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The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of in vivo dopamine synthesis and release, and putative synaptic levels.
We focused on the role of dopamine postsynaptic regulation using [123I] iodobenzamide (IBZM) SPECT. We compared D2/3 receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia.
The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI −0.11 to 0.11; F = 0.00, df = 1, 69; p = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = −0.01(binding ratio); 95% CI −0.01 to −0.004; F = 11.5, df = 1, 69; p = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores.
Medication-naïve patients with recent-onset schizophrenia have similar D2/3 receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release.
This chapter provides a wide-ranging review of the clinical pharmacology of drugs for the treatment of schizophrenia and psychosis other than clozapine. These are dopamine receptor antagonists and dopamine partial agonists (as per the new Neuroscience-based Nomenclature (NbN) classification). This chapter covers their pharmacodynamics, pharmacokinetics, adverse effects, the latest evidence regarding their ‘antipsychotic’ mechanism of action, their use in the acute and maintenance treatment of schizophrenia, other therapeutic indications and some controversies that surround their use.
Dopamine receptor antagonists and dopamine partial agonists are commonly referred to as antipsychotics. As a clinical shorthand the term ‘antipsychotic’ is likely to remain in use.
Out of hours, there is only one on-site junior doctor. First year psychiatry trainees (CT1s) and GP trainees may have no prior experience in psychiatry. On-call shifts are therefore potentially daunting for new trainees.
Expand the resources available for trainees when on-call.
We issued questionnaires to CT1s asking if they would have appreciated more information about on-call scenarios and in what format.
Based on the questionnaire results we implemented some changes. These were:
– a printed “pocket-guide” summarising common on-call scenarios;
– a training video on common on-call scenarios.
The handout was given to new trainees in February 2016 and in August 2016. The video was shown to new trainees in August 2016. Trainees provided feedback on the resources.
Of 24 CT1s, 15 (63%) were “neutral” or “disagreed” that they had felt prepared for on-calls.
CT1s wanted additional resources, especially a paper handout or phone download.
Feedback on the “pocket-guide” from trainees in February 2016 (n = 8) was positive (62.5% reported increased confidence in on-call situations). Feedback is also being collected from trainees who received the guide in August 2016.
Trainees in August 2016 (n = 36) liked the video – no trainees “disagreed” with statements asking if the video had been useful.
The video improved the confidence of trainees about on-call situations by an average of 2.8 points.
We have expanded available resources relating to on-calls and improved confidence. Further improvements would include making resources more easily available in downloadable formats.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Ascarid parasites infect a variety of hosts and regular anthelmintic treatment is recommended for all species. Parascaris spp. is the only ascarid species with widespread anthelmintic resistance, which allows for the study of resistance mechanisms. The purpose of this study was to establish an in vitro drug exposure protocol for adult anthelmintic-naïve Parascaris spp. and report a preliminary transcriptomic analysis in response to drug exposure. Live worms were harvested from foal necropsies and maintained in RPMI-1640 at 37 °C. Serial dilutions of oxibendazole (OBZ) and ivermectin (IVM) were prepared for in vitro drug exposure, and worm viability was monitored over time. In a second drug trial, worms were used for transcriptomic analysis. The final drug concentrations employed were OBZ at 40.1 μm (10 μg mL−1) and IVM at 1.1 μm (1 μg mL−1) for 24 and 3 h, respectively. The RNA-seq analysis revealed numerous differentially expressed genes, with some being potentially related to drug detoxification and regulatory mechanisms. This report provides a method for in vitro drug exposure and the phenotypic responses for Parascaris spp., which could be extrapolated to other ascarid parasites. Finally, it also provides preliminary transcriptomic data following drug exposure as a reference point for future studies of Parascaris spp.
Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.
To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.
In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia (‘patients’) and controls were matched for age, gender, ethnicity and body surface area.
Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = −0.82, P = 0.001), LV end-systolic volume (d = −0.58, P = 0.02), LV stroke volume (d = −0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = −0.79, P = 0.002), RV end-systolic volume (d = −0.58, P = 0.02), and RV stroke volume (d = −0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration.
Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.
Children of parents with mood and psychotic disorders are at elevated risk for a range of behavioral and emotional problems. However, as the usual reporter of psychopathology in children is the parent, reports of early problems in children of parents with mood and psychotic disorders may be biased by the parents' own experience of mental illness and their mental state.
