Implementing and Evaluating a National Integrated Digital Registry and Clinical Decision Support System in Early Intervention in Psychosis Services (Early Psychosis Informatics Into Care): Co-Designed Protocol.

BACKGROUND: Early intervention in psychosis (EIP) services are nationally mandated in England to provide multidisciplinary care to people experiencing first-episode psychosis, which disproportionately affects deprived and ethnic minority youth. Quality of service provision varies by region, and people from historically underserved populations have unequal access. In other disease areas, including stroke and dementia, national digital registries coupled with clinical decision support systems (CDSSs) have revolutionized the delivery of equitable, evidence-based interventions to transform patient outcomes and reduce population-level disparities in care. Given psychosis is ranked the third most burdensome mental health condition by the World Health Organization, it is essential that we achieve the same parity of health improvements. OBJECTIVE: This paper reports the protocol for the program development phase of this study, in which we aimed to co-design and produce an evidence-based, stakeholder-informed framework for the building, implementation, piloting, and evaluation of a national integrated digital registry and CDSS for psychosis, known as EPICare (Early Psychosis Informatics into Care). METHODS: We conducted 3 concurrent work packages, with reciprocal knowledge exchange between each. In work package 1, using a participatory co-design framework, key stakeholders (clinicians, academics, policy makers, and patient and public contributors) engaged in 4 workshops to review, refine, and identify a core set of essential and desirable measures and features of the EPICare registry and CDSS. Using a modified Delphi approach, we then developed a consensus of data priorities. In work package 2, we collaborated with National Health Service (NHS) informatics teams to identify relevant data currently captured in electronic health records, understand data retrieval methods, and design the software architecture and data model to inform future implementation. In work package 3, observations of stakeholder workshops and individual interviews with representative stakeholders (n=10) were subject to interpretative qualitative analysis, guided by normalization process theory, to identify factors likely to influence the adoption and implementation of EPICare into routine practice. RESULTS: Stage 1 of the EPICare study took place between December 2021 and September 2022. The next steps include stage 2 building, piloting, implementation, and evaluation of EPICare in 5 demonstrator NHS Trusts serving underserved and diverse populations with substantial need for EIP care in England. If successful, this will be followed by stage 3, in which we will seek NHS adoption of EPICare for rollout to all EIP services in England. CONCLUSIONS: By establishing a multistakeholder network and engaging them in an iterative co-design process, we have identified essential and desirable elements of the EPICare registry and CDSS; proactively identified and minimized potential challenges and barriers to uptake and implementation; and addressed key questions related to informatics architecture, infrastructure, governance, and integration in diverse NHS Trusts, enabling us to proceed with the building, piloting, implementation, and evaluation of EPICare. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50177.

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial.

BACKGROUND: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. METHODS: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. DISCUSSION: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. TRIAL REGISTRATION: ISRCTN12682719 registration date 24/11/2020.

Spatial and non-spatial feature binding impairments in visual working memory in schizophrenia.

Working memory (WM) impairments are well recognized in schizophrenia patients (PSZ) and contribute to poor psycho-social outcomes in this population. Distinct neural networks underlay the ability to encode and recall visual and spatial information raising the possibility that profile of visual working memory performance may help pinpoint dysfunctional neural correlates in schizophrenia. This study assessed the resolution and associative aspects of visual working memory deficits in schizophrenia and whether these deficits arise during encoding or maintenance processes. A total of 60 participants (30 PSZ and 30 healthy controls) matched in age, gender and education assessed on a modified object in place (OiPT), a delayed non-match-to-sample (DNMST) and a delayed spatial estimation (DSET) task. Patients demonstrated lower accuracy than controls in binding visual features of the same object and recognizing novel objects as well as lower precision recalling the location of a memorized target. Moreover, response choice set size affected recognition accuracy more in PSZ than controls. However, delay duration affected spatial recall precisions, binding, and recognition accuracy equally in the two groups. Our results suggest that visual working memory (vWM) impairments in schizophrenia predominantly reflect spatial and non-spatial binding deficits, with largely preserved discrete feature information. Moreover, these impairments likely arise more during encoding than during maintenance. These binding deficits may reflect impaired effective neural functional connectivity observed in schizophrenia.

Spatial Binding Impairments in Visual Working Memory following Temporal Lobectomy.

Disorders of the medial temporal lobe (MTL) adversely affect visual working memory (vWM) performance, including feature binding. It is unclear whether these impairments generalize across visual dimensions or are specifically spatial. To address this issue, we compared performance in two tasks of 13 epilepsy patients, who had undergone a temporal lobectomy, and 15 healthy controls. In the vWM task, participants recalled the color of one of two polygons, previously displayed side by side. At recall, a location or shape probe identified the target. In the perceptual task, participants estimated the centroid of three visible disks. Patients recalled the target color less accurately than healthy controls because they frequently swapped the nontarget with the target color. Moreover, healthy controls and right temporal lobectomy patients made more swap errors following shape than space probes. Left temporal lobectomy patients, showed the opposite pattern of errors instead. Patients and controls performed similarly in the perceptual task. We conclude that left MTL damage impairs spatial binding in vWM, and that this impairment does not reflect a perceptual or attentional deficit.

Oxidative Stress and the Pathophysiology and Symptom Profile of Schizophrenia Spectrum Disorders.

Schizophrenia is associated with increased levels of oxidative stress, as reflected by an increase in the concentrations of damaging reactive species and a reduction in anti-oxidant defences to combat them. Evidence has suggested that whilst not the likely primary cause of schizophrenia, increased oxidative stress may contribute to declining course and poor outcomes associated with schizophrenia. Here we discuss how oxidative stress may be implicated in the aetiology of schizophrenia and examine how current understanding relates associations with symptoms, potentially via lipid peroxidation induced neuronal damage. We argue that oxidative stress may be a good target for future pharmacotherapy in schizophrenia and suggest a multi-step model of illness progression with oxidative stress involved at each stage.

Motor-related oscillatory activity in schizophrenia according to phase of illness and clinical symptom severity.

Magnetoencephalography (MEG) measures magnetic fields generated by synchronised neural current flow and provides direct inference on brain electrophysiology and connectivity, with high spatial and temporal resolution. The movement-related beta decrease (MRBD) and the post-movement beta rebound (PMBR) are well-characterised effects in magnetoencephalography (MEG), with the latter having been shown to relate to long-range network integrity. Our previous work has shown that the PMBR is diminished (relative to controls) in a group of schizophrenia patients. However, little is known about how this effect might differ in patients at different stages of illness and degrees of clinical severity. Here, we extend our previous findings showing that the MEG derived PMBR abnormality in schizophrenia exists in 29 recent-onset and 35 established cases (i.e., chronic patients), compared to 42 control cases. In established cases, PMBR is negatively correlated with severity of disorganization symptoms. Further, using a hidden Markov model analysis, we show that transient pan-spectral oscillatory "bursts", which underlie the PMBR, differ between healthy controls and patients. Results corroborate that PMBR is associated with disorganization of mental activity in schizophrenia.

Impaired recollection-based episodic memory as a cognitive endophenotype in schizophrenia.

INTRODUCTION: Patients with schizophrenia show impaired recollection but largely preserved familiarity-based episodic memory. This study was done to clarify the endophenotypic nature of recollection and familiarity-based episodic memory in schizophrenia and the role of emotional valence of memoranda and degree of recall confidence in it. METHOD: Twenty-five patients with schizophrenia, one unaffected sibling of each patient, and twenty-three healthy controls completed two tasks assessing recollection and familiarity-based processes in episodic memory. In the first task, participants were asked to remember positive, negative, and neutral emotional valence words in a remember-know paradigm. In the second task, in addition to recollection and familiarity-based responses, participants were asked to make confidence judgments about their responses. RESULTS: Patients with schizophrenia and their first-degree relatives (FDRs) performed poorly on recollection but not familiarity-based responses, compared to healthy controls; performance of first-degree relatives was in between and significantly different from that of both patients and controls. The differences in recollection and familiarity-based responses across the three groups were not moderated by recall confidence judgments or emotional valence of memoranda. Furthermore, there was no correlation between recollection-based memory impairments and duration or severity of illness or current medication exposure. CONCLUSIONS: Impaired recollection-based memory constitutes a potential cognitive endophenotype in schizophrenia. Furthermore, selective impairment of recollection-based, but sparing of familiarity-based, memory in patients and their FDRs supports the distinct nature of recollection and familiarity-based episodic memories.

