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Background: Clozapine is uniquely effective in treatment-resistant psychosis. In the UK, patients must discontinue clozapine indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their haematological parameters fall below particular thresholds. Under exceptional circumstances, patients can be rechallenged on clozapine under an off-licence agreement. In the USA in 2015, restrictive practice was discontinued to allow greater flexibility for clozapine maintenance. The absolute neutrophil count leading to treatment interruption was lowered from less than 1·5 × 109/L to less than 1·0 × 109/L and platelet and white cell count monitoring were ceased. We aimed to investigate the implications of a similar policy change on clozapine use in the UK. Methods: This was a modelling study of all patients registered on the UK CNRD. First, we determined the proportion of patients placed on the database in the UK who would have had to discontinue clozapine treatment under the US Food and Drug Administration (FDA) criteria. Second, we compared the haematological characteristics of patients who did or did not meet FDA criteria for discontinuing clozapine, including the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration. Third, we investigated the success rates of clozapine re-challenge for patients that had been placed on the CNRD. Successful rechallenge was defined as no recurrence of CNRD registration. Findings: Between May 2, 2002 and March 1, 2021, 3731 patients were placed on the CNRD, with a mean age of 47 years (SD 15), including 1420 (38%) women and 2311 (62%) men, of whom 3089 (83%) were White, 360 (10%) were Black, 190 (5%) were Asian, and 92 (2%) were classified as other. 566 (15%) of 3731 patients met the equivalent criteria for clozapine discontinuation under the FDA guidelines. The median time to CNRD registration from clozapine initiation was 1·6 years (IQR 0·2–4·9). Data for 519 rechallenged patients were examined; 419 (81%) were successful. Clozapine rechallenge success rates were broadly similar between individuals who did not meet the US CNRD registration criteria (36 [78%] of 46) and those who did meet the criteria (383 [81%] of 473). Interpretation: Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for haematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health. Funding: None.

Background Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose–response and (iv) select primary outcomes for future trials. Methods In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment. Results A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30–40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = −0.48 to −0.76), improved symptoms of paranoia (d = −0.19 to −0.38), and lower depressed and anxious mood (d = −0.03 to −0.29). The intervention effect was evident after the third session. Conclusions CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies. Multi-echo resting-state fMRI data was acquired at approximately 1h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDRFDRFDR

BACKGROUND Evidence suggests that Digital Mental Health Interventions (DMHIs) for common mental health conditions can be effective. However, these digital interventions, like face-to-face therapies, pose risks to patients. OBJECTIVE Review the literature to assess how DMHIs are assessing safety, what risks are reported, and how they are mitigated both in research and post-market. To build on existing recommendations for assessing, reporting, and mitigating safety in DMHI and standardizing practice. METHODS Psycinfo, EMBASE, and Medline were searched for studies that address the safety of DMHIs. The inclusion criteria were any study that addressed the safety of a clinical DMHI even if not as a main outcome, in an adult population, and in English. Results were synthesized in the form of tables and percentages. We calculated odds ratios and confidence intervals, wherever published data permitted, to illustrate the use of a single common safety metric across studies. RESULTS Twenty-three studies were included in this review. While many of the included studies assessed safety by actively collecting adverse events data, over one third did not assess or collect any safety data. The methods and frequency of safety data collection varied widely and very few studies performed any formal statistical analyses. The main treatment-related reported adverse event was deterioration in symptoms. The main method used to mitigate risk was exclusion of high-risk groups. A secondary online search found that six DMHIs were available for users/patients to use (post-market), all of which used indications and contraindications for use to mitigate risk although there was no evidence of ongoing safety review. CONCLUSIONS This review produced seven specific, measurable and achievable recommendations with the potential to bring immediate impact to the field, were they to be implemented across ongoing and future research. Beyond this, the review highlighted a pressing need for consensus-building research to standardize practice across a number of areas, including measurement, classification, analysis, interpretation and post-market refresh of safety. Improving the quality of DMHI safety data will allow meaningful assessment of the safety of DMHIs and confidence about whether the benefits of a new DMHI outweigh its risks. CLINICALTRIAL PROSPERO CRD42022333181.

Social isolation has been suggested to foster paranoia. Here we investigate whether social company (i.e., being alone vs. not) and its nature (i.e., stranger/distant vs. familiar other) affects paranoia differently depending on psychosis risk. Social interactions and paranoid thinking in daily life were investigated in 29 patients with clinically stable non-affective psychotic disorders, 20 first-degree relatives, and 26 controls (n = 75), using the experience sampling method (ESM). ESM was completed up to ten times daily for 1 week. Patients experienced marginally greater paranoia than relatives [b = 0.47, p = 0.08, 95% CI (− 0.06, 1.0)] and significantly greater paranoia than controls [b = 0.55, p = 0.03, 95% CI (0.5, 1.0)], but controls and relatives did not differ [b = 0.07, p = 0.78, 95% CI (− 0.47, 0.61)]. Patients were more often alone [68.5% vs. 44.8% and 56.2%, respectively, p = 0.057] and experienced greater paranoia when alone than when in company [b = 0.11, p = 0.016, 95% CI (0.02, 0.19)]. In relatives this was reversed [b = − 0.17, p b = − 0.02, p = 0.67, 95% CI (− 0.09, 0.06)]. The time-lagged association between being in social company and subsequent paranoia was non-significant and paranoia did not predict the likelihood of being in social company over time (both p’s = 0.68). All groups experienced greater paranoia in company of strangers/distant others than familiar others [X2(2) = 4.56, p = 0.03] and being with familiar others was associated with lower paranoia over time [X2(2) = 4.9, p = 0.03]. Patients are frequently alone. Importantly, social company appears to limit their paranoia, particularly when being with familiar people. The findings stress the importance of interventions that foster social engagement and ties with family and friends.

Aim: In this study, we sought to determine clinical outcomes at 1 year for patients prescribed penfluridol in an inner London National Health Service Trust. Using noninterventional data, we describe the use, effectiveness and safety of this treatment modality. Results: We retrospectively followed up 17 patients prescribed penfluridol as part of routine clinical practice. All patients took penfluridol once weekly. Of these patients, 12 (70.6%) were considered treatment resistant. The average duration of illness for this cohort was 10 years (SD = 6.7). At 1 year, nine (53%) patients remained on treatment. Median survival time was not reached at 1-year follow-up; mean time on penfluridol was 251 days (95% confidence interval (CI), 184–318). The mean number of admissions to hospital in the year following penfluridol initiation was 0.6 compared with 0.8, 1 year before initiation ( p = 0.465). The median number of bed days 1 year before penfluridol initiation was 24, whereas in the year following penfluridol initiation, it was 0 ( p = 0.514). Clinical Implications: Although penfluridol is unlicensed in the United Kingdom, limited data suggest that this long-acting oral therapy has the potential to be used safely and effectively for the treatment of psychotic disorders. However, more data are required to establish the place of penfluridol and other potential long-acting oral antipsychotic formulations in the treatment of psychotic disorders.

Aims Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates. Method We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons. Results One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita. Conclusions Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

Background Carers of people with eating disorders (EDs) are known to experience a lack of support, high levels of unmet needs and resulting distress. Specific support and interventions for carers may benefit both the carer, and their loved one with an ED. Individuals with co-occurring autism and EDs may present with additional needs and difficulties relating to their Autism Spectrum Condition (ASC) that impact their carers. However, there is a lack of research exploring whether carers of people with ASC and EDs have specific support needs, and what kinds of support may be most beneficial for this population. Methods This study used a qualitative interview design, utilising peer interviews. Eleven carers participated in interviews about their experiences as a carer, and their views on existing support systems and potential improvements. As the study took place during the initial UK coronavirus lockdown, the impact of the lockdown also emerged as a topic during the interviews. Interviews were transcribed and analysed using thematic analysis. Results Five themes were identified: challenges associated with co-occurring Autism and EDs, a lack of existing support for carers from healthcare services, the personal impact of caring for someone with both ASC and EDs, ideas for how carers can be best supported, and the impact of the coronavirus on carers. Conclusions Carers of loved ones with both ASC and EDs described the experience as having a significant personal impact on their lives, but also experienced a lack of support from healthcare services. There was a perception that caring for someone with both an ASC and EDs presents additional challenges compared to caring for someone with an ED only, and that this population therefore requires specialised support. Recommendations for possible support options, and for further research, are outlined.

Background and AimsIn the United Kingdom, patients on clozapine whose hematological parameters fall below certain thresholds are placed on the Central Non-Rechallenge Database (CNRD), meaning that they cannot be prescribed clozapine again except under exceptional circumstances. This practice was discontinued in the United States in 2015 by expanding the hematological monitoring guidelines, allowing more patients to receive clozapine. Our objective was to investigate the implications this policy change would have on clozapine utilization in the United Kingdom.MethodsThis was an observational, retrospective analysis of patients registered on the CNRD in a large mental health trust. The first objective was to compare the number of patients placed on the CNRD under the United Kingdom and the US Food and Drug Administration (FDA) criteria. The second objective was to explore the hematological and clinical outcomes of CNRD patients. The third objective was to investigate the hematological outcomes of patients rechallenged on clozapine after nonrechallengeable status.ResultsOne hundred and fifteen patients were placed on CNRD from 2002 to 2019, of whom 7 (6%) met the equivalent criteria for clozapine discontinuation under the FDA guidelines. Clinical outcomes, as measured by the Clinical Global Impression-Severity scale, were worse 3 months after clozapine cessation than on clozapine (t = −7.4862; P < .001). Sixty-two (54%) patients placed on CNRD were rechallenged. Fifty-nine of those (95%) were successfully rechallenged; 3 patients were placed back on CNRD, only one of which would have had to stop clozapine again under FDA criteria.ConclusionImplementation of the updated FDA’s monitoring criteria in the United Kingdom would significantly reduce clozapine discontinuation due to hematological reasons. The evidence suggests an urgent need for revising the UK clozapine monitoring guidelines to improve outcomes in treatment-resistant schizophrenia.

Virtual reality (VR) is becoming an increasingly popular tool in neuroscience and mental health research. In recent years, efforts have been made to virtualise neuropsychological testing with the intent to increase the ecological validity of cognitive assessments. However, there are some gaps in the literature. Feasibility and acceptability data are often not reported or available, and most studies have a small sample size. In this study, we describe the development and establish the feasibility and acceptability of administering a novel functional cognition VR shopping task, VStore, in three separate samples. Two studies included healthy volunteers from across the age spectrum and one study included patients with psychosis, with the total sample size of 210. Main VStore outcomes were: 1) verbal recall of 12 grocery items, 2) time to collect items, 3) time to select items on a self-checkout machine, 4) time to make the payment, 5) time to order hot drink, and 6) total time. Feasibility and acceptability were assessed by the completion rate across the three studies. VR induced adverse effects were tested for pre- and post-VStore administration to establish tolerability. Finally, as an exploratory objective, VStore’s ability to differentiate between age groups, and patients and gender and age matched healthy controls was probed to provide a preliminary indication of its potential utilities. The overall completion rate across the studies was exceptionally high (99.95%), and VStore did not induce any adverse effects. Additionally, there was a clear difference in VStore performance between patients and controls and younger and older age groups, suggesting that the VR assessment may have some clinical utility. These findings demonstrate that VStore is a promising neuropsychological tool that is well-tolerated and feasible to administer to both healthy and clinical populations. We discuss the implications for future research involving neuropsychological testing based on our experience and the contemporary literature.

Schizophrenia (SZ) and bipolar disorder (BD) are highly heritable, share symptomatology, and have a polygenic architecture. The impact of recent polygenic risk scores (PRS) for psychosis, which combine multiple genome-wide associated risk variations, should be assessed on heritable brain phenotypes also previously associated with the illnesses, for a better understanding of the pathways to disease. We have recently reported on the current SZ PRS's ability to predict 1st episode of psychosis case-control status and general cognition. Herein, we test its penetrance on white matter microstructure, which is known to be impaired in SZ, in BD and their relatives, using 141 participants (including SZ, BP, relatives of SZ or BP patients, and healthy volunteers), and two white matter integrity indexes: fractional anisotropy (FA) and mean diffusivity (MD). No significant correlation between the SZ PRS and FA or MD was found, thus it remains unclear whether white matter changes are primarily associated with SZ genetic risk profiles.

