A major output of the group has been the development of the Cognitive Neuropsychological Model (see article below), based on a series of our studies. This showed that antidepressant drugs act to bias emotional processing towards positive information much earlier than antidepressant effects on mood can be detected. Such changes are believed to contribute to the recovery from depression and explain why antidepressants often take a long time to have a noticeable effect. The theory states that this delay is due to the time needed for changes in emotional biases to cause gradual relearning of more positive associations. This is how antidepressants eventually will lead to subjective improvement in mood.

Graphic image of a pill bottle

Godlewska BR. and Harmer CJ., (2020)

The cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment.

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Associations Between Statin Use and Negative Affective Bias During COVID-19: An Observational, Longitudinal UK Study Investigating Depression Vulnerability.

Gillespie AL, Wigg C, Van Assche I, Murphy SE, Harmer.

We tested whether statin use is associated with cognitive markers previously found to indicate psychological vulnerability to depression within the context of the COVID-19 pandemic. We conducted an observational online study of 2043 adults in the United Kingdom. Participants completed cognitive tasks assessing processes related to depression vulnerability, including affective bias and reward processing. We also measured working memory, medication use, and current psychiatric symptoms. Using mixed analysis of covariance and regression models, we compared participants on statins alone (n = 81), antihypertensive medication alone (n = 126), both medications (n = 111), and on neither medication (n = 1725). Statin use was associated with cognitive markers indicative of reduced psychological vulnerability to depression, supporting their potential use as a prophylactic treatment for depression.

Gillespie AL, et al. Biol Psychiatry. 2022 Oct 1;92(7):543-551. 

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The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain.

de Cates AN, Martens MAG, Wright LC, Gould van Praag CD, Capitão LP, Gibson D, Cowen PJ, Harmer CJ, Murphy SE.

5-HT4 receptor agonists show promise in both animal models of depression and cognitive deficit. We therefore studied the effect of the 5-HT4 partial agonist prucalopride (1 mg daily for 6 days) on the neural processing of emotional faces in 43 healthy participants using a randomised placebo-controlled design. Participants receiving prucalopride were more accurate at identifying the gender of emotional faces. In whole brain analyses, prucalopride was also associated with reduced activation in a network of regions corresponding to the default mode network. However, there was no evidence that prucalopride treatment produced a positive bias in the neural processing of emotional faces. Our study provides further support for a pro-cognitive effect of 5-HT4 receptor agonism in humans.

de Cates AN, et al. Front Psychiatry. 2022 Apr 12;13:859123.

Full Article

Positive and negative personality descriptors: UK dataset of self-referential valence, imageability and subjective frequency ratings of 300 adjectives for use in cognitive-emotional tasks.

Raslescu A, Kreicker S, Gillespie AL, Berners-Lee W, Murphy SE, Harmer CJ.

This article discusses the importance of experimental tasks in measuring emotional cognitive domains and their usefulness as biomarkers for depression and antidepressant drug action. The development of such tasks requires the selection and matching of words based on their attributes, including valence, imageability, and subjective frequency. However, the ratings of self-referential valence have been seldom included in databases despite frequent investigation. The article presents a dataset of subjective ratings for 150 positive and 150 negative adjectives describing personality characteristics, rated on self-referential valence, imageability, and subjective frequency by a representative sample of 200 UK-based, English-speaking adults to aid in the selection and matching process required in cognitive-emotional task development.

Raslescu A et al., 2022 Dec 16;46:108831. 

Full Article


The knowns and unknowns of SSRI treatment in young people with depression and anxiety: efficacy, predictors, and mechanisms of action.

Murphy SE., Capitão LP., Giles SLC., Cowen PJ., Stringaris A., Harmer CJ.

The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based.

Murphy SE. et al, (2021), Lancet Psychiatry, 8, 824 – 835

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Graphic image of a woman

Online behavioural activation during the COVID-19 pandemic decreases depression and negative affective bias.

Ruzickova T., Carson J., Argabright S., Gillespie A., Guinea C., Pearse A., Barwick R., Murphy S., Harmer CJ.