Independent observers rated psychopathology using the Test Observation Form in 378 children and youth between the ages of 4 and 24 (mean = 11.01, s.d. = 4.40) who had a parent with major depressive disorder, bipolar disorder, schizophrenia, or no history of mood and psychotic disorders.
Observed attentional problems were elevated in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia (effect sizes ranging between 0.31 and 0.56). Oppositional behavior and language/thought problems showed variable degrees of elevation (effect sizes 0.17 to 0.57) across the three high-risk groups, with the greatest difficulties observed in offspring of parents with bipolar disorder. Observed anxiety was increased in offspring of parents with major depressive disorder and bipolar disorder (effect sizes 0.19 and 0.25 respectively) but not in offspring of parents with schizophrenia.
Our results suggest that externalizing problems and cognitive and language difficulties may represent a general manifestation of familial risk for mood and psychotic disorders, while anxiety may be a specific marker of liability for mood disorders. Observer assessment may improve early identification of risk and selection of youth who may benefit from targeted prevention.
Researchers in different social science disciplines have successfully used Facebook to recruit subjects for their studies. However, such convenience samples are not generally representative of the population. We developed and validated a new quota sampling method to recruit respondents using Facebook advertisements. Additionally, we published an R package to semi-automate this quota sampling process using the Facebook Marketing API. To test the method, we used Facebook advertisements to quota sample 2432 US respondents for a survey on climate change public opinion. We conducted a contemporaneous nationally representative survey asking identical questions using a high-quality online survey panel whose respondents were recruited using probability sampling. Many results from the Facebook-sampled survey are similar to those from the online panel survey; furthermore, results from the Facebook-sampled survey approximate results from the American Community Survey (ACS) for a set of validation questions. These findings suggest that using Facebook to recruit respondents is a viable option for survey researchers wishing to approximate population-level public opinion.
Robust and persistent links between early-life adversities and later-life mental distress have previously been observed. Individual and social resources are associated with greater mental health and resilience. This study aimed to test these resources as moderators and mediators of the association between childhood psychosocial adversity and later-life mental distress.
Participant data came from the Medical Research Council National Survey of Health and Development, a nationally-representative birth cohort study. The General Health Questionnaire-28 (GHQ-28) captured mental distress at ages 53, 60–64, and 68–69. An eight-item cumulative psychosocial adversity score was created (0, 1, 2, ≥3 adversities). Individual (i.e., education, occupational status, physical activity) and social (i.e., social support, neighborhood cohesion) resources were examined as mediators and moderators of CPA and GHQ-28 in longitudinal multilevel models.
Greater adversity was associated with an average GHQ-28 score increase of 0.017, per unit adversity (β = 0·017, p < 0·001, 95% CI 0·011, 0·022). Lower mental distress was associated with higher levels of physical activity, occupational status, education, social support, and neighborhood cohesion. There was no evidence that resources moderated the relationship between GHQ-28 and adversity. All resources, save for physical activity and occupational status, partly mediated this relationship.
Individual and social resources were associated with lower mental distress. They did not modify, but partly mediated the association between childhood adversity and adult mental distress. Social support was the most important mediator, suggesting that interventions to promote greater social support may offset psychosocial adversities experienced in childhood to foster better mental health in older adults.
Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.
Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.
No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.
The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.
Converging lines of evidence implicate an important role for the immune system in schizophrenia. Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of in vivo PET imaging studies of microglia activation in patients with schizophrenia compared with healthy controls.
Demographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model (Hedge's g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage.
In total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's g = 0.31; p = 0.03) but no significant differences when VT was used (Hedge's g = −0.22; p = 0.29).
In conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes.
The properties of the acoustic modes are sensitive to magnetic activity. The unprecedented long-term Kepler photometry, thus, allows stellar magnetic cycles to be studied through asteroseismology. We search for signatures of magnetic cycles in the seismic data of Kepler solar-type stars. We find evidence for periodic variations in the acoustic properties of about half of the 87 analysed stars. In these proceedings, we highlight the results obtained for two such stars, namely KIC 8006161 and KIC 5184732.
Although Zwaan et al. (2018) have made a compelling case as to why direct replications should occur more frequently than they do, they do not address how such replications attempts can best be encouraged. We propose a novel method for incentivising replication attempts and discuss some issues surrounding its implementation.
The extent of metabolic and lipid changes in first-episode psychosis (FEP) is unclear.
