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.

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.

Experimental tasks comparing participants' performance for categorising, remembering, and recognising positive and negative words are widely used in the emotional cognitive domain. Such tasks are commonly used in experimental psychology and psychiatry research, and have been shown to be sensitive biomarkers of depression and antidepressant drug action [1,2]. In addition, several of these tasks investigate self-referential processing i.e., the processing of information relevant to oneself; this has been shown to modify the way emotional words are encoded and remembered and may be a target that is amenable to treatment [3,4]. In practice, the development of such tasks for implementation in research studies often depends on the selection and matching of words according to characteristics such as valence or arousal, imageability, word frequency and word length to investigate differences in a chosen domain of interest whilst keeping important confounds constant. This introduces a need for ratings covering a range of word attributes that have been shown to affect processing. In particular, ratings of self-referential valence (how positively or negatively subjects feel about a word when this is used to describe themselves/their circumstances) have been seldom included in databases, despite the frequent investigation of the concept in research [1,5]. Other important attributes often considered in the process of matching and selection are word imageability and subjective frequency [6,7]. To facilitate the word selection and matching process required in cognitive-emotional task development, the present dataset provides subjective ratings for 150 positive and 150 negative adjectives describing personality characteristics. Across four online surveys, the 300 words were rated on self-referential valence, imageability and subjective frequency by representative samples of 200 UK-based, English-speaking adults. Basic demographics and data on depressive symptoms and state anxiety were collected from all participants. Comprehensive descriptive statistics and word length were calculated for each of the 300 words. All data cleaning and statistical analysis was performed in R. Our work is based on years of experience using the Oxford Emotional Task Battery [1,5] and may be particularly relevant for researchers using self-referential cognitive tasks with UK-based samples.

Pharmacological targeting of cognitive impairment in depression: recent developments and challenges in human clinical research.

Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition.

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

BACKGROUND: There is growing interest in the antidepressant potential of statins. 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. METHODS: Between April 2020 and February 2021, 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). RESULTS: Statin use was associated with reduced recognition of angry and fearful faces (F1 = 9.19, p = .002; F1 = 6.9, p = .009) and with increased misclassification of these expressions as positive. Increased recognition of angry faces at baseline predicted increased levels of depression and anxiety 10 months later (ß = 3.61, p = .027; ß = 2.37, p = .002). Statin use was also associated with reduced learning about stimuli associated with loss (F1,1418 = 9.90, p = .002). These indicators of reduced negative bias were not seen in participants taking antihypertensive medication alone, suggesting that they were related to statin use in particular rather than nonspecific demographic factors. In addition, we found no evidence of an association between statin use and impairment in working memory. CONCLUSIONS: Statin use was associated with cognitive markers indicative of reduced psychological vulnerability to depression, supporting their potential use as a prophylactic treatment for depression.

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

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.

Mental health workers perceptions of disaster response in China.

BACKGROUND: The post-disaster mental health crisis intervention (MHCI) system in China remains immature and unsystematic. We aim to report the perceptions of a large sample of MHCI workers and government administrators and provide recommendations for developing a national mental health disaster response management plan in China. METHODS: An in-depth qualitative study was conducted, collecting data from 20 focus-group discussions and 25 key stakeholder interviews. These recruited participants who had been involved in different types of disaster rescue across 7 provinces/cities where disasters have recently occurred. We used thematic analysis to analyze the data and relevant findings were extracted for policy recommendation. RESULTS: Mental health workers' perspectives were examined in detailed according to four core themes: forms of organization, intervention pathway, intervention strategy and technique, and public health information. Post-disaster MHCI should be approached in teams that are integrated with emergency medicine systems, and be led by unified command management. All levels of local health and family planning commission should prepare post-disaster MHCI work plans and build response teams/emergency centres. Future training for MHCI workers should focus on: building a sense of trust within the team; clarifying each member's role; strengthening the screening, assessment and referrals training for psychological professionals; and providing psychological intervention training for Chinese psychiatrists. It is necessary to set up guiding principles for disaster research ethics, mental health rehabilitation and media interaction. CONCLUSIONS: Through exploring and analyzing the perceptions of current disaster response mental health workers and government administrators, our findings provide essential recommendations for developing a national to county level post-disaster MHCI emergency management plan and can guide the formulation of relevant laws and regulation in China.

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review.

BACKGROUND: Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes. METHOD: A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics). RESULTS: Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons. CONCLUSIONS: Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.