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Individuals with Disruptive Behavior Disorders in youth and antisocial personality disorder and psychopathy as adults share some clinical characteristics, but also diverge in important ways. Existing meta-analyses of structural imaging studies suggest abnormalities within these disorders, however to date none have examined the role of variability. Hence, we performed a meta-analysis to examine both variability (log coefficient of variation ratio) and magnitude of brain volume differences between antisocial groups and healthy non-offenders (quantified using Hedges g). Twenty-seven studies met inclusion criteria. In antisocial individuals, there was significantly increased variability for total gray matter and overall decreases in mean volume for: total whole brain; intracranial volume; total gray matter; and amygdala, compared with healthy non-offenders. This suggests a key role for structural variability in clinical divergence within these disorders. Further studies should seek to specify how this neurobiological variability maps to clinical variability and whether this holds potential value as a biomarker to guide prognosis or treatment selection.

Objective Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC).Methods Twenty-four patients with schizophrenia and twelve HC underwent [18F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients.Results Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384).Conclusion Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.

Q.Clear is a Bayesian penalised likelihood (BPL) reconstruction algorithm available on General Electric (GE) Positron Emission Tomography (PET)-Computed Tomography (CT) and PET-Magnetic Resonance (MR) scanners. This algorithm is regulated by a β value which acts as a noise penalisation factor and yields improvements in signal to noise ratio (SNR) in clinical scans, and in contrast recovery and spatial resolution in phantom studies. However, its performance in human brain imaging studies remains to be evaluated in depth. This pilot study aims to investigate the impact of Q.Clear reconstruction methods using different β value versus ordered subset expectation maximization (OSEM) on brain kinetic modelling analysis of low count brain images acquired in the PET-MR.Six [When comparing a standard OSEM reconstruction of 6 iterations/16 subsets and 5 mm filter with Q.Clear with different β values under low counts, the bias and RC were lower for Q.Clear with β100 for the SN (RC = 2.17), Th (RC = 0.08) and GP (RC = 0.22) and with β200 for the St (RC = 0.14), Cd (RC = 0.18)and Pt (RC = 0.10). The p-values in the 2-way ANOVA model corroborate these findings. ICC values obtained for Th, St, GP, Pt and Cd demonstrate good reliability (0.87, 0.99, 0.96, 0.99 and 0.96, respectively). For the SN, ICC values demonstrate poor reliability (0.43).BP

Dopaminergic dysfunction is thought to be central to schizophrenia symptomatology. Previous meta-analyses of prodopaminergic drugs in schizophrenia have important limitations, and also did not include dopamine D2/D3 partial agonists. We investigated the effect of medications which increase dopamine signalling on schizophrenia symptoms by meta-analysing double-blind, placebo-controlled RCTs. 59 RCTs were included: 29 of prodopaminergic treatments, 30 of partial agonists. Partial agonists were significantly superior to placebo against positive (SMD=-0.33,p = 1.2 ×10

Importance Ketamine hydrochloride is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like or psychotomimetic symptoms. Despite this risk, the consistency and magnitude of symptoms induced by ketamine or what factors are associated with these symptoms remain unknown. Objective To conduct a meta-analysis of the psychopathological outcomes associated with ketamine in healthy volunteers and patients with schizophrenia and the experimental factors associated with these outcomes. Data Sources MEDLINE, Embase, and PsychINFO databases were searched for within-participant, placebo-controlled studies reporting symptoms using the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) in response to an acute ketamine challenge in healthy participants or patients with schizophrenia. Study Selection Of 8464 citations retrieved, 36 studies involving healthy participants were included. Inclusion criteria were studies (1) including healthy participants; (2) reporting symptoms occurring in response to acute administration of subanesthetic doses of ketamine (racemic ketamine, s-ketamine, r-ketamine) intravenously; (3) containing a placebo condition with a within-subject, crossover design; (4) measuring total positive or negative symptoms using BPRS or PANSS; and (5) providing data allowing the estimation of the mean difference and deviation between the ketamine and placebo condition. Data Extraction and Synthesis Two independent investigators extracted study-level data for a random-effects meta-analysis. Total, positive, and negative BPRS and PANSS scores were extracted. Subgroup analyses were conducted examining the effects of blinding status, ketamine preparation, infusion method, and time between ketamine and placebo conditions. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Main Outcomes and Measures Standardized mean differences (SMDs) were used as effect sizes for individual studies. Standardized mean differences between ketamine and placebo conditions were calculated for total, positive, and negative BPRS and PANSS scores. Results The overall sample included 725 healthy volunteers (mean [SD] age, 28.3 [3.6] years; 533 [73.6%] male) exposed to the ketamine and placebo conditions. Racemic ketamine or S-ketamine was associated with a statistically significant increase in transient psychopathology in healthy participants for total (SMD = 1.50 [95% CI, 1.23-1.77]; P Conclusions and Relevance This study found that acute ketamine administration was associated with schizophrenia-like or psychotomimetic symptoms with large effect sizes, but there was a greater increase in positive than negative symptoms and when a bolus was used. These findings suggest that bolus doses should be avoided in the therapeutic use of ketamine to minimize the risk of inducing transient positive (psychotic) symptoms.

