An exploratory, randomised, crossover study to investigate the effect of nicotine on cognitive function in healthy adult smokers who use an electronic cigarette after a period of smoking abstinence.

BACKGROUND: As well as being associated with serious negative health outcomes, smoking has been reported to have an array of physiological and psychological effects, including effects on mood and cognitive function. Post-cessation, loss of such effects (including temporary deficits in cognitive function) have been cited as reasons for resumption of smoking. The effects of e-cigarettes and nicotine delivered by e-cigarettes on these functions have not been widely researched but may play a role in the effectiveness of e-cigarettes as a satisfactory alternative to combustible cigarettes for people who smoke, and in encouraging individuals who would otherwise continue to smoke, to transition to e-cigarettes. METHODS: The study was an exploratory, randomised, partially-blinded, single-centre, five-arm crossover trial that recruited 40 healthy male and female people who smoke. At 5 study sessions, following a 12-h period of nicotine abstinence, participants were randomly assigned to use either a combustible cigarette, an e-cigarette of three varying nicotine strengths (18 mg/mL, 12 mg/mL or 0 mg/mL respectively) or observe a no product usage session. Participants completed pre- and post-product usage assessments to examine the product usage effect on cognitive performance (using the Cambridge Neuropsychological Test Automated Battery (CANTAB)), subjective mood and smoking urges. RESULTS: A significant improvement in sustained attention task performance was observed following use of both the nicotine containing e-cigarettes and combustible cigarette compared to no product use. Additionally, there were no significant differences between the nicotine containing products, indicating that nicotine use enhanced sustained attention regardless of delivery format. Nicotine containing e-cigarette and combustible cigarette use also significantly improved overall mood of participants compared to no product use, with no significant differences observed between the nicotine containing products. Nicotine containing e-cigarette and combustible cigarette use significantly reduced smoking urges compared to no product use, though combustible cigarette use elicited the greatest reduction in smoking urges. CONCLUSIONS: Overall, the nicotine containing products improved sustained attention and mood while reducing smoking urges, with the studied e-cigarettes having comparable effects to combustible cigarettes across the assessed cognitive parameters and mood measures. These results demonstrate the potential role of e-cigarettes to provide an acceptable alternative for combustible cigarettes among people who would otherwise continue to smoke. Trial registration ISRCTN (identifier: ISRCTN35376793).

Measuring functional outcomes in schizophrenia in an increasingly digital world.

With an unmet clinical need for effective interventions for cognitive and negative symptoms in patients with schizophrenia, measures of functional status (often a co-primary endpoint) remain key clinical trial outcomes. This review aims to give an overview of the different types of functional assessments commonly used in clinical trials and research involving patients with schizophrenia and highlight pertinent challenges surrounding the use of these as reliable, sensitive, and specific assessments in intervention trials. We provide examples of commonly used functional measures and highlight emerging real-time digital assessment tools. Informant- and clinician-rated functional outcome measures and functional capacity assessments are valid, commonly used measures of functional status that try to overcome the need for often overly ambitious and insensitive 'real world' milestones. The wide range of scientific and practical challenges associated with these different tools leave room for the development of improved functional outcome measures for use in clinical trials. In particular, many existing measures fail to capture small, but meaningful, functional changes that may occur over the course of typically short intervention trials. Adding passive digital data collection and short active real-time digital assessments whilst patients go about their day offers the opportunity to build a more fine-grained picture of functional improvements that, if thoughtfully developed and carefully applied, could provide the sensitivity needed to accurately evaluate functional status in intervention studies, aiding the development of desperately needed treatments.

The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials.

The role of nutrition in mental health is becoming increasingly acknowledged. Along with dietary intake, nutrition can also be obtained from "nutrient supplements", such as polyunsaturated fatty acids (PUFAs), vitamins, minerals, antioxidants, amino acids and pre/probiotic supplements. Recently, a large number of meta-analyses have emerged examining nutrient supplements in the treatment of mental disorders. To produce a meta-review of this top-tier evidence, we identified, synthesized and appraised all meta-analyses of randomized controlled trials (RCTs) reporting on the efficacy and safety of nutrient supplements in common and severe mental disorders. Our systematic search identified 33 meta-analyses of placebo-controlled RCTs, with primary analyses including outcome data from 10,951 individuals. The strongest evidence was found for PUFAs (particularly as eicosapentaenoic acid) as an adjunctive treatment for depression. More nascent evidence suggested that PUFAs may also be beneficial for attention-deficit/hyperactivity disorder, whereas there was no evidence for schizophrenia. Folate-based supplements were widely researched as adjunctive treatments for depression and schizophrenia, with positive effects from RCTs of high-dose methylfolate in major depressive disorder. There was emergent evidence for N-acetylcysteine as a useful adjunctive treatment in mood disorders and schizophrenia. All nutrient supplements had good safety profiles, with no evidence of serious adverse effects or contraindications with psychiatric medications. In conclusion, clinicians should be informed of the nutrient supplements with established efficacy for certain conditions (such as eicosapentaenoic acid in depression), but also made aware of those currently lacking evidentiary support. Future research should aim to determine which individuals may benefit most from evidence-based supplements, to further elucidate the underlying mechanisms.

The Use of Cognitive Screening in Pharmacotherapy Trials for Cognitive Impairment Associated With Schizophrenia.

There are currently no regulatory approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). One possibility is that trial methodology itself is hindering their development. Emerging evidence suggests that patients with schizophrenia may show limited benefit from pro-cognitive interventions if they already exhibit intact cognitive performance, relative to normative thresholds. The aim of this report was to examine the extent to which objectively assessed cognitive performance has been used as an eligibility and/or stratification criterion in CIAS pharmacotherapy trials. On 16th January 2019, we conducted a systematic search of studies listed on ClinicalTrials.gov to identify randomized, double-blind, placebo-controlled, add-on pharmacotherapy trials conducted in patients with a diagnosis of schizophrenia, in which a paper-and-pencil or computerized cognitive task (or battery) was specified as a primary outcome measure. Of the 87 trials that met our inclusion criteria, 10 (11.5%) required the presence of an objectively assessed cognitive deficit as part of their patient eligibility criteria. No studies reported stratifying patients according to the presence or degree of cognitive impairment they exhibited. These results suggest that the vast majority of CIAS trials may have been underpowered due to the inclusion of cognitively "normal" patients. Purposive screening for cognitive impairment could increase CIAS trial success.

What Is the Role of Dietary Inflammation in Severe Mental Illness? A Review of Observational and Experimental Findings.

Severe mental illnesses (SMI), including major depressive disorder, bipolar disorder, and schizophrenia, are associated with increased inflammation. Given diet's role in modulating inflammatory processes, excessive calorie-dense, nutrient-deficient processed food intake may contribute toward the heightened inflammation observed in SMI. This review assesses the evidence from observational and experimental studies to investigate how diet may affect physical and mental health outcomes in SMI through inflammation-related pathways. Cross-sectional studies indicate that individuals with SMI, particularly schizophrenia, consume more pro-inflammatory foods and fewer anti-inflammatory nutrients than the general population. Cohort studies indicate that high levels of dietary inflammation are associated with increased risk of developing depression, but there is currently a lack of evidence for schizophrenia or bipolar disorder. Randomized controlled trials show that dietary interventions improve symptoms of depression, but none have tested the extent to which these benefits are due to changes in inflammation. This review summarizes evidence on dietary inflammation in SMI, explores the directionality of these links, and discusses the potential use of targeted nutritional interventions for improving psychological well-being and physical health outcomes in SMI. Establishing the extent to which diet explains elevated levels of inflammatory markers observed in SMI is a priority for future research.

Exploring functional impairment in young people at ultra-high risk for psychosis: A qualitative study.

AIM: Many young people at ultra-high risk (UHR) of developing psychosis exhibit marked and persistent impairments in social and occupational functioning. We aimed to explore UHR patients' subjective experiences of these difficulties and their causes. METHODS: We conducted semi-structured interviews with 20 UHR individuals recruited from Early Detection and Intervention Teams in Northwest England. Topics covered included how participants spent their time, their interpersonal relationships, academic and occupational performance, premorbid functioning and clinical treatment. Thematic analysis was used to examine the prevailing themes. RESULTS: The sample included individuals with varying degrees of functional impairment, ranging from mild to severe difficulties in functioning. Analysis of the qualitative data elicited themes around 2 topics: breadth of functional difficulties and subjective reasons for poor functioning. Participants reported a range of impairments in their social and occupational functioning which they attributed to a combination of clinical, cognitive and psychological factors. These included variables previously identified in the quantitative literature such as psychiatric symptoms, adverse life experiences and cognitive deficits. However, our findings also included other factors which have received comparably little attention such as self-stigmatizing attitudes and dysfunctional metacognitive beliefs. CONCLUSIONS: We propose a model that attempts to explain how these variables interact to drive and sustain functional impairment in the UHR population. This will assist in the development of clinical interventions aimed at promoting functional recovery among UHR individuals.

Investigating Domain-Specific Cognitive Impairment Among Patients With Multiple Sclerosis Using Touchscreen Cognitive Testing in Routine Clinical Care.

Cognitive dysfunction is present in up to 70% of patients with multiple sclerosis (MS) and has been reported at all stages and in all subtypes of the disease. These deficits have been reported across a variety of cognitive domains, but are generally under-recognized and incompletely evaluated in routine clinical practice. The aim of this study was to investigate the spectrum of cognitive impairment in patients with MS presenting to a specialist MS clinic using the Cambridge Neuropsychological Test Automated Battery (CANTAB), administered on a touchscreen platform. Ninety MS patients completed computerized CANTAB tasks assessing working memory, executive function, processing speed, attention, and episodic memory. Scores were adjusted for age, sex, and level of education and classified as normal or impaired based on comparison with a large normative data pool. We also investigated the impact of clinical and demographic variables which could potentially influence cognitive performance including patient educational level (a proxy for cognitive reserve), disease status (duration, course, and severity of MS), and depression. CANTAB testing detected cognitive impairment in 40 patients (44% of the sample). The most frequently impaired domain was executive function, present in 55% of cognitively impaired individuals. Disease duration and severity were significantly associated with performance across various cognitive domains. Patients with depressive symptoms were also more likely to exhibit impaired processing speed. Results from this study confirm that cognitive impairment is common and occurs across a range of domains among MS patients attending routine clinical visits. CANTAB tasks provide a sensitive and practical approach to cognitive testing in MS patients as part of a holistic patient assessment.

Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis.

We sought to examine the effectiveness of acetylcholinesterase inhibitors (AChEIs) and stimulant-based medications for improving cognitive performance in patients with multiple sclerosis (MS). An electronic database search was conducted on 25th March 2017. Eligible studies were double-blind, randomised, placebo-controlled trials that examined the efficacy of compounds that act primarily as AChEIs or stimulants (administered daily for ≥1 week) on cognitive outcome measures in patients with MS. Where suitable data was reported, we generated effect sizes and corresponding 95% confidence intervals and performed meta-analyses using random-effects models to investigate the effectiveness of these drug types across cognitive domains. Sixteen trials were included in the systematic review, with eleven trials (N = 734 MS patients) providing sufficient data for meta-analysis. Whilst there was only a limited pool of relatively small trials and a number of different compounds, we found that collectively, both AChEIs (donepezil and rivastigmine) and stimulants (methylphenidate, modafinil, l-amphetamine sulfate and lisdexamfetamine dimesylate) offered no significant benefits over placebo on measures of processing speed, working memory, verbal fluency, verbal memory, visuospatial memory or executive functioning.

Social cognitive dysfunction as a clinical marker: A systematic review of meta-analyses across 30 clinical conditions.

Social cognition includes a range of cognitive processes that help individuals to understand how others think and feel. There is emerging evidence that social cognitive deficits may represent a transdiagnostic issue, potentially serving as a marker of neurological abnormality. We performed an electronic database search in order to identify published, peer-reviewed meta-analyses that compared facial emotion recognition or theory of mind task performance between individuals meeting clinical criteria for a psychiatric, neurological or developmental condition against healthy controls. We identified 31 meta-analyses eligible for inclusion that examined performance across relevant tasks among 30 different clinical populations. The results suggest that social cognitive deficits appear to be a core cognitive phenotype of many clinical conditions. Across the clinical groups, deficits in social cognitive domains were broadly similar in magnitude to those previously reported for more established aspects of cognition, such as memory and executive function. There is a need to clarify the 'real world' impact of these deficits, and to develop effective transdiagnostic interventions for those individuals that are adversely affected.