Antipsychotic pharmacotherapy is considered a first-line treatment in schizophrenia-related disorders and is associated with favorable prognosis and lower mortality rates. However, low adherence rates present a major clinical challenge. In this paper, we will review contemporary approaches to improve adherence to antipsychotic treatment, considering their mechanism of action, safety, tolerability and acceptability.Novel pharmacological delivery methods included different routes of administration of registered medications (such as intramuscular clozapine preparation and transdermal asenapine), modifications of existing compounds (such as 3-monthly injectable formulation of paliperidone palmitate), and increased interest in oral long-acting medication formulations (such as with penfluridol). In addition, we reviewed innovative technology to monitor adherence, based on the use of electronic digital medicine systems and ingestible sensors.All of these diverse approaches were clinically relevant in enhancing treatment adherence and found to be safe and tolerable. The place of each approach is predicated on a personalized approach in each patient, and future research could usefully use large comparative studies to establish robust treatment guidelines. The implementation of new and varied approaches to antipsychotic treatment adherence is welcomed and have the potential to make a significant impact on morbidity in this often difficult-to-treat population.

Background: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. Aims: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. Methods: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. Results: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. Conclusions: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast’s role in improving cognitive flexibility deficits in this clinical population.

SUMMARYSecond-generation antipsychotic medications (SGAs) have advanced the treatment of schizophrenia over the past 30 years. However, a number of potentially life-threatening cardiac side-effects associated with these treatments concern and can discourage prescribers from administering these evidence-based treatments. This review provides a practical, psychiatrist-oriented understanding of the relative frequencies, mechanisms, investigations and treatments associated with these cardiac toxicities. We aim to highlight that these are relatively rare complications of an effective class of drug and to promote the advantages of early involvement of cardiologists in the psychiatric multidisciplinary team to guide the investigation and management of these conditions.LEARNING OBJECTIVESAfter reading this article you will be able to: •understand the relative incidence of cardiotoxic side-effects of the various SGAs•perform preliminary investigations to diagnose the common cardiotoxic side-effects of SGAs•understand the treatments for these cardiac side-effects and the role of cardiologists involved the care of these patients.

Background: Information sampling is the cognitive process of accumulating information before committing to a decision. Patients across numerous disorders show decreased information sampling relative to controls. Aims: Here, we used the Beads and the Best Choice Tasks to study the role of dopamine signaling in information sampling. Methods: Participants were given placebo, amisulpride, or ropinirole in each session, in a double-blind cross-over design. Results: We found that ropinirole (agonist) increased the number of beads drawn in the Beads Task specifically when participants faced a loss, and decreased the rank of the chosen option in the Best Choice Task. Conclusions: These effects are likely driven by a combination of effects at presynaptic D2 receptors, which affect dopamine release, and post-synaptic D2 receptors. Increased D2 relative to D1 receptor activation in the striatum leads to increased sampling in the loss condition in the Beads Task. It also leads to choice of a poorer ranked option in the Best Choice Task. Decreased D2 relative to D1 receptor activation leads to decreased sampling in the Beads Task in the loss condition.

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20–35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22–28 and at 30–36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