This chapter presents case histories illustrating key aspects of the treatment of schizophrenia based on the authors’ clinical experience of patients that they have treated over the years, although identifying details have been changed. The art of clinical practice includes interpreting and applying evidence to help individual patients who often do not fit into the categories used in clinical trials. The cases show the application of evidence, and also its limitations, in real-world settings. This emphasizes the need for the evidence discussed throughout this book to be considered in the individual context of each patient. You will see variation in the approaches taken by the expert clinicians discussing their cases, reflecting how they interpret and apply evidence in a given clinical context. Each case is followed by a series of learning points and links to other chapters in the book where the issue is considered further.

Clear, accepted definitions of treatment resistance and response are needed so that clinical trials of treatments can be compared, and evidence can be meaningfully interpreted to inform clinical practice. In this chapter, we review the definitions of treatment response and resistance used in clinical trials, highlighting the variability in definitions used across studies, as well as a number of problems with the definitions used, including mixing treatment-intolerant patients with treatment-resistant patients and limited evaluation of the adequacy of treatment in many cases. The chapter then summarizes the work undertaken by the Treatment Response and Resistance in Psychosis working group to produce consensus guidelines and benchmarks to address these issues. Also reviewed are the principles underlying the concept of resistance developed by the working group. Finally, the chapter discusses the implications of these findings for clinical practice.

Ethnic minority individuals have an increased risk of developing a psychotic disorder, particularly if they live in areas of ethnic segregation, or low own group ethnic density. The neurobiological mechanisms underlying this ethnic minority associated risk are unknown. We used functional MRI to investigate neural responses to faces of different ethnicity, in individuals of black ethnicity, and a control group of white British ethnicity individuals.In total 20 individuals of black ethnicity, and 22 individuals of white British ethnicity underwent a 3T MRI scan while viewing faces of black and white ethnicity. Own group ethnic density was calculated from the 2011 census. Neighbourhood segregation was quantified using the Index of Dissimilarity method.At the within-group level, both groups showed greater right amygdala activation to outgroup faces. Between groups, the black ethnicity group showed greater right amygdala activation to white faces, compared to the white ethnicity group. Within the black ethnicity group, individuals living in areas of lower own group ethnic density showed greater right amygdala reactivity to white faces (r = -0.61, p = 0.01).This is the first time an increased amygdala response to white faces has been demonstrated in individuals of black ethnicity. In the black ethnicity group, correlations were observed between amygdala response and neighbourhood variables associated with increased psychosis risk. These results may have relevance for our understanding of the increased rates of paranoia and psychotic disorders in ethnic minority individuals.

Background Studies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum. Methods EMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed. Results Twenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges’ g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003). Conclusion In individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.

In the classical worlds of Julius Caesar and Coriolanus Shakespeare finds the conditions in which to isolate and analyze the Christian doctrine of vocation, the idea that individuals are destined to fill a place in the body politic or the congregation of believers. Many of Shakespeare's plays pit character against calling. In the Roman tragedies the tension is especially acute. The principals struggle to discern a call in a world dismembered by revolution to the point that a voice can come from a wound. Repeatedly, civic turmoil is described in terms of creation and apocalypse; vocation, hinted at through plot turns and Pauline phrasing, should span and structure the interim. But both plays present a monolithic title character whose all‐consuming integrity threatens to annihilate the society that produced him. Under the pressure of events, Brutus' identity splits, while his co‐conspirators scramble for parts that suddenly seem too few to go around. Coriolanus despises “the many” and their trades t...

