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It has been traditionally accepted that antipsychotics have a 'delayed onset' of action with various authors claiming 2–3 weeks of delay. Data from the previous few years has contradicted this notion.
The talk will review this data, identify its theoretical implications and implications for practise. In an initial meta-analysis of over 8,000 patient data it was shown that antipsychotic action is not delayed at all but evident in teh first week, this change is not non-specific sedation but a specific anti-'psychotic' effect, and is seen with all evaluated antipsychotics. In more recent studies we have been able to show that this effect is even discernable in the first 24 hours, is related to dopmaine D2 occupancy achieved early on, and early non-response is a very strong predictor of subsequent non-response.
This early onset is not only an isolated improvement in psychosis-but, can also be seen on quality of life and social functionign indicators. These data raise interesting questions regarding the mechanism of improvement: they question the standard 'depolarisation block' hypothesis of antispychotic action-and suggest a simpler dopamine occupancy hypothesis instead; since change occurs early it is possible to map different trajectories and our most recent findigns show that drug-treated patients show a distinct trajectory from those observed in placebo-treated patients. Finally, these findings have implications for the design of clinical trials and clinical practise. In clinical trials it is possible to use early-response to devise adpative or enriched designs that are more clinically relevant - example of a recent such application will be discussed and at a clinical level it may be possible to reconsider the standard notion that an antipsychotic must be tried for 6 weeks before considering an alterative option.
It has long been known that cannabis can elicit an acute psychotic reaction. Recent work shows that, of the 60 cannabinoid molecules in the plant, delta-9-tetrahydrocannibinol is responsible for the central effects of cannabis. Here we aimed to investigate, in more detail, the psychological effects of synthetic intravenous THC in healthy subjects. Over 2 experimental sessions, participants (N=22) were administered 2.5mg IV THC or placebo under randomised, double-blind conditions. Psychological reactions were assessed using standard rating instruments and a battery of cognitive tests was completed.
Following THC, there was a significant increase in self-rated and observer-rated positive psychotic symptoms which were highly correlated (r=0.62, p=0.001).Phenomena centered on de-synchronisation of self-agency (ipseity disturbance) and hypersalience/paranoia. Participants also reported a significant increase in negative symptomatology under THC conditions, which was not explained by sedation. Finally, working memory/executive functioning was markedly and consistently impaired by THC.
Here we provide further evidence that THC can elicit an acute psychotic reaction in a proportion of healthy subjects. Acute THC-psychosis elicits positive, negative and cognitive symptoms. Compared with other drug models THC recreates symptomatology across 3 major dimensions of schizophrenic psychosis without sedation/clouding of consciousness. Here we also present preliminary evidence that the molecule cannabidiol (CBD) inhibits THC-elicited positive symptoms. Current work in our laboratory is exploring the underlying mechanisms.
Alcohol use is a major cause of morbidity and mortality and is less understood than other addictive disorders. Humans vary in alcohol responses which could be related to genetic susceptibility for alcoholism. The objective of the present study was to examine the prevalence of OPRM1 polymorphisms in addicts. The opioid receptor mu1 (OPRM1) mediates the action of morphine and is a major determinant of striatal dopamine responses to alcohol. Two polymorphism, C17T and A11G of exon I were screened in subjects with addiction to alcohol and opioids and compared with subjects without a history of any sort of drug addiction using restriction fragment length polymorphism, which was further validated by DNA sequencing. The allelic frequencies between the two groups were compared and the difference was found to be of statistical significant (p < 0.0001), with the 17T allele having a 3.06-fold higher risk of alcohol addiction (risk ratio (RR) = 3.069, 95%CI of RR = 2.0339 to 4.6127, odds ratio (OR) = 3.9554; 95%CI of OR = 2.4175 to6.4718) and 118G allele having a 1.81-fold higher risk of alcohol addiction (risk ratio (RR) = 1.8096, 95%CI of RR = 13459 to 2.433, odds ratio (OR) = 2.2025; 95%CI of OR = 1.479 to 3.2799). Similar differences were observed in the case of opiate addiction, RR = 1.1369 to 2.7647, OR = 1.9367; 95%CI = 1.1625 to 3.2263 and RR = 1.7363, 95%CI of RR = 1.3043 to 2.3112, OR = 2.0725; 1.42 to 3.0248) for 17T and 118G respectively. Further studies to unravel the epigenetic control of expression of these candidate genes are underway.
Cognitive impairment in schizophrenia is a strong predictor of the functional outcome and no effective treatments are available. MATRICS Consensus Cognitive Battery (MCCB) is approved by the FDA as outcome measure for trials of cognitive-enhancing drugs in schizophrenia. CogState Schizophrenia Battery (CSB) provides a briefer cognition assessment with minimal practice effects and a strong correlation between the CSB and MCCB composite scores. We tested the sensitivity of CSB as a cognitive outcome measure in a clinical trial in schizophrenia, where a cognitive-enhancing drug and cognitive training were combined.
49 participants with schizophrenia were enrolled in a double-blind, placebo-controlled study. Participants were randomised to modafinil (200mg/day) or placebo and underwent a cognitive training program for 10 weekdays. CSB was administered twice at baseline to minimise practice effects, at the last day of the intervention and two weeks after the completion of the intervention.
There was a significant time effect at the end of the intervention on the CSB composite score (p=0.042). There was no significant treatment effect on CSB composite score at the end of the intervention (p=0.686) or at follow up (p=0.120).
Multiple administrations of CSB were well tolerated by participants. The significant time effects on the composite score may suggest the operation of practice effects. Several factors could have contributed to the lack of treatment effects on CSB, such as the burden of multiple neuropsychological testing in a relatively brief study, the duration of modafinil treatment and also the intensive nature of cognitive training.
Experiences of depression and anxiety are common among patients with persecutory delusions. It has been theorized that emotional disturbances affect the formation and appraisal of persecutory delusions directly and possibly via increasing the sense of aberrant salience.
Using a time-lagged analysis of experience sampling data, this study modelled the role of momentary levels of negative emotions and aberrant salience in maintaining persecutory delusions in patients with active delusions.
Clinically acute participants with at least a mild level of persecutory delusions were assessed using experience sampling method (ESM; 7 entries per day for 14 days) and clinical rating scales. ESM data of participants who completed at least 30 ESM entries were analysed by using multilevel regression modelling.
The final sample consisted of 14 participants, with a total of 1161 momentary observations. Time-lagged analysis revealed that both negative emotions (B = 0.125, P = .009) and aberrant salience (B = 0.267, P< .001) predicted an increase in persecutory delusions in the next moment. Conversely, persecutory delusions did not predict change in negative emotions or change in aberrant salience in the next moment (ps> .05). Negative emotions also predicted an increase in aberrant salience in the next moment (B = 0.087, P = .009).
Our results supported the hypothesis that both negative emotions and aberrant salience exacerbate persecutory delusions, rather than being merely the sequelae of the symptoms. Our results suggested both direct and indirect (via aberrant salience) pathways from negative emotions to persecutory delusions.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Peste des petits ruminants virus (PPRV) causes a contagious disease of high morbidity and mortality in small ruminant populations globally. Using cross-sectional serosurvey data collected in 2016, our study investigated PPRV seroprevalence and risk factors among sheep, goats and cattle in 20 agropastoral (AP) and pastoral (P) villages in northern Tanzania. Overall observed seroprevalence was 21.1% (95% exact confidence interval (CI) 20.1–22.0) with 5.8% seroprevalence among agropastoral (95% CI 5.0–6.7) and 30.7% among pastoral villages (95% CI 29.3–32.0). Seropositivity varied significantly by management (production) system. Our study applied the catalytic framework to estimate the force of infection. The associated reproductive numbers (R0) were estimated at 1.36 (95% CI 1.32–1.39), 1.40 (95% CI 1.37–1.44) and 1.13 (95% CI 1.11–1.14) for sheep, goats and cattle, respectively. For sheep and goats, these R0 values are likely underestimates due to infection-associated mortality. Spatial heterogeneity in risk among pairs of species across 20 villages was significantly positively correlated (R2: 0.59–0.69), suggesting either cross-species transmission or common, external risk factors affecting all species. The non-negligible seroconversion in cattle may represent spillover or cattle-to-cattle transmission and must be investigated further to understand the role of cattle in PPRV transmission ahead of upcoming eradication efforts.
The 2008 economic recession was associated with an increase in suicide internationally. Studies have focused on the impact in the general population with little consideration of the effect on people with a mental illness.
To investigate suicide trends related to the recession in mental health patients in England.
Using regression models, we studied suicide trends in mental health patients in England before, during and after the recession and examined the demographic and clinical characteristics of the patients. We used data from the National Confidential Inquiry into Suicide and Safety in Mental Health, a national data-set of all suicide deaths in the UK that includes detailed clinical information on those seen by services in the last 12 months before death.
Between 2000 and 2016, there were 21 224 suicide deaths by patients aged 16 or over. For male patients, following a steady fall of 0.5% per quarter before the recession (quarterly percent change (QPC) 2000–2009 –0.46%, 95% CI –0.66 to –0.27), suicide rates showed an upward trend during the recession (QPC 2009–2011 2.37%, 95% CI –0.22 to 5.04). Recession-related rises in suicide were found in men aged 45–54 years, those who were unemployed or had a diagnosis of substance dependence/misuse. Between 2012 and 2016 there was a decrease in suicide in male patients despite an increasing number of patients treated. No significant recession-related trends were found in women.
Recession-associated increases in suicide were seen in male mental health patients as well as the male general population, with those in mid-life at particular risk. Support and targeted interventions for patients with financial difficulties may help reduce the risk at times of economic hardship. Factors such as drug and alcohol misuse also need to be considered. Recent decreases in suicide may be related to an improved economic context or better mental healthcare.
Declaration of interest
N.K. is supported by Greater Manchester Mental Health NHS Foundation Trust. L.A. chairs the National Suicide Prevention Strategy Advisory Group at the Department of Health (of which N.K. is also a member) and is a non-executive Director for the Care Quality Commission. N.K. chairs the National Institute for Health and Care Excellence (NICE) depression in adults guideline and was a topic expert member for the NICE suicide prevention guideline.
The care received by people presenting to hospital following self-harm varies and it is unclear how different types of treatment affect risk of further self-harm.
Observational cohort data from the Manchester Self-Harm Project, UK, included 16 456 individuals presenting to an Emergency Department with self-harm between 2003 and 2011. Individuals were followed up for 12 months. We also used data from a smaller cohort of individuals presenting to 31 hospitals in England during a 3-month period in 2010/2011, followed up for 6 months. Propensity score (PS) methods were used to address observed confounding. Missing data were imputed using multiple imputation.
Following PS stratification, those who received a psychosocial assessment had a lower risk of repeat hospital attendance for self-harm than those who were not assessed [RR 0.87, 95% confidence interval (CI) 0.80–0.95]. The risk was reduced most among people less likely to be assessed. Following PS matching, we found no associations between risks of repeat self-harm and admission to a medical bed, referral to outpatient psychiatry or admission to a psychiatric bed. We did not find a relationship between psychosocial assessment and repeat self-harm in the 31 centre cohort.
This study shows the potential value of using novel statistical techniques in large mental health datasets to estimate treatment effects. We found that specialist psychosocial assessment may reduce the risk of repeat self-harm. This type of routine care should be provided for all individuals who present to hospital after self-harm, regardless of perceived risk.
Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better.
A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years’ duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models.
In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning.
As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.
Introduction: The process of triage is used to prioritize the care of patients arriving in the emergency department (ED). To our knowledge, self-triage has not been previously studied in the general emergency department (ED) setting. In an attempt to test the feasibility of implementing this in the ED, we sought to assess the ability of ED patients to triage themselves using an electronic questionnaire. Methods: This was a prospective observational study. An iPad-based questionnaire was designed with a series of ‘yes’ or ‘no’ answers related to common chief complaints. A score corresponding to a Canadian Triage and Acuity Scale (CTAS) category was assigned based on their answers, without the knowledge of patients or ED staff. These scores were subsequently compared to the official CTAS score assigned by triage nurses. A convenience sample of ambulatory patients arriving at the ED were enrolled over a four week period. Patients arriving by ambulance were excluded. We also sought to assess patients’ ability to predict their ultimate disposition. Results: A total of 492 patients were enrolled. The mean age of enrolled patients was 43.9. Of enrolled patients, 56 (11.4%) were under 20 years old, 168 (34.1%) between ages 20-39, 116 (23.6%) between ages 40-59 and 152 (30.9%) older than 60 years. We had 245 (49.8%) patients identify as male. Patient-determined CTAS scores were as follows: 146 CTAS 1 (26.7%), 66 CTAS 2 (13.4%), 176 CTAS 3 (35.8%) and 104 CTAS 4 and 5 (21.1%). Formal triage CTAS scores were: 47 CTAS 2 (9.6%), 155 CTAS 3 (31.5%), and 290 CTAS 4 and 5 (59%). With our survey tool, 22.2% of patients matched their official triage scores. We found that that 69.9% of participants over-estimated their CTAS score while 7.9% underestimated it. Two hundred and three patients (41.3%) felt that they needed to be admitted. In fact, 73 patients (17.3%) were admitted to hospital. Conclusion: Using an electronic questionnaire, ambulatory patients frequently overestimated the acuity of their presenting complaint. Patients were also not unable to accurately predict their disposition. Further study of different approaches to self-triage is needed before possible implementation in EDs.
Observations in psychiatric in-patient settings are used to reduce suicide, self-harm, violence and absconding risk. The study aims were to describe the characteristics of in-patients who died by suicide under observation and examine their service-related antecedents.
A national consecutive case series in England and Wales (2006–2012) was examined.
There were 113 suicides by in-patients under observation, an average of 16 per year. Most were under intermittent observation. Five deaths occurred while patients were under constant observation. Patient deaths were linked with the use of less experienced staff or staff unfamiliar with the patient, deviation from procedures and absconding.