AimsCOVID-19 causes cognitive, neurophysical and psychiatric sequalae that persist beyond the acute illness. These appear to be independent of the direct impact on respiratory function although the impact of multiorgan, especially brain pathology, may be a contributory factor – as may psycho-social effects of the disease. We performed a systematic review of literature to assess the sequelae of post-acute COVID-19 syndrome to better understand the need for dedicated interventions to improve functioning.MethodsWe conducted a systematic review of reports included in MEDLINE, PsycINFO, and EMBASE. We searched for cohort studies exploring psychiatric and neuro-cognitive sequelae of post-acute COVID-19 in adults with a sample size of at least 100. The search was conducted on 4 February 2022. Findings are reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two authors independently assessed the included studies’ methodological quality using The National Institute of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies and all records were rated as good or fair.ResultsOur search identified 66 records and 14 met protocol requirements. The studies varied in sample size ranging from 100 to 3762 participants. Time to follow-up ranged from 1–12 months. Main symptoms identified by a majority of the studies were; Fatigue (25% to 85%) and Sleep problems (20% to 79%). Psychiatric symptoms; Anxiety (19% to 56%), Depression (11% to 47%), PTSD (6% to 43%) and altered sense of reality (3% to 15%). Neuro-cognitive symptoms; Cognitive dysfunction (25% to 85%), brain fog (12% to 81%), memory problems (24% to 73%), concentration difficulties (25% to 54%), and attention deficit (27%).Female sex, advanced age, pre-morbid asthma or COPD, increased disease severity, high BMI and new neurological complications during hospitalisation were some of the identified risk factors for persistent symptoms in post-acute COVID-19. One study identified male sex as a risk factor for moderate to severe PTSD. Current evidence suggests that symptoms decrease over time.ConclusionThere is clear evidence of neuro-physical, psychiatric and neurocognitive sequelae in post-acute COVID-19 syndrome. Differences in assessing and reporting findings makes it difficult to synthesize meaningful information. Identifying and formulating standardised assessments for outcome measures and reporting systems would be useful in future research. Further research into symptoms of post-acute COVID-19, to understand the pathophysiology will better enable us to raise public awareness, introduce preventative measures and incorporate appropriate treatment strategies for rehabilitation.

Rationale Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. Objectives Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia. Methods This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest. Results Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03). Conclusions Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia. Trial registration NCT02079844.

Patients with schizophrenia show reduced cooperation and less sensitivity to social cues in pairwise interactions, however, it remains unclear whether these mechanisms are also present in interactions within social groups. We used a public goods game to investigate cooperation and sensitivity to social feedback in group interactions in 27 patients with schizophrenia and 27 healthy controls. Participants played 40 trials in two conditions: 1) no fine (20 trials): participants had the choice of investing into the public good (i.e. cooperating) or not (i.e. defecting), 2) fine (20 trials): participants had the same choice but defectors could be punished by the other players. On the first trial, patients invested less in the public good than healthy controls. In the no fine condition, controls decreased their investments over time, but patients did not. The possibility of being fined for defecting and actually being fined led to significantly higher cooperation in both groups. This shows that the groups were equally sensitive to social enforcement and social feedback. Our findings suggest that patients tend to approach social group interactions with less cooperative behaviour, which could contribute to social dysfunction in daily-life. However, an intact sensitivity to social enforcement and feedback indicates that patients can adjust their behaviour accordingly in group interactions.

Cognitive impairments in learning and memory are core symptoms of schizophrenia, associated with reduced self-reported quality of life. The most effective treatment of cognitive impairments is drill and practice cognitive training. Still, to date no study has investigated the effect of varying the frequency of training on cognitive outcomes. Here we utilized a verbal memory based language learning task, tapping into implicit cognitive processes, to investigate the role of training intensity on learning rates in individuals with schizophrenia. Data from 47 participants across two studies was utilized, one with a daily training regimen over 5 days and the other with a more intensive schedule of 5 sessions delivered over 2 days. The primary outcome measure was the change in implicit learning performance across five sessions, quantified with the Matthews Correlation Coefficient (MCC). Participants in the daily training group showed improved performance compared to the intensive group only at session 4. This is the first study to show that implicit learning rates are influenced by training intensity, with daily sessions outperforming a more intensive regimen; a period of consolidation overnight may be necessary to optimize cognitive training for individuals with schizophrenia.

J Corey Fowler,1 Nathan Cope,2 Jonathan Knights,3 Hui Fang,4 Taisa Skubiak,5 Sukhi S Shergill,6 Peter Phiri,7 Shanaya Rathod,7 Timothy Peters-Strickland1 1Global Clinical Development, CNS and Digital Medicine, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 2Program Management, Otsuka Pharmaceutical Europe Ltd., Wexham, SL3 6PJ, UK; 3Data Insights and Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 4Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 5Clinical Management, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 6Institute of Psychiatry, Psychology and Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, London, SE5 8AF, UK; 7Southern Health NHS Foundation Trust, Moorgreen Hospital, Clinical Trials Facility, Research Department, Southampton, SO30 3JB, UKCorrespondence: J Corey FowlerOtsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USATel +1 919 475 4823Email corey.fowler@otsuka-us.comPurpose: Symptoms of psychotic disorders can complicate efforts to accurately evaluate patients’ medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders.Methods: This was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT 03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥ 80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs).Results: From May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥ 80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported.Conclusion: The DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.Keywords: digital medicine, antipsychotic, digital health, medication adherence

Background: Clozapine is the only licensed treatment for treatment refractory schizophrenia. Despite this, it remains grossly underused relative to the prevalence of refractory schizophrenia. The extent of underuse in the United Kingdom compared to other European countries, and the extent of any regional variation within the UK remains unclear. Methods: We obtained data relating to all clozapine prescribing in the UK from the relevant clozapine registries. We compared the UK rate of clozapine use per 100,000 population to that described in other European countries. We also examined regional variation in clozapine use across England, corrected for the known prevalence of Severe Mental Illness (SMI). Findings: Clozapine prescribing rate in the UK was lower than in several European countries. Only a third of patients eligible for clozapine were prescribed the drug whilst there was substantial variation in prescribing across different regions of England. Interpretation: There is clear regional inequity in access to the most effective treatment in refractory schizophrenia. Strategies to increase clozapine use, by overcoming both real and perceived barriers, are urgently necessary to reduce treatment inequity for patients with refractory schizophrenia. Funding Statement: No funding was received for this project. Declaration of Interests: None. Ethics Approval Statement: The study was approved by the Drugs and Therapeutics Committee of the South London and Maudsley NHS Foundation Trust.

COVID-19 has highlighted potential shortcomings in our approach to psychological health that had perhaps become the accepted status quo within cardiology. Importantly, the pandemic may offer a unique opportunity to redress them. During 2020, physicians have had to question their ability to deliver optimal care with scarce resources, limited knowledge, concerns about personal safety and, by extension, the safety of one’s family. For some, these challenges may have a lasting psychological impact. Encouragingly, many staff have acknowledged the potential effect of these pressures on their mental health, making short-term adaptations and promoting staff camaraderie. However, achieving long-lasting changes in our approach to supporting those affected could create a positive legacy to this pandemic. The idea of ‘moral injury’, originally recognised within the military, describes the psychological distress which may follow ethical or moral beliefs being challenged. Such situations can lead to overwhelming feelings of culpability, shame or anger, which increase someone’s vulnerability to develop, or exacerbate, mental ill health including post-traumatic stress disorder (PTSD) and depression.1 The attribution of moral injury to healthcare workers during the pandemic is increasingly recognised.2 Equally important is the concept of post-traumatic growth,3 which recognises that most people will survive and psychologically develop following these unwished-for experiences. Evidence shows that good organisational structures, management and psychologically savvy teamwork can calibrate this and push the needle more towards growth and away from injury. Although moral injury in cardiology has yet to be substantiated, evidence suggests that cardiologists report some of the highest levels of burn-out and work longer hours than other physicians. However, only 23% report being willing to seek professional help for feelings of depression or suicidality.4 This may result from a stoicism existing within cardiology where a culture of appearing impervious to pressure prevails and is lauded, suggesting that many …

OBJECTIVES Theory of Mind (ToM) plays a role in social functioning and is impaired in patients with schizophrenia and to a lesser degree in first-degree relatives, compared to healthy controls. This study investigates whether attachment styles moderate these observed group differences in ToM. METHODS This cross-sectional study included a sample of 51 patients, 23 first-degree relatives, and 49 controls who completed assessments of anxious and avoidant attachment (Psychosis Attachment Measure), ToM (Reading the Mind in the Eyes Test), and estimated cognitive ability. Patients' symptoms were assessed with the Positive and Negative Syndrome Scale. RESULTS Patients differed from controls and relatives in ToM performance but not in attachment avoidance or attachment anxiety. Attachment anxiety showed an interaction with group over ToM. The interaction was significant only between patients and controls but not between patients and relatives or relatives and controls. Post-hoc analysis showed that patients and controls showed differential ToM performance at average and high attachment anxiety. In patients, symptom levels did not moderate the association between attachment and ToM. CONCLUSIONS Attachment anxiety is related to poorer levels of ToM in patients, suggesting this may have a contributory role in schizophrenia. The findings stress the need for longitudinal research into the directionality of the relationship between ToM and attachment anxiety. PRACTITIONER POINTS Relationships with significant others might be a factor that influences the way in which social information is processed by persons with a diagnosis of a psychotic disorder. In patients, higher levels of attachment anxiety - that is, low self-worth, fear of abandonment and rejection, continuous vigilance of threat-related cues - were associated with a lower ability to understand the mental states of others. However, at lower levels of attachment anxiety, their ToM performance was comparable to that of relatives and controls. This effect was not influenced by symptom severity. Further research is required to confirm the potential influence of attachment insecurity on ToM ability as the latter is strongly related to patient's functional outcomes.