Acute transient psychotic disorder precipitated by Brexit vote.

A man in his 40s was brought to the accident and emergency department in an acute psychotic state, 3 weeks after the European Union referendum results in the UK were declared. His mental health had deteriorated rapidly following the announcement of the results, with significant concerns about Brexit. He presented as agitated, confused and thought disordered. He had auditory hallucinations, and paranoid, referential, misidentification and bizarre delusions. He recovered completely within 2 weeks after a brief admission and treatment with olanzapine. He had experienced a similar episode of much less severity 13 years previously after major work related stress which resolved completely within a few days. He was experiencing stress related to work and family prior to the current episode which could potentially have been a contributory factor. Political events can act as major psychological stressors and have a significant impact on the mental health of people, especially those with a predisposition to develop mental illness.

Effect of Olanzapine on Clinical and Polysomnography Profiles in Patients with Schizophrenia.

Acute and short-term administration of olanzapine has a favorable effect on sleep in schizophrenia patients. This study aimed to clarify the effect of olanzapine on polysomnographic profiles of schizophrenia patients during the acute phase of illness after controlling for previous drug exposure. Twenty-five drug-naïve or drug-free schizophrenia patients were assessed at baseline and after six weeks of olanzapine treatment on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), and Udvalg for Kliniske Undersogelser (UKU) side-effect rating scale and a whole-night polysomnography; fifteen patients completed the study. There was a significant reduction in all psychopathological variables with maximum reduction in PANSS total, BPRS total, and PANSS positive scores. A significant increase in total sleep time (TST), sleep efficiency (SE), nonrapid eye movement (NREM) stage 1 duration, stage 3 duration, stage 4 duration, and stage 4 percentage of TST, number of rapid eye movement (REM) periods, REM duration, and REM percentage of TST was observed. REM latency at baseline inversely predicted the reduction in BPRS total and PANSS total and positive scores. In summary, short-term treatment with olanzapine produced significant improvement in clinical and polysomnography profiles of patients with schizophrenia with shorter REM latency predicting a good clinical response.

Human Parahippocampal Cortex Supports Spatial Binding in Visual Working Memory.

Studies investigating the functional organization of the medial temporal lobe (MTL) suggest that parahippocampal cortex (PHC) generates representations of spatial and contextual information used by the hippocampus in the formation of episodic memories. However, evidence from animal studies also implicates PHC in spatial binding of visual information held in short term, working memory. Here we examined a 46-year-old man (P.J.), after he had recovered from bilateral medial occipitotemporal cortex strokes resulting in ischemic lesions of PHC and hippocampal atrophy, and a group of age-matched healthy controls. When recalling the color of 1 of 2 objects, P.J. misidentified the target when cued by its location, but not shape. When recalling the position of 1 of 3 objects, he frequently misidentified the target, which was cued by its color. Increasing the duration of the memory delay had no impact on the proportion of binding errors, but did significantly worsen recall precision in both P.J. and controls. We conclude that PHC may play a crucial role in spatial binding during encoding of visual information in working memory.

Comparison of anticraving efficacy of right and left repetitive transcranial magnetic stimulation in alcohol dependence: a randomized double-blind study.

The objective of this study was to compare the anticraving efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right versus left dorsolateral prefrontal cortex (DLPFC) in patients with alcohol dependence. Twenty patients with alcohol dependence syndrome were randomly allocated to receive either right or left rTMS over the right DLPFC (10 sessions at 10 Hz frequency; 20 trains per session; 4.9 seconds per train and intertrain interval 30 seconds) and were assessed on the Alcohol Craving Questionnaire (ACQ-NOW) to measure craving. Two-way repeated-measures analysis of variance for ACQ-NOW total score showed no main effect of group (F[1,18] = 0.0001 but significant main effect of time (F[1,18] = 185.91, p<0.0001, η(2) = 0.912). The interaction effect between group and time was not significant. There was significant reduction in craving scores in patients receiving either right or left rTMS with large effect size. However, there was no difference in anticraving efficacy between the two groups.

