Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

An online experimental medicine trial on the effect of 28-day simvastatin administration on emotional processing, reward learning, working memory and salivary cortisol in healthy volunteers at risk for depression: OxSTEP protocol.

BACKGROUND: 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. AIMS: 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. METHOD: 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.

An experimental medicine study of the effects of simvastatin on emotional processing, reward learning, verbal memory, and inflammation in healthy volunteers.

RATIONALE: Clinical studies suggest that the highly lipophilic, anti-inflammatory molecule, simvastatin, might be an ideal candidate for drug repurposing in the treatment of depression. The neuropsychological effects of simvastatin are not known, but their ascertainment would have significant translational value about simvastatin's influence on mood and cognition. OBJECTIVES: We aimed to investigate the effects of simvastatin on a battery of psychological tests and inflammatory markers in healthy volunteers. METHODS: Fifty-three healthy subjects were randomly assigned to 7 days of either simvastatin (N = 27) or sucrose-based placebo (N = 26) given in a double-blind fashion. Then, participants were administered questionnaires measuring subjective rates of mood and anxiety, and a battery of tasks assessing emotional processing, reward learning, and verbal memory. Blood samples for C-reactive protein were also collected. RESULTS: Compared to placebo, participants on simvastatin showed a higher number of positively valenced intrusions in the emotional recall task (F1,51 = 4.99, p = 0.03), but also an increase in anxiety scores (F1,51 = 5.37, p = 0.02). An exploratory analysis of the females' subgroup (N = 27) showed lower number of misclassifications as sad facial expression in the simvastatin arm (F1,25 = 6.60, p = 0.02). No further statistically significant changes could be observed on any of the other outcomes measured. CONCLUSIONS: We found limited evidence that 7-day simvastatin use in healthy volunteer induces a positive emotional bias while also being associated with an increase in anxiety, potentially reflecting the early effects of antidepressants in clinical practice. Such effect might be more evident in female subjects. Different drug dosages, treatment lengths, and sample selection need consideration in further experimental medicine and clinical studies. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04652089.

The effects of statin monotherapy on depressive symptoms: A systematic review and meta-analysis.

INTRODUCTION: Statins have been proposed as a strategy for treating depression, but their benefit in the absence of concurrent antidepressant treatment is unclear. This meta-analysis investigated the antidepressant effects of statin monotherapy in the general population. METHODS: We conducted a literature search of randomised controlled trials using any statin monotherapy versus any control condition for depressive symptoms. Our primary efficacy outcome was the mean value on any standardised scale for depression at study endpoint. We also measured efficacy at three further timepoints (<6 months, 6-12 months, >12 months), as well as acceptability, tolerability, and safety. Respectively, continuous and dichotomous outcomes were computed using standardised mean difference (SMD) or relative risk (RR) with 95% confidence intervals (CI) using a random-effect model. RESULTS: Pooled analyses did not show that statin monotherapy improves depressive symptoms at endpoint (N = 2712 SMD = -0.18; 95% CI = -0.41 to 0.04), nor at any other specific timepoint. No difference between statins and control was identified for any of the other outcome measures. DISCUSSION: These results differ from those of previous meta-analyses and, compounded by more recently available evidence, suggest that statins may not have intrinsic antidepressant properties, but may be useful for the management of depression in add-on to antidepressants. LIMITATIONS: Data from heterogeneous populations and using different statins were pooled, though several sensitivity and subgroup analyses were performed to account for that. PROSPERO registration: CRD42022306653. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=306653.