A randomized controlled trial was conducted to investigate the efficacy of online behavioural activation (BA) for mild to moderate low mood during the COVID-19 pandemic. The study found that BA, administered by non-specialists, was effective in reducing depression, anxiety, and anhedonia while increasing activation and social support. Additionally, participants’ negative affective bias decreased, and early changes in bias were associated with later therapeutic gain. These findings suggest that online BA could be a cost-effective mental health intervention during crisis situations such as pandemics.

Ruzickova T. et al, (2021), Psychol Med, 1 – 18.

Full Article

Translating the promise of 5HT4 receptor agonists for the treatment of depression.

Murphy SE., de Cates AN., Gillespie AL., Godlewska BR., Scaife JC., Wright LC., Cowen PJ., Harmer CJ.

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.

Murphy SE. et al, (2021), Psychol Med, 51, 1111 – 1120

Full Article

A Translational Perspective on the Anti-Anhedonic Effect of Ketamine and its Neural Underpinnings.

Erdem Pulcu, Calum Guinea, Philip J. Cowen, Susannah E. Murphy & Catherine J. Harmer.

Anhedonia, a pronounced reduction in interest or pleasure in any of life’s daily activities, is a cardinal symptom of major depression. In this Perspective article, we synthesise the recent evidence from rodent, monkey and human neuroimaging literature to highlight how the habenula, a small evolutionarily conserved subcortical structure located in the midbrain, may orchestrate the behavioural expression of anhedonia across fronto-mesolimbic networks. We then review how this circuitry can be modulated by ketamine, an NMDA receptor antagonist with rapid antidepressant properties. We propose that experimental paradigms founded in reinforcement learning and value-based decision-making can usefully probe this network and thereby help elucidate the mechanisms underlying ketamine’s rapid antidepressant action.

PULCU E. et al, (2021), Molecular Psychiatry.

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Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task.

de Cates AN., Wright LC., Martens MAG., Gibson D., Türkmen C., Filippini N., Cowen PJ., Harmer CJ., Murphy SE.

Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT4 receptor is a promising potential treatment target for cognitive impairment because in animal studies 5-HT4 receptor agonists enhance hippocampal-dependent memory processes. To date, there has been little work translating these effects to humans. We tested whether short-term administration of the 5-HT4 partial agonist, prucalopride, modified behavioural and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model. We found that participants who had received six days of prucalopride treatment were significantly better at recalling previously seen neutral images and distinguishing them from new images. At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo. Taken together, these findings demonstrate the potential of 5-HT4-receptor activation for cognitive enhancement in humans, and support the potential of this receptor as a treatment target for cognitive impairment.

de Cates AN. et al, (2021), Transl Psychiatry, 11

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Lithium modulates striatal reward anticipation and prediction error coding in healthy volunteers.

Volman I., Pringle A., Verhagen L., Browning M., Cowen PJ., Harmer CJ.

This study was designed to test whether lithium administration may stabilize mood via effects on reward processing. It was hypothesized that lithium administration would modulate reward processing in the striatum and affect both anticipation and outcome computations. Thirty-seven healthy human participants (18 males, 33 with suitable fMRI data) received 11 (±1) days of lithium carbonate or placebo intervention (double-blind), after which they completed the monetary incentive delay task while fMRI data were collected. The monetary incentive delay task is a robust task with excellent test-retest reliability and is well suited to investigate different phases of reward processing within the caudate and nucleus accumbens. Lithium administration enhanced activity in the caudate during reward anticipation compared to placebo. In contrast, lithium administration reduced caudate and nucleus accumbens activity during reward outcome. This latter effect seems related to learning as reward prediction errors showed a positive correlation with caudate and nucleus accumbens activity during placebo, which was absent after lithium administration. Lithium differentially modulates the anticipation relative to the learning of rewards. This suggests that lithium might reverse dampened reward anticipation while reducing overactive reward updating in patients with bipolar disorder. This specific effect of lithium suggests that a targeted modulation of reward learning may be a viable approach for novel interventions in bipolar disorder.

Volman I. et al, (2021), Neuropsychopharmacology, 46, 386 – 393

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© 2023 Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX