Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

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 which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h 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 pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

User-Centered Development of STOP (Successful Treatment for Paranoia): Material Development and Usability Testing for a Digital Therapeutic for Paranoia.

BACKGROUND: Paranoia is a highly debilitating mental health condition. One novel intervention for paranoia is cognitive bias modification for paranoia (CBM-pa). CBM-pa comes from a class of interventions that focus on manipulating interpretation bias. Here, we aimed to develop and evaluate new therapy content for CBM-pa for later use in a self-administered digital therapeutic for paranoia called STOP ("Successful Treatment of Paranoia"). OBJECTIVE: This study aimed to (1) take a user-centered approach with input from living experts, clinicians, and academics to create and evaluate paranoia-relevant item content to be used in STOP and (2) engage with living experts and the design team from a digital health care solutions company to cocreate and pilot-test the STOP mobile app prototype. METHODS: We invited 18 people with living or lived experiences of paranoia to create text exemplars of personal, everyday emotionally ambiguous scenarios that could provoke paranoid thoughts. Researchers then adapted 240 suitable exemplars into corresponding intervention items in the format commonly used for CBM training and created 240 control items for the purpose of testing STOP. Each item included newly developed, visually enriching graphics content to increase the engagement and realism of the basic text scenarios. All items were then evaluated for their paranoia severity and readability by living experts (n=8) and clinicians (n=7) and for their item length by the research team. Items were evenly distributed into six 40-item sessions based on these evaluations. Finalized items were presented in the STOP mobile app, which was co-designed with a digital health care solutions company, living or lived experts, and the academic team; user acceptance was evaluated across 2 pilot tests involving living or lived experts. RESULTS: All materials reached predefined acceptable thresholds on all rating criteria: paranoia severity (intervention items: ≥1; control items: ≤1, readability: ≥3, and length of the scenarios), and there was no systematic difference between the intervention and control group materials overall or between individual sessions within each group. For item graphics, we also found no systematic differences in users' ratings of complexity (P=.68), attractiveness (P=.15), and interest (P=.14) between intervention and control group materials. User acceptance testing of the mobile app found that it is easy to use and navigate, interactive, and helpful. CONCLUSIONS: Material development for any new digital therapeutic requires an iterative and rigorous process of testing involving multiple contributing groups. Appropriate user-centered development can create user-friendly mobile health apps, which may improve face validity and have a greater chance of being engaging and acceptable to the target end users.

Clozapine augmentation with long-acting antipsychotic injections: A case series and systematic review.

BACKGROUND: Up to 30% of patients with a diagnosis of treatment-resistant psychosis remain symptomatic despite an optimal trial with the gold standard treatment, clozapine. Emerging evidence suggests the clinical utility of long-acting injections (LAI) in such clinical scenarios. In this study, we aimed to describe clozapine augmentation with LAIs in an inner London hospital and explore the literature on the clinical effectiveness of this treatment modality. METHODS: Patients prescribed clozapine, who were commenced on a LAI between 2007 and 2023 by the United Kingdom's largest mental health trust, were identified from electronic patient records. First, routine clinical data were used to describe the use, effectiveness, and safety of this augmentation strategy. Second, we conducted a literature search up to 1st June 2023 to identify published studies describing clinical outcomes after clozapine augmentation with a LAI. Clinical outcomes were collated and presented in a table, including hospitalisation rates and quantitative clinical assessments using validated scales. RESULTS: Of the 1248 patients prescribed clozapine in SLaM, three patients (0.2%) received augmentation with the following LAIs: olanzapine embonate, paliperidone palmitate and pipotiazine palmitate. This treatment strategy was clinically effective and generally well tolerated in all three cases. Twelve published studies between 2010 and 2022 were included in the review. Eight distinct LAIs were reported (4 first and 4 second generation antipsychotics), with risperidone and paliperidone most widely studied. All the identified studies were observational including mirror-image studies, case series and case reports. Duration of follow up varied from 3 months to 3 years. There was evidence that the use of LAIs with clozapine can significantly reduce clinical symptoms, hospitalisation rates and bed days. No serious adverse effects were reported. CONCLUSION: This preliminary evidence suggests clinical utility of LAIs in alleviating residual symptoms and subsequently reducing hospitalisation rates in patients optimised on clozapine treatment. The current study warrants further investigations including a randomised controlled study to establish the clinical efficacy, tolerability, and place in therapy of this treatment modality.

The Safety of Digital Mental Health Interventions: Systematic Review and Recommendations.

BACKGROUND: Evidence suggests that digital mental health interventions (DMHIs) for common mental health conditions are effective. However, digital interventions, such as face-to-face therapies, pose risks to patients. A safe intervention is considered one in which the measured benefits outweigh the identified and mitigated risks. OBJECTIVE: This study aims to review the literature to assess how DMHIs assess safety, what risks are reported, and how they are mitigated in both the research and postmarket phases and building on existing recommendations for assessing, reporting, and mitigating safety in the DMHI and standardizing practice. METHODS: PsycINFO, Embase, and MEDLINE databases were searched for studies that addressed 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. As the outcome data were mainly qualitative in nature, a meta-analysis was not possible, and qualitative analysis was used to collate the results. Quantitative results were synthesized in the form of tables and percentages. To illustrate the use of a single common safety metric across studies, we calculated odds ratios and CIs, wherever possible. RESULTS: Overall, 23 studies were included in this review. Although many of the included studies assessed safety by actively collecting adverse event (AE) data, over one-third (8/23, 35%) did not assess or collect any safety data. The methods and frequency of safety data collection varied widely, and very few studies have performed formal statistical analyses. The main treatment-related reported AE was symptom deterioration. The main method used to mitigate risk was exclusion of high-risk groups. A secondary web-based search found that 6 DMHIs were available for users or patients to use (postmarket phase), all of which used indications and contraindications to mitigate risk, although there was no evidence of ongoing safety review. CONCLUSIONS: The findings of this review show the need for a standardized classification of AEs, a standardized method for assessing AEs to statically analyze AE data, and evidence-based practices for mitigating risk in DMHIs, both in the research and postmarket phases. This review produced 7 specific, measurable, and achievable recommendations with the potential to have an immediate impact on the field, which were implemented across ongoing and future research. Improving the quality of DMHI safety data will allow meaningful assessment of the safety of DMHIs and confidence in whether the benefits of a new DMHI outweigh its risks. TRIAL REGISTRATION: PROSPERO CRD42022333181; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=333181.

Neuroimaging glutamatergic mechanisms differentiating antipsychotic treatment-response.

Glutamatergic dysfunction is associated with failure to respond to antipsychotic medication in individuals with schizophrenia. Our objective was to combine neurochemical and functional brain imaging methods to investigate glutamatergic dysfunction and reward processing in such individuals compared with those with treatment responsive schizophrenia, and healthy controls. 60 participants played a trust task, while undergoing functional magnetic resonance imaging: 21 classified as having treatment-resistant schizophrenia, 21 patients with treatment-responsive schizophrenia, and 18 healthy controls. Proton magnetic resonance spectroscopy was also acquired to measure glutamate in the anterior cingulate cortex. Compared to controls, treatment responsive and treatment-resistant participants showed reduced investments during the trust task. For treatment-resistant individuals, glutamate levels in the anterior cingulate cortex were associated with signal decreases in the right dorsolateral prefrontal cortex when compared to those treatment-responsive, and with bilateral dorsolateral prefrontal cortex and left parietal association cortex when compared to controls. Treatment-responsive participants showed significant signal decreases in the anterior caudate compared to the other two groups. Our results provide evidence that glutamatergic differences differentiate treatment resistant and responsive schizophrenia. The differentiation of cortical and sub-cortical reward learning substrates has potential diagnostic value. Future novel interventions might therapeutically target neurotransmitters affecting the cortical substrates of the reward network.

Do loneliness and social exclusion breed paranoia? An experience sampling investigation across the psychosis continuum.

Background: The role of loneliness and social exclusion in the development of paranoia is largely unexplored. Negative affect may mediate potential associations between these factors. We investigated the temporal relationships of daily-life loneliness, felt social exclusion, negative affect, and paranoia across the psychosis continuum. Method: Seventy-five participants, including 29 individuals with a diagnosis of non-affective psychosis, 20 first-degree relatives, and 26 controls used an Experience Sampling Method (ESM) app to capture the fluctuations in loneliness, feelings of social exclusion, paranoia, and negative affect across a 1-week period. Data were analysed with multilevel regression analyses. Results: In all groups, loneliness and feelings of social exclusion were independent predictors of paranoia over time (b = 0.05, p < .001 and b = 0.04, p < .05, respectively). Negative affect predicted paranoia (b = 0.17, p < .001) and partially mediated the associations between loneliness, social exclusion, and paranoia. It also predicted loneliness (b = 0.15, p < .0001), but not social exclusion (b = 0.04, p = .21) over time. Paranoia predicted social exclusion over time, with more pronounced effects in controls (b = 0.43) than patients (b = 0.19; relatives: b = 0.17); but not loneliness (b = 0.08, p = .16). Conclusion: Paranoia and negative affect worsen in all groups following feelings of loneliness and social exclusion. This highlights the importance of a sense of belonging and being included for mental well-being. Loneliness, feeling socially excluded, and negative affect were independent predictors of paranoid thinking, suggesting they represent useful targets in its treatment.

Clozapine haematological monitoring for neutropenia: a global perspective.

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.

Alpha3/alpha2 power ratios relate to performance on a virtual reality shopping task in ageing adults.

Background: Aspects of cognitive function decline with age. This phenomenon is referred to as age-related cognitive decline (ARCD). Improving the understanding of these changes that occur as part of the ageing process can serve to enhance the detection of the more incapacitating neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we employ novel methods to assess ARCD by exploring the utility of the alpha3/alpha2 electroencephalogram (EEG) power ratio - a marker of AD, and a novel virtual reality (VR) functional cognition task - VStore, in discriminating between young and ageing healthy adults. Materials and methods: Twenty young individuals aged 20-30, and 20 older adults aged 60-70 took part in the study. Participants underwent resting-state EEG and completed VStore and the Cogstate Computerised Cognitive Battery. The difference in alpha3/alpha2 power ratios between the age groups was tested using t-test. In addition, the discriminatory accuracy of VStore and Cogstate were compared using logistic regression and overlying receiver operating characteristic (ROC) curves. Youden's J statistic was used to establish the optimal threshold for sensitivity and specificity and model performance was evaluated with the DeLong's test. Finally, alpha3/alpha2 power ratios were correlated with VStote and Cogstate performance. Results: The difference in alpha3/alpha2 power ratios between age cohorts was not statistically significant. On the other hand, VStore discriminated between age groups with high sensitivity (94%) and specificity (95%) The Cogstate Pre-clinical Alzheimer's Battery achieved a sensitivity of 89% and specificity of 60%, and Cogstate Composite Score achieved a sensitivity of 83% and specificity of 85%. The differences between the discriminatory accuracy of VStore and Cogstate models were statistically significant. Finally, high alpha3/alpha2 power ratios correlated strongly with VStore (r = 0.73), the Cogstate Pre-clinical Alzheimer's Battery (r = -0.67), and Cogstate Composite Score (r = -0.76). Conclusion: While we did not find evidence that the alpha3/alpha2 power ratio is elevated in healthy ageing individuals compared to young individuals, we demonstrated that VStore can classify age cohorts with high accuracy, supporting its utility in the assessment of ARCD. In addition, we found preliminary evidence that elevated alpha3/alpha2 power ratio may be linked to lower cognitive performance.

Neuroimaging oxytocin modulation of social reward learning in schizophrenia.

BACKGROUND: Conventional pharmacological approaches have limited effectiveness for schizophrenia. There is interest in the application of oxytocin, which is involved in social cognition. Clinical trials have yielded mixed results, with a gap in understanding neural mechanisms. AIMS: To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced. METHOD: We recruited 20 clinically stable right-handed men diagnosed with schizophrenia or schizoaffective disorder. In a double-blind cross-over randomised controlled study, 40 IU of oxytocin or placebo were administered before functional magnetic resonance imaging of participants playing a multi-round economic exchange game of trust. Participants had the role of investors (investment trials) receiving repayment on their investments (repayment trials), playing one session against a computer and a second against a player believed to be human. RESULTS: During investment trials, oxytocin increased neural signalling in the right lateral parietal cortex for both human and computer player trials, and attenuated signalling in the right insula for human player trials. For repayment trials, oxytocin elicited signal increases in left insula and left ventral caudate, and a signal decrease in right amygdala during the human player trials; conversely it resulted in right dorsal caudate activation during the computer player trials. We did not find a significant change in behavioural performance associated with oxytocin administration, or any associations with symptoms. CONCLUSIONS: During a social learning task oxytocin modulates cortical and limbic substrates of the reward-processing network. These perturbations can be putatively linked to the pathoaetiology of schizophrenia.

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation.

BACKGROUND: Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. METHODS: A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, 'at risk mental state' or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. RESULTS: We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). CONCLUSIONS: Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.

Vortioxetine as adjunctive therapy in the treatment of schizophrenia.