Background and objectives Cognitive models of psychosis implicate interpretation biases as one of the mechanisms involved in the formation and maintenance of symptoms. First we measured the strength of association between interpretation biases and psychosis-relevant traits. Next we manipulated these biases and quantified the effects of doing so on psychosis-relevant outcomes. Methods Experiment 1 used two measures of interpretation bias in a healthy sample (n = 70). Experiment 2 used a novel cognitive bias modification procedure (CMB-pa) in individuals with moderate trait paranoia (n = 60). Results Experiment 1 revealed that over a third of the variance in interpretation bias could be explained by the combined effect of trait measures of paranoia/psychosis. In Experiment 2, CBM-pa produced training-congruent changes in the interpretation of new ambiguous information and influenced the interpretation, attribution and distress associated with a real-life social event. Limitations The potentially confounding effects of elevated anxiety and depression on interpretation bias and the restricted range of outcome measures to assess the wider effects of CBM-pa. Conclusions These studies are consistent with interpretation biases contributing to the maintenance of paranoia. CBM-pa could next be adapted and evaluated to test its efficacy as a therapeutic intervention.

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity ( p=0.04) and working memory-related theta oscillations ( p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

Background Treatment-resistant schizophrenia is a major disabling illness which often proves challenging to manage in a secondary care setting. The National Psychosis Unit (NPU) is a specialised tertiary in-patient facility that provides evidence-based, personalised, multidisciplinary interventions for complex treatment-resistant psychosis, in order to reduce the risk of readmission and long-term care costs. Aims This study aimed to assess the long-term effectiveness of treatment at the NPU by considering naturalistic outcome measures. Method Using a mirror image design, we compared the numbers of psychiatric and general hospital admissions, in-patient days, acuity of placement, number of psychotropic medications and dose of antipsychotic medication prescribed before and following NPU admission. Data were obtained from the Clinical Records Interactive Search system, an anonymised database sourced from the South London and Maudsley NHS Trust electronic records, and by means of anonymous linkage to the Hospital Episode Statistics system. Results Compared with the 2 years before NPU admission, patients had fewer mental health admissions (1.65 ± 1.44 v. 0.87 ± 0.99, z = 5.594, P < 0.0001) and less mental health bed usage (335.31 ± 272.67 v. 199.42 ± 261.96, z = 5.195 P < 0.0001) after NPU admission. Total in-patient days in physical health hospitals and total number of in-patient days were also significantly reduced (16.51 ± 85.77 v. 2.83 ± 17.38, z = 2.046, P = 0.0408; 351.82 ± 269.09 v. 202.25 ± 261.05, z = 5.621, P < 0.0001). The reduction in level of support required after treatment at the NPU was statistically significant (z = −8.099, P < 0.0001). Conclusions This study demonstrates the long-term effectiveness of a tertiary service specialising in treatment-resistant psychosis.

BackgroundClozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored.AimsThis was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period.MethodSuccessful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication.ResultsAmong 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14–1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11–1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling.ConclusionsIntramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.