To investigate whether individuals with FEP and no or minimal antipsychotic exposure show lipid and adipocytokine abnormalities compared with healthy controls.
We conducted a meta-analysis of studies examining lipid and adipocytokine parameters in individuals with FEP and no or minimal antipsychotic exposure v. a healthy control group. Studies reported fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and leptin levels.
Of 2070 citations retrieved, 20 case–control studies met inclusion criteria including 1167 patients and 1184 controls. Total cholesterol and LDL cholesterol levels were significantly decreased in patients v. controls, corresponding to an absolute reduction of 0.26mmol/L and 0.15mmol/L respectively. Triglyceride levels were significantly increased in the patient group, corresponding to an absolute increase of 0.08 mmol/L However, HDL cholesterol and leptin levels were not altered in patients v. controls.
Total and LDL cholesterol levels are reduced in FEP, indicating that hypercholesterolaemia in patients with chronic disorder is secondary and potentially modifiable. In contrast, triglycerides are elevated in FEP. Hypertriglyceridaemia is a feature of type 2 diabetes mellitus, therefore this finding adds to the evidence for glucose dysregulation in this cohort. These findings support early intervention targeting nutrition, physical activity and appropriate antipsychotic prescription.
Avian malaria, caused by Plasmodium spp., is an emerging disease in New Zealand (NZ). To detect Plasmodium spp. infection and quantify parasite load in NZ birds, a real-time polymerase chain reaction (PCR) (qPCR) protocol was used and compared with a nested PCR (nPCR) assay. A total of 202 blood samples from 14 bird species with known nPCR results were tested. The qPCR prevalences for introduced, native and endemic species groups were 70, 11 and 21%, respectively, with a sensitivity and specificity of 96·7 and 98%, respectively, for the qPCR, while a sensitivity and specificity of 80·9 and 85·4% were determined for the nPCR. The qPCR appeared to be more sensitive in detecting lower levels of parasitaemia. The mean parasite load was significantly higher in introduced bird species (2245 parasites per 10 000 erythrocytes) compared with endemic species (31·5 parasites per 10 000 erythrocytes). In NZ robins (Petroica longipes), a significantly lower packed cell volume was found in birds that were positive for Plasmodium spp. compared with birds that were negative. Our data suggest that introduced bird species, such as blackbirds (Turdus merula), have a higher tolerance for circulating parasite stages of Plasmodium spp., indicating that introduced species are an important reservoir of avian malaria due to a high infection prevalence and parasite load.
Introduction: Resuscitation is a dynamic, complex and time-sensitive field which encompasses management of both critically-ill patients as well as large multidisciplinary teams. Expertise in this area has not been adequately defined, and to date, no research has directly examined the decision-making and cognitive processes involved. The evolving paradigm of competency-based medical education (CBME) makes better defining expertise in this field of critical importance to aid in the development of both educational and assessment methods. The technique of cognitive task analysis (CTA) has been used in a variety of fields to explicate the cognitive underpinnings of experts. Experts, however, often have limited insight and incomplete recall of their decision-making processes. We hypothesized that the use of eye-tracking, which provides the combination of first-person video as well as an overlying gaze indicator, could be used to enhance CTA to better understand the defining characteristics of experts in resuscitation. Methods: Over an 18-month period a sample of 11 traumatic resuscitations were obtained, each led by one of four pre-selected expert physicians outfitted with the Tobii Pro Eye-Tracking Glasses. After each resuscitation, the participant was debriefed using a cued-recall, think-aloud protocol while watching his or her corresponding eye-tracking video. A subsequent qualitative analysis of the resulting video and debrief transcript was performed using an ethnographic approach to establish emerging themes and behaviours of the expert physicians. Results: The expert participants demonstrated specific, common patterns in their cognitive processes. In particular, participants exhibited similar anticipatory and visual behaviours, dynamic communication strategies and the ability to distinguish between task-relevant and task-redundant information. All participants reported that this technique uncovered otherwise subconscious aspects of their cognition. Conclusion: The novel combination of eye-tracking technology to supplement the CTA of expert resuscitationists enriched our understanding of expertise in this field and yielded specific findings that can be applied to better develop and assess resuscitation skills.
We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors.
The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance.
From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset.
The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.
Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity.
We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography.
There was no significant difference in aberrant salience between the groups [F1,32 = 1.12, p = 0.30 (implicit); F1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = −0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = −2.05, p = 0.04).
Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.