Long-term maintenance and effects of exercise in early psychosis.

AIM: The aims of this study were to examine if people with first-episode psychosis (FEP) are able to continue adhering to exercise after a supervised intervention and to explore if the benefits of exercise can be sustained. METHODS: Twenty-eight persons with FEP took part in a 10-week exercise intervention that provided each participant with twice-weekly accompaniment to exercise activities of their own choice, of whom 20 were re-assessed 6 months after the intervention. Long-term adherence to exercise was assessed, and measures of psychiatric symptoms, physical health, neurocognition and social functioning were administered at baseline, post-intervention and 6-month follow-up. RESULTS: During the supervised intervention, participants achieved 124.4 min of moderate-to-vigorous exercise per week. After 6 months, physical activity levels had decreased significantly (P = 0.025) and only 55% of participants had continued to exercise weekly. Repeated-measures analysis of variance found that the significant improvements in psychiatric symptoms and social functioning observed immediately after the intervention were maintained at 6 months (P = 0.001). However, post hoc analyses showed that symptomatic reductions were only maintained for those who continued to exercise, whereas symptom scores increased among those who had ceased exercising. Previously observed improvements in waist circumference and verbal memory were lost by 6 months. CONCLUSION: Long-term exercise participation is associated with significant benefits for symptoms, cognition and social functioning in FEP. However, adherence to unsupervised exercise is low. Future research should explore the effectiveness of 'step-down' support following supervised interventions, and aim to establish sustainable methods for maintaining regular exercise in order to facilitate functional recovery and maintain physical health.

Challenges in implementing an exercise intervention within residential psychiatric care: A mixed methods study.

Physical exercise is increasingly recognized as an important component of psychiatric care, although the feasibility of implementing exercise in residential care settings is not well understood. We evaluated the feasibility of a 10-week intervention of weekly fitness classes (delivered by a personal trainer) and other exercise activities using a mixed-methods approach. This was offered to across four residential care services, to all 51 residents who had severe mental illness (SMI). Of these, 27.5% consented to the exercise intervention. Participants averaged 87.6 min of moderate-to-vigorous exercise per-week, although fitness classes were poorly attended, and 35.7% dropped-out over 10 weeks. Of those who completed the intervention, increased physical activity was associated with significantly reduced negative symptoms. In conclusion, implementing exercise interventions in residential psychiatric care is challenging; given that supervised exercise classes may not be appealing to many residents, while unsupervised exercise is poorly adhered to. Future interventions should consider that better tailored exercise programs are required to adequately confront motivational issues, and to account for participant preference in order to increase engagement.

Examining the physical health and lifestyle of young people at ultra-high risk for psychosis: A qualitative study involving service users, parents and clinicians.

Emerging evidence suggests young people at ultra-high risk for psychosis (UHR) are also at-risk for poor physical health, and display high rates of modifiable cardiometabolic risk factors. However, before we can develop effective interventions there is a need to understand factors affecting lifestyle choices in the UHR group. We conducted semi-structured qualitative interviews with 20 UHR individuals (50% male; mean age 21.7), 5 parents (4 mothers, 1 father), and 6 clinicians from early intervention services in the Northwest of England to identify barriers and facilitators to living a healthy lifestyle, including achieving regular exercise, eating well and refraining from excessive substance use. Thematic analysis revealed the main barriers to living a healthy lifestyle related to psychiatric symptoms, beliefs about self, social withdrawal and practical considerations such as accessibility and cost. Provision of social support and promoting autonomy emerged as the two main themes which would facilitate a healthy lifestyle. Promoting physical health in people with emerging symptoms of psychosis is an important, yet neglected area of mental health practice and warrants further investigation. UHR individuals experience numerous barriers to living a healthy lifestyle, and interventions should focus primarily on targeting autonomous motivation and providing social support to facilitate this change.

The pro-cognitive mechanisms of physical exercise in people with schizophrenia.