Social deficits are key hallmarks of the Clinical High Risk for Psychosis (CHR-P) state and of established psychotic disorders, and contribute to impaired social functioning, indicating a potential target for interventions. However, current treatments do not significantly ameliorate social impairments in CHR-P individuals. Given its critical role in social behaviour and cognition, the oxytocinergic (OT) system is a promising target for novel interventions in CHR-P subjects. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using functional magnetic resonance imaging (fMRI) on two occasions, once after 40IU self-administered intranasal OT and once after placebo. A modified version of the Sally-Anne task was used to assess brain activation during inferring others’ beliefs and social emotions. The Reading the Mind in the Eyes Test was acquired prior to the first scan to test whether OT effects were moderated by baseline social-emotional abilities. OT did not modulate behavioural performances but reduced activation in the bilateral inferior frontal gyrus compared with placebo while inferring others’ social emotions. Furthermore, the relationship between brain activation and task performance after OT administration was moderated by baseline social-emotional abilities. While task accuracy during inferring others’ social emotion increased with decreasing activation in the left inferior frontal gyrus in CHR-P individuals with low social-emotional abilities, there was no such relationship in CHR-P individuals with high social-emotional abilities. Our findings may suggest that acute OT administration enhances neural efficiency in the inferior frontal gyrus during inferring others’ social emotions in those CHR-P subjects with low baseline social-emotional abilities.

Cognitive difficulties are common in people with psychosis and associated with considerable disability. Cognitive remediation (CR) can reduce the burden of cognitive difficulties and improve functioning. While mental health care has predominantly shifted to the community, people with greater illness severity and complexity, and those with poor response to treatment and concomitant greater cognitive difficulties, continue to receive inpatient care. The aim of this study is to review and evaluate the acceptability and efficacy of CR for inpatients with psychosis. A systematic search was used to identify randomized controlled trials of CR for inpatients with psychosis. Demographic and clinical information was extracted by independent raters together with therapy outcomes. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Standardized mean change for cognitive and functional outcomes was calculated using Hedges's g and used to infer therapy effects with meta-analysis. Twenty studies were identified considering 1509 participants. Results from random-effect models suggested that CR was effective in improving processing speed (g = 0.48), memory (g = 0.48) and working memory (g = 0.56). While there was an indication of improvements in the levels of vocational, social and global functioning, these were less reliable. On average, 7% of participants dropped-out of treatment. Studies methodological quality was moderate. CR is an acceptable intervention for inpatients with psychosis and can lead to significant cognitive improvements. Evidence for improvement in functioning requires more robust and converging evidence. Future research should extend the evaluation of inpatient CR to subsequent post-discharge community functioning and further need for care.

Background Cognitive deficits are present in several neuropsychiatric disorders, including Alzheimer disease, schizophrenia, and depression. Assessments used to measure cognition in these disorders are time-consuming, burdensome, and have low ecological validity. To address these limitations, we developed a novel virtual reality shopping task—VStore. Objective This study aims to establish the construct validity of VStore in relation to the established computerized cognitive battery, Cogstate, and explore its sensitivity to age-related cognitive decline. Methods A total of 142 healthy volunteers aged 20-79 years participated in the study. The main VStore outcomes included verbal recall of 12 grocery items, time to collect items, time to select items on a self-checkout machine, time to make the payment, time to order coffee, and total completion time. Construct validity was examined through a series of backward elimination regression models to establish which Cogstate tasks, measuring attention, processing speed, verbal and visual learning, working memory, executive function, and paired associate learning, in addition to age and technological familiarity, best predicted VStore performance. In addition, 2 ridge regression and 2 logistic regression models supplemented with receiver operating characteristic curves were built, with VStore outcomes in the first model and Cogstate outcomes in the second model entered as predictors of age and age cohorts, respectively. Results Overall VStore performance, as indexed by the total time spent completing the task, was best explained by Cogstate tasks measuring attention, working memory, paired associate learning, and age and technological familiarity, accounting for 47% of the variance. In addition, with λ=5.16, the ridge regression model selected 5 parameters for VStore when predicting age (mean squared error 185.80, SE 19.34), and with λ=9.49 for Cogstate, the model selected all 8 tasks (mean squared error 226.80, SE 23.48). Finally, VStore was found to be highly sensitive (87%) and specific (91.7%) to age cohorts, with 94.6% of the area under the receiver operating characteristic curve. Conclusions Our findings suggest that VStore is a promising assessment that engages standard cognitive domains and is sensitive to age-related cognitive decline.