Background: The evidence for safe and effective interventions to treat the negative and cognitive symptoms of schizophrenia is lacking. Objectives: Vortioxetine is a novel antidepressant that has been used as adjunctive therapy for the treatment of psychosis; however, its effectiveness in clinical practice is relatively unknown. In this study, we aimed to determine the potential clinical effectiveness and safety and tolerability of vortioxetine in psychosis. Design: This is a non-interventional, retrospective study on the add-on use of vortioxetine in a group of people with schizophrenia-spectrum disorders in a large UK NHS mental health trust. Methods: Clinical effectiveness of vortioxetine was retrospectively assessed through the Clinical Global Impression - Severity (CGI-S) scale at 3 months. Safety and tolerability were evaluated through treatment discontinuation rates at 3, 6, and 12 months, and clinical reasons were evaluated at the primary endpoint of 3 months. Results: Data were available for 40 subjects with a diagnosis of schizophrenia or schizoaffective disorder-prescribed vortioxetine treatment; 30 (75%) remained on treatment at 3 months. At CGI-S assessment, 15 of the 35 evaluated subjects reported at least a 1-point improvement, from 5 at baseline to 4 after 3 months of treatment. Twenty-six (65%) remained on treatment at 1-year follow-up. The main reasons for those discontinuing treatment were inadequate response (10%) and manic switch (7.5%), while one subject refused treatment. Tolerability to treatment was good, and 36 subjects (90%) reported no adverse events specific to vortioxetine treatment. Conclusion: Schizophrenia is a complex illness, and there is insufficient treatment response in many individuals. A significant proportion of whom may require adjunctive treatments depending on the nature of the residual symptoms. Vortioxetine could be a potentially safe and effective option in such people, but further controlled studies are required.

Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study.

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.

A Novel Virtual Reality Assessment of Functional Cognition: Validation Study.

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.

Stimulating learning: A functional MRI and behavioral investigation of the effects of transcranial direct current stimulation on stochastic learning in schizophrenia.

Transcranial direct current stimulation (tDCS) of the medial prefrontal cortex (mPFC) is under clinical investigation as a treatment for cognitive deficits. We investigate the effects of tDCS over the mPFC on performance SSLT in individuals with schizophrenia, and the underlying neurophysiological effect in regions associated with learning values and stimulus-outcome relationships. In this parallel-design double-blind pilot study, 49 individuals with schizophrenia, of whom 28 completed a fMRI, were randomized into active or sham tDCS stimulation groups. Subjects participated in 4 days of SSLT training (days 1, 2, 14, 56) with tDCS applied at day-1, and during a concurrent MRI scan at day-14. The SSLT demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 and at day-56. Active tDCS was associated with increased insular activity, and reduced amygdala activation. tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia, with this study being the first to show a longer-term effect on SSLT.

Evaluation of the effectiveness and acceptability of the long-acting oral antipsychotic penfluridol: Illustrative case series.

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.

Social isolation and psychosis: an investigation of social interactions and paranoia in daily life.

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 < 0.001, 95% CI (- 0.28, - 0.07)] and in controls non-significant [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.

New approaches to antipsychotic medication adherence - safety, tolerability and acceptability.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

A systematic review of TMS and neurophysiological biometrics in patients with schizophrenia.

BACKGROUND: Transcranial magnetic stimulation can be combined with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) to evaluate the excitatory and inhibitory functions of the cerebral cortex in a standardized manner. It has been postulated that schizophrenia is a disorder of functional neural connectivity underpinned by a relative imbalance of excitation and inhibition. The aim of this review was to provide a comprehensive overview of TMS-EMG and TMS-EEG research in schizophrenia, focused on excitation or inhibition, connectivity, motor cortical plasticity and the effect of antipsychotic medications, symptom severity and illness duration on TMS-EMG and TMS-EEG indices. METHODS: We searched PsycINFO, Embase and Medline, from database inception to April 2020, for studies that included TMS outcomes in patients with schizophrenia. We used the following combination of search terms: transcranial magnetic stimulation OR tms AND interneurons OR glutamic acid OR gamma aminobutyric acid OR neural inhibition OR pyramidal neurons OR excita* OR inhibit* OR GABA* OR glutam* OR E-I balance OR excitation-inhibition balance AND schizoaffective disorder* OR Schizophrenia OR schizophreni*. RESULTS: TMS-EMG and TMS-EEG measurements revealed deficits in excitation or inhibition, functional connectivity and motor cortical plasticity in patients with schizophrenia. Increased duration of the cortical silent period (a TMS-EMG marker of γ-aminobutyric acid B receptor activity) with clozapine was a relatively consistent finding. LIMITATIONS: Most of the studies used patients with chronic schizophrenia and medicated patients, employed cross-sectional group comparisons and had small sample sizes. CONCLUSION: TMS-EMG and TMS-EEG offer an opportunity to develop a novel and improved understanding of the physiologic processes that underlie schizophrenia and to assess the therapeutic effect of antipsychotic medications. In the future, these techniques may also help predict disease progression and further our understanding of the excitatory/inhibitory balance and its implications for mechanisms that underlie treatment-resistant schizophrenia.