Schizophrenia is associated with pervasive cognitive deficits which are unresponsive to antipsychotic medications. Physical exercise has been shown to improve cognitive functioning in people with schizophrenia, although the mechanisms for this are unclear. We conducted a systematic review of all exercise intervention studies which reported changes in brain structure, connectivity or peripheral biomarkers which could underlie cognitive improvements from exercise in schizophrenia. An electronic database search was conducted on 22 September 2016 using keywords relevant to exercise and neurocognition in schizophrenia. The search returned 2342 articles. Sixteen were eligible for inclusion, reporting data from 14 independent trials of 423 patients with schizophrenia. Seven studies used neuroimaging to examine the impact of exercise on brain structure and connectivity in schizophrenia, whereas seven other studies examined peripheral biomarkers to assess the effects of exercise. Imaging studies collectively indicated that exercise can increase brain volume in people with schizophrenia, although the regions which responded to exercise varied across studies. Most biomarker studies assessed the effects of exercise on serum levels of BDNF. Several studies found significant increases from exercise along with positive correlations between BDNF and cognitive enhancements (indicating a mechanistic link), although other studies did not observe this relationship. In conclusion, the cognitive benefits of exercise in schizophrenia may be due to exercise stimulating neurogenesis, perhaps by up-regulating BDNF, although current evidence is insufficient to draw definitive conclusions. Further exploration of the pro-cognitive mechanisms of exercise in schizophrenia would inform the development of optimal interventions for reducing cognitive impairments in this population. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Prolonged duration of untreated psychosis: a problem that needs addressing.

AIM: The duration of untreated psychosis (DUP) refers to the period of time between the emergence of psychotic symptoms and the initiation of appropriate clinical treatment. Prolonged DUP is associated with a range of adverse consequences, including more severe illness course, cognitive deficits and poor functioning. Problems with recognition of illness and in seeking help contribute to DUP, but another major cause of prolonged DUP is delays within secondary mental health services. In an attempt to reduce these delays, National Health Service England and the Department of Health have set new targets to improve access to early intervention services which will come into effect in April 2016. Given this background, we aimed to examine the DUP and pathways to care of new patients entering an early intervention service. We also examined whether they were receiving National Institute for Health and Care Excellence (NICE) concordant treatment. This will enable us to establish a baseline so that the impact of the new targets can be determined and to assess the degree of change that will be required to implement these. METHODS: De-identified electronic records of 165 patients accepted into the service over a 12-month period were analysed. RESULTS: Median DUP was 6 months. There was a median of 2 contacts prior to service entry. Community Mental Health Teams were the largest source of referrals. CONCLUSIONS: The majority of patients had a DUP exceeding the international target of 3 months. The findings appear to support previous evidence that this may be partially attributable to significant delays within the mental health care system.

Long-term employment among people at ultra-high risk for psychosis.

BACKGROUND: Psychotic disorders are associated with high rates of sustained unemployment, however, little is known about the long-term employment outcome of people at ultra-high risk (UHR) of developing psychosis. We sought to investigate the long-term unemployment rate and baseline predictors of employment status at follow-up in a large UHR cohort. METHOD: 268 UHR patients recruited from the Personal Assessment and Crisis Evaluation clinic in Melbourne, Australia were followed-up over 2-14years after initial presentation to the service. Individuals in no form of employment or education were classed as unemployed. Logistic regression analyses were used to examine predictors of employment outcome. RESULTS: A high rate of unemployment was present at follow-up in this UHR sample (23%). At baseline, those who were unemployed at follow-up had a longer duration of untreated illness, more severe negative symptoms, lower IQ, poorer social and occupational functioning and reported more childhood trauma than the employed group. At follow-up, unemployed individuals exhibited significantly more severe symptoms on all measures and were more likely to have been diagnosed with a mood, anxiety, psychotic or substance use disorder. Childhood trauma and the duration of untreated illness at baseline were significant independent predictors of employment status at follow-up in the multivariate analyses. CONCLUSIONS: Nearly a quarter of this UHR sample was unemployed at long-term follow-up. The duration of untreated illness and the effects of childhood trauma are potentially modifiable risk factors for long-term employment outcome in this group. Vocational support may be beneficial for many UHR patients presenting to services.