We identified key elements of observation that could improve safety, including only using experienced and skilled staff for the intervention and using observation levels determined by clinical need not resources.
Several often-cited meta-analyses have reported that the efficacy of antidepressant medications depends on the severity of depression. They found that drug–placebo differences increased as a function of initial severity, which was attributed to decreased responsiveness to placebo among patients with severe depression rather than to increased responsiveness to medication. We retested this using patient-level data and also undertaking a meta-analysis of trial-level data from 34 randomised placebo controlled trials (n = 10 737) from the NEWMEDS registry. Although our trial-level data support prevous findings, patient-level data did not show any significant effect of initial depression severity on drug v. placebo difference.
Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia.
This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18–60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 μg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later.
SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo.
Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.
One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear.
We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group.
Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes.
Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.
Patients with schizophrenia have substantially reduced subjective well-being (SW) compared to healthy individuals. It has been suggested that diminished SW may be related to deficits in the neural processing of reward but this has not been shown directly. We hypothesized that, in schizophrenia, lower SW would be associated with attenuated reward-related activation in the reward network.
Twenty patients with schizophrenia with a range of SW underwent a functional magnetic resonance imaging (fMRI) reward task. The brain activity underlying reward anticipation and outcome in schizophrenia was examined and compared to that of 12 healthy participants using a full factorial analysis. Region of interest (ROI) analyses of areas within the reward network and whole-brain analyses were conducted to reveal neural correlates of SW.
Reward-related neural activity in schizophrenia was not significantly different from that of healthy participants; however, the patients with schizophrenia showed significantly diminished SW. Both ROI and whole-brain analyses confirmed that SW scores in the patients correlated significantly with activity, specifically in the dorsal anterior cingulate cortex (dACC), during both reward anticipation and reward outcome. This association was not seen in the healthy participants.
In patients with schizophrenia, reduced activation of the dACC during multiple aspects of reward processing is associated with lower SW. As the dACC has been widely linked to coupling of reward and action, and the link to SW is apparent over anticipation and outcome, these findings suggest that SW deficits in schizophrenia may be attributable to reduced integration of environmental rewarding cues, motivated behaviour and reward outcome.
Studies of diet and disease risk in India and among other Asian-Indian populations are hindered by the need for a comprehensive dietary assessment tool to capture data on the wide variety of food and nutrient intakes across different regions and ethnic groups. The nutritional component of the India Health Study, a multicentre pilot cohort study, included 3908 men and women, aged 35–69 years, residing in three regions of India (New Delhi in the north, Mumbai in the west and Trivandrum in the south). We developed a computer-based, interviewer-administered dietary assessment software known as the ‘NINA-DISH (New Interactive Nutrition Assistant – Diet in India Study of Health)’, which consisted of four sections: (1) a diet history questionnaire with defined questions on frequency and portion size; (2) an open-ended section for each mealtime; (3) a food-preparer questionnaire; (4) a 24 h dietary recall. Using the preferred meal-based approach, frequency of intake and portion size were recorded and linked to a nutrient database that we developed and modified from a set of existing international databases containing data on Indian foods and recipes. The NINA-DISH software was designed to be easily adaptable and was well accepted by the interviewers and participants in the field. A predominant three-meal eating pattern emerged; however, patterns in the number of foods reported and the primary contributors to macro- and micronutrient intakes differed by region and demographic factors. The newly developed NINA-DISH software provides a much-needed tool for measuring diet and nutrient profiles across the diverse populations of India with the potential for application in other South Asian populations living throughout the world.
Bipolar disorder (BD) has been reported to be associated with high risk of suicide. We aimed to investigate the frequency and characteristics of suicide in people with BD in a national sample.
Suicide in BD in England from 1996 to 2009 was explored using descriptive statistics on data collected by the National Confidential Inquiry into Suicide and Homicide by People with Mental Illness (NCI). Suicide cases with a primary diagnosis of BD were compared to suicide cases with any other primary diagnosis.
During the study period 1489 individuals with BD died by suicide, an average of 116 cases/year. Compared to other primary diagnosis suicides, those with BD were more likely to be female, more than 5 years post-diagnosis, current/recent in-patients, to have more than five in-patient admissions, and to have depressive symptoms. In BD suicides the most common co-morbid diagnoses were personality disorder and alcohol dependence. Approximately 40% were not prescribed mood stabilizers at the time of death. More than 60% of BD suicides were in contact with services the week prior to suicide but were assessed as low risk.
Given the high rate of suicide in BD and the low estimates of risk, it is important that health professionals can accurately identify patients most likely to experience poor outcomes. Factors such as alcohol dependence/misuse, personality disorder, depressive illness and current/recent in-patient admission could characterize a high-risk group. Future studies need to operationalize clinically useful indicators of suicide risk in BD.