Evaluation of spontaneous dense array gamma oscillatory activity and minor physical anomalies as a composite neurodevelopmental endophenotype in schizophrenia.

OBJECTIVE: Minor physical anomalies (MPAs) and gamma oscillatory activity have been proposed as associated endophenotypes in schizophrenia. Combining these endophenotypes to create a composite endophenotype may help identify those at risk for schizophrenia better. The present study aims to investigate MPAs and gamma oscillatory activity in schizophrenia patients, their unaffected first degree relatives and healthy controls and appreciate whether they can be used together as a composite endophenotype. METHODS: This was a cross sectional family study conducted at a tertiary care mental health setup. Ninety participants including schizophrenia patients, their first degree relatives and controls (thirty each) were assessed for MPAs on the Extended Waldrop Scale. All participants underwent an awake, resting 192-channel EEG recording. Spectral power and coherence in 30-100Hz gamma bands were estimated using Welch's averaged periodogram method. One-way ANOVA, chi square test were used for comparing socio-demographic-clinical variables. MANOVA supplemented by one-way ANOVAs (post hoc Tukey HSD) were done for comparison of spectral measures. Pearson's correlation, step-by-step linear discriminant functional and intra-familial correlation analysis were subsequently performed. RESULTS: An endophenotype pattern of finding was found for MPAs in the craniofacial region, the total number of MPAs, spectral power in right temporal region on all bands and in the right parietal region in 50-70Hz and 70-100Hz gamma bands. The three groups were most accurately classified when MPA total score, right temporal 30-50Hz gamma power and right occipital 'intra hemispheric' 50-70Hz gamma coherence were considered together than when considered independently. Significant intra familial correlation was seen for MPA total score and right temporal gamma 30-50Hz power. CONCLUSION: Composite evaluation of two developmentally linked markers i.e. MPAs and gamma spectral measures may prove useful in categorizing schizophrenia and identifying at-risk individuals.

Fine-grained, local maps and coarse, global representations support human spatial working memory.

While sensory processes are tuned to particular features, such as an object's specific location, color or orientation, visual working memory (vWM) is assumed to store information using representations, which generalize over a feature dimension. Additionally, current vWM models presume that different features or objects are stored independently. On the other hand, configurational effects, when observed, are supposed to mainly reflect encoding strategies. We show that the location of the target, relative to the display center and boundaries, and overall memory load influenced recall precision, indicating that, like sensory processes, capacity limited vWM resources are spatially tuned. When recalling one of three memory items the target distance from the display center was overestimated, similar to the error when only one item was memorized, but its distance from the memory items' average position was underestimated, showing that not only individual memory items' position, but also the global configuration of the memory array may be stored. Finally, presenting the non-target items at recall, consequently providing landmarks and configurational information, improved precision and accuracy of target recall. Similarly, when the non-target items were translated at recall, relative to their position in the initial display, a parallel displacement of the recalled target was observed. These findings suggest that fine-grained spatial information in vWM is represented in local maps whose resolution varies with distance from landmarks, such as the display center, while coarse representations are used to store the memory array configuration. Both these representations are updated at the time of recall.

Sufism and mental health.

Human experience in, health and disease, always has a spiritual dimension. pirituality is accepted as one of the defining determinants of health and it no more remains a sole preserve of religion and mysticism. In recent years, pirituality has been an area of research in neurosciences and both in the nderstanding of psychiatric morbidity and extending therapeutic interventions it seems to be full of promises. Sufism has been a prominent spiritual tradition in Islam deriving influences from major world religions, such as, Christianity and Hinduism and contributing substantially toward spiritual well-being of a large number of people within and outside Muslim world. Though Sufism started in early days of Islam and had many prominent Sufis, it is in the medieval period it achieved great height culminating in many Sufi orders and their major proponents. The Sufism aims communion with God through spiritual realization; soul being the agency of this communion, and propounding the God to be not only the cause of all existence but the only real existence. It may provide a vital link to understand the source of religious experience and its impact on mental health.

