The serotonin 4 receptor (5-HT4R) is a promising target for the treatment of depression. Highly selective 5-HT4R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established.

To determine whether prucalopride (a 5-HT4R agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system.

Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders.

Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76–0.99; P = 0.038; n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69–0.91; P < 0.001; n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses.

These findings support preclinical data and suggest a role for 5-HT4R agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.

Evidence suggests inflammation may be a key mechanism by which psychosocial stress, including loneliness, predisposes to depression. Observational and clinical studies have suggested simvastatin, with its anti-inflammatory properties, may have a potential use in the treatment of depression. Previous experimental medicine trials investigating 7-day use of statins showed conflicting results, with simvastatin displaying a more positive effect on emotional processing compared with atorvastatin. It is possible that statins require longer administration in predisposed individuals before showing the expected positive effects on emotional processing.

Here, we aim to test the neuropsychological effects of 28-day simvastatin administration versus placebo, in healthy volunteers at risk for depression owing to loneliness.

This is a remote experimental medicine study. One hundred participants across the UK will be recruited and randomised to either 28-day 20 mg simvastatin or placebo in a double-blind fashion. Before and after administration, participants will complete an online testing session involving tasks of emotional processing and reward learning, processes related to vulnerability to depression. Working memory will also be assessed and waking salivary cortisol samples will be collected. The primary outcome will be accuracy in identifying emotions in a facial expression recognition task, comparing the two groups across time.

Adolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression.

Thirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited (‘Maintain’) or to reinterpret the content of the pictures to reduce negative affect (‘Reappraise’). Significant activations were identified using whole-brain analysis.

No significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo.

These data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects.

Studies suggest that d-cycloserine (DCS) may have antidepressant potential through its interaction with the glycine site of the N-methyl-D-aspartate receptor; however, clinical evidence of DCS's efficacy as a treatment for depression is limited. Other evidence suggests that DCS affects emotional learning which may also be relevant for the treatment of depression and anxiety. The aim of the present investigation was to assess the effect of DCS on emotional processing in healthy volunteers and to further characterise its effects on emotional and autobiographical memory.

Forty healthy volunteers were randomly allocated to a single dose of 250 mg DCS or placebo in a double-blind design. Three hours later, participants performed an Emotional Test Battery [including Facial Expression Recognition Task (FERT), Emotional Categorisation Task (ECAT), Emotional Recall Task (EREC), Facial Dot-Probe Task (FDOT) and Emotional Recognition Memory Task (EMEM)] and an Autobiographical Memory Test (AMT). Also, participants performed the FERT, EREC and AMT tasks again after 24 h in order to assess longer lasting effects of a single dose of DCS.

DCS did not significantly affect the FERT, EMEM and FDOT performance but significantly increased emotional memory and classification for positive words v. negative words. Also, DCS enhanced the retrieval of more specific autobiographical memories, and this effect persisted at 24 h.

These findings support the suggestion that low-dose DCS increases specific autobiographical memory retrieval and positive emotional memory. Such effects make it an intriguing agent for further investigation in clinical depression, which is characterised by decreased autobiographical memory specificity and increased negative bias in memory recall. It also underscores the potential role of DCS as an adjunct to cognitive behavioural therapy in depression.

5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion.

Forty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity.

Prucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks.

These findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing.

C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.

To explore CRP in MDD and its phenotypic associations.

We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.

Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.

CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.

S.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.

The possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths [1.5–3 Tesla (T)], it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 T allows clear spectral resolution of glutamate and glutamine.

We studied 55 un-medicated depressed patients and 50 healthy controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen (PUT). Neurometabolites were calculated using the unsuppressed water signal as a reference.

Compared with controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 12% in the PUT (p < 0.001).

The increase in glutamine in PUT is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the PUT. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted.

Depression is associated with increased risk of several general medical conditions, including diabetes and cardiovascular disease. The nature of the association is complex and may involve bidirectional causation or a common pathophysiology.

To determine whether young people without depression but at increased familial risk have altered metabolic and blood pressure markers relative to matched controls.

We studied young people (n = 85), who had a parent with depression but no personal history of depressive illness (FH+) and healthy controls (n = 69). Cardiovascular risk profile was assessed by a fasting blood sample to measure insulin, glucose, lipids and high-sensitivity C-reactive protein (CRP) and blood pressure was measured centrally and peripherally. Arterial stiffness and waking cortisol concentration were also measured.

Compared with controls, the FH+ group demonstrated increased peripheral and central systolic blood pressure, increased arterial stiffness and diminished insulin sensitivity but they did not differ from controls in measures of lipids, CRP or waking cortisol.

Our data suggest that young people at increased familial risk of depression show evidence of altered cardiovascular risk profile in young adulthood even in the absence of depressive symptoms. It is possible therefore that vulnerability to conditions such as hypertension and diabetes may precede the onset of major depression and may share common risk factors.

Antidepressant prescribing is widespread. Nonetheless, response to antidepressants is variable. If it was possible to predict response to medication and thus tailor treatment accordingly, this would not only improve patient outcomes but may also have economic benefits.

To test the hypothesis that individuals with more severe depression would benefit more from noradrenaline reuptake inhibitors (NARIs) than selective serotonin reuptake inhibitors (SSRIs) compared with individuals with less severe depression.

Individuals recruited from UK primary care who met ICD-10 criteria for a depressive episode and scored 15 or more on the Beck Depression Inventory (BDI) were randomised to either an SSRI (citalopram 20mg daily) or a NARI (reboxetine 4mg twice daily). Randomisation was by means of a remote automated telephone system. The main outcome was depressive symptoms measured by the BDI total score 6 weeks after randomisation. (Trial registration: ISRCTN31345163.)

In total, 601 participants were randomised (citalopram: n = 298, reboxetine: n = 303). Ninety-one per cent were followed up at 6 weeks (citalopram: n = 274, reboxetine: n = 272). There was little evidence to support an interaction between treatment and severity of depression (interaction term: 0.02, 95% CI −0.59 to 0.62, P = 0.96). Adjustment for potential confounders (age, gender, employment status, history of depression, number of life events and social support) did not affect the findings (interaction term: 0.06, 95% CI −0.54 to 0.66, P = 0.85).

Treatment with NARIs does not confer any advantage over SSRI treatment for outcome in those with more severe depressive illness presenting in primary care.