression than controls. Cognitive performance was a risk marker for future depression in both groups but in opposing directions. Neuroimaging metrics provided little predictive value. Clinical implications: Personalised risk factor assessment for depression is likely to be dependent on depression history. Those without previous history of diagnosed depression are at higher risk of future depression when cognitive performance is lower at baseline. RD is a high-risk group for future depression, and those with relatively higher cognitive performance may be more likely to report future depressive symptoms.

Introduction: Cognitive impairments are common in depression and often persist beyond mood resolution. However, the relationship between cognitive performance, its neurological underpinnings, and future depression risk is unclear, limiting strategies for primary and secondary prevention. Our objective was to determine whether cognition associates with subsequent depression, including both relapse and first-episode occurrences. Methods: 2094 UK Biobank participants with previous ICD-10-defined depression currently in remission (RD) (mean(SD) age: 52.4(7.25) years) were age- and sex-matched to 2094 participants without depression history or current antidepressant use. Cognitive scores were compared between groups at the composite (z-score), domain, and task levels. MRI-derived phenotypes assessed brain network structure and functional connectivity. Longitudinal associations with future depression were assessed using logistic regression models controlling for key confounders. Results: Participants with RD had a higher risk of future depression (30%) than controls (8.5%). Composite cognitive performance in controls was inversely associated with future depression risk (risk estimated marginal means: 0.48% at -1SD, 0.37% at mean, 0.28% at +1SD). In RD, this relationship was reversed (1.56% at -1SD, 1.80% at mean, 2.08% at +1SD). Executive functioning, processing speed, and reasoning task scores all contributed. Higher grey matter in default mode network regions was associated with better concurrent cognitive performance across all participants, but not with future depression risk. Other MRI findings were limited. Conclusion: RD carried a threefold higher risk of future depression than controls. Cognitive performance was a risk marker for future depression in both groups but in opposing directions. Neuroimaging metrics provided little predictive value. What is already known on this topic: Neurocognitive impairments are common in depression, even after low mood has resolved and outside of comorbid neurodegenerative processes. However, the specific relationship between cognitive performance and risk of future depression is unclear, including how this relates to previous history of depression. What this study adds: Cognitive performance is a differential risk marker for future depression in those with previous depression compared to matched controls: without previous history of depression, poorer cognitive scores confer the highest risk; in remitted depression, higher levels of cognitive performance are associated with greater risk of depressive relapse. How this study might affect research, practice or policy: Further research should explore targeting interventions based on specific cognitive profiles, especially in high-risk populations such as those with previous episodes of depression.

Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT ₄ receptor (5-HT ₄ R) 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-HT ₄ R 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-HT ₄ R agonist prucalopride, PF-04995274 had limited effects on behavioural measures of memory. The results demonstrate that short term 5-HT ₄ R 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-HT ₄ Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT ₄ R activation in modulating memory-related brain circuits in MDD and highlights its therapeutic potential for treating cognitive symptoms of depression.

Background: Cognitive impairment is a common and persistent feature of depression, yet remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT ₄ receptors (5-HT ₄ R) enhances neuroplasticity and rapidly improves learning and memory. This study is the first to examine the cognitive effects of 5-HT ₄ R agonism in adults with a history of recurrent depression. We hypothesised that short term 5-HT ₄ R agonist administration would produce a broad profile of pro-cognitive effects. Methods: 50 participants not currently depressed but with at least two previous episodes of depression (remitted depression) were randomised in a double-blind design to receive either prucalopride (2mg daily titrated from 1mg over 2 days) or placebo for 7-10 days. Participants completed self-report questionnaires and a cognitive task battery assessing declarative memory, working memory, emotional processing, and executive function before and after medication. Results: Compared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task, and was associated with faster response times on a complex working memory task without loss of accuracy. It also improved the accurate recognition of rapidly presented facial expressions. Prucalopride had minimal effects on emotionally-valenced cognitive tasks, consistent with previous findings. Cognitive improvements were independent of baseline mood symptoms or self-reported cognitive difficulties. Conclusions: Short-term 5-HT ₄ R agonism improved performance on multiple objective cognitive measures in individuals with a history of depression. These findings replicate our previous results in healthy volunteers using prucalopride and support a role for 5-HT ₄ Rs as a promising target for cognitive enhancement in mood disorders.

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