Increased spontaneous gamma power and synchrony in schizophrenia patients having higher minor physical anomalies.

The higher frequency of minor physical anomalies (MPAs) in schizophrenia provides morphological evidence for the neurodevelopmental theory. Abnormal gamma oscillations (>30 Hz) seen in the electroencephalogram (EEG) in schizophrenia have been hypothesized to result from developmental insults. This study investigated spontaneous gamma oscillations in schizophrenia patients having higher and lower number of MPAs. Forty drug naïve/free schizophrenia patients and 20 matched healthy controls were assessed for MPAs on the Extended Waldrop Scale (EWS). All participants underwent an awake, resting 192-channel EEG recording. Spontaneous gamma spectral power and coherence were estimated in the low- (30-50 Hz) and high-gamma (51-70 and 71-100 Hz) bands. Significantly higher power was observed in high-MPA than healthy control group in low-gamma band over right frontal, parietal and temporal regions. Spectral power in the high-gamma band (71-100 Hz) was also significantly higher in the high-MPA schizophrenia subgroup than in the healthy control group over left frontal, parietal and temporal regions. Additionally, regional intra-hemispheric and inter-hemispheric coherence in the low-gamma band was significantly higher in the high-MPA schizophrenia subgroup than on the healthy control group. This study is the first to provide evidence of increased spontaneous gamma power and synchrony in schizophrenia patients having higher MPAs, supporting the idea that it may represent a distinct subgroup of schizophrenia with a neurodevelopmental basis.

Efficacy of paroxetine in primary palmoplantar hyperhidrosis occurring with juvenile myoclonic epilepsy.

Primary palmoplantar hyperhidrosis (PPH) is believed to be a dysfunction of emotional sweating, with an estimated prevalence of around 3%. Several treatment options including topical antiperspirants, tap water iontophoresis, botulinum toxin injections, oral anticholinergics, and tricyclic antidepressants are available, each with a significant adverse event profile. For the first time, we report a PPH patient with comorbid juvenile myoclonic epilepsy (JME) treated successfully with a combination of paroxetine and divalproex sodium. Paroxetine resulted in improvement in PPH, possibly through its anticholinergic and/or noradrenergic actions. Though the occurrence of PPH and JME together seems to be a chance association, some common frontal lobe mechanisms may be involved that need to be explored further.

Slow wave sleep deficits as a trait marker in patients with schizophrenia.

BACKGROUND: Among the sleep abnormalities found in schizophrenia, slow wave sleep deficits have been found to persist even after the resolution of active psychotic symptoms. Further, such abnormalities are observed in young healthy individuals at high risk of schizophrenia, which suggest that slow wave sleep deficits might be trait marker in schizophrenia. METHODS: Sleep EEG was recorded in 20 right handed patients aged 18-45 years with ICD-10 DCR diagnosis of schizophrenia, 14 first degree relatives and 20 age and sex matched controls. Patients were rated on Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) for assessment of psychopathology. RESULTS: There was significant difference between the three groups in total sleep period (p<.01), total sleep time (p<.01), stage shifts (p<.05), stage 1 percentage of total sleep time (p<.05), stage 2 duration (p<.05), stage 3 latency (p<.05), stage 4 duration (p<.01) and stage 4 percentage of total sleep time (p<.01). There was significant positive correlation of REM percentage of total sleep time with BPRS total score (r(s) = .488, p = .029) and PANSS positive score (r(s) = .583, p = .007), whereas significant negative correlation of REM latency was found with BPRS total score (r(s) = -.640, p = .002) and PANSS positive score (r(s) = -.657, p = .002) in the patients. CONCLUSIONS: Slow wave sleep deficits are a possible trait marker in patients with schizophrenia, which needs replication in further studies.