Development of small contractors for the construction industry has been advocated and explored in two different contexts in sub-Saharan Africa. This experience could prove useful in relation to the larger debate. Certainly, investigation of the two strands of small contractor development suggested that lessons could be learned for future small contractor development and employment generation from the experience of large programmes of labour-intensive construction and maintenance of rural roads. In particular, the need for a “programme” approach which would include a linked training programme is strongly identified.

Two major themes of Botswana's Fifth and Sixth Development Plans (1976–1991) have been the creation of employment and rural development. As one means of fulfilling both objectives the Government of Botswana explicitly decided that labour-intensive methods should be used by District Councils to improve and maintain the 11,000 km of non-gazetted roads for which they were responsible. To this end, between 1980 and 1982, a Pilot Project was carried out to examine the potential of labour-intensive methods. In 1982, following its evaluation of the Pilot Project, the Ministry of Local Government and Lands decided that the methods developed during the Pilot Project should be replicated throughout Botswana. As a result District Council Roads Units have been established in all districts of Botswana. Over 2,000 people are employed.

The first eleven storey blocks of flats in the UK were built in the early fifties. Only twenty years later over half a million people are housed in blocks varying from eleven to 31 storeys in height. These buildings have been built under the responsibility of public authorities responsible for the provision, management and maintenance of housing. Now, however, the provision of this type of housing has almost come to a halt. The widespread use of high flats has been seen as the inevitable result of advances in building technology. The recent rapid decline in numbers built has been attributed primarily to the concern arising from the inhuman social conditions which must inevitably result from such an unnatural form of housing. This paper argues that while high flats stemmed in part from technological advances, it is not possible to attribute their use to such advances. To do so ignores factors which were at work within national and local government, the building industry and the architectural profession. It is equally insufficient to attribute their decline to social concern. It is more probable that financial pressures and a change in national policy away from new building to restoration of older houses was of greater importance than the social problems created by high flats. However, one factor which helped to unite the various parties responsible for the introduction and use of high flats in housing policy, was a widespread belief in the possibilities of modern technologies in relation to the housing problem. Different aspects of the concept appealed to the different protagonists. This paper briefly describes some of the interactions between the different parties concerned with high flats. The major conclusion is that as an innovation high flats have not conformed to the theoretical postulates expounded about them, and that they have been greatly influenced by existing economic and social structures.

From the late 1950s to the late 1970s the use of industrialised methods of building in the U.K. took place almost entirely in the public sector: local authorities and new towns. Having first established this proposition, the paper continues to describe in quantitative terms: (i) the proportion of all local authority housing built by industrialised methods; (ii) the distribution of industrialised building among regions and local authorities; (iii) the type of dwelling produced in relation to the form of the building, the method of construction and the material used; (iv) the major systems involved, and finally (v) the costs. A summary of the major findings of such a quantitative analysis may be found in the conclusions.

The UK building industry has been held to be reasonably resistant to the adoption of advanced technology. In the period 1964 to 1977 this may not strictly be said of several large building companies as the overwhelming majority of industrialised dwellings were produced by very large national or regional contractors. After substantiating this proposition the paper then proceeds to outline the five sets of internal reasons why industrialised building developed: first, internal technical developments combined with the increase in the use of similar building types and the side effects of government policies on other issues; secondly, specific government action related to industrialised building intimated or ensured large markets which would protect the initial investment and lead to both higher turnover and high profit; thirdly, theoretical premises related to the benefits of prefabrication; fourthly, particular stress on the need to increase labour output in the face of a shortage of craft skills; and, fifthly, the effect of fashion.

Between 1965 and 1977 industrialised methods of building were used to construct 27% of the dwellings constructed in the UK public housing sector; in 1969 the proportion was as high as 42%. Technical efficiency is achieved if a technologically sound product is obtained at an economically competitive price. The paper deals first with the extent to which the technical efficiency of industrialised building affected the decline in their use. Secondly, we will discuss technical efficiency in the long run since it is still important to current and future housing policy.

During the 1950s and 1960s policies based on the principles of industrialised building were introduced in many countries. The paper will summarise the data on the extent to which industrialised methods of building were used in the countries of Eastern and Western Europe. The major conclusion from the paper is that the widespread and continued use of industrialised building was directly related to the scale of the public housing sector.

Despite strong evidence of the neurodevelopmental origins of psychosis, current pharmacological treatment is not usually initiated until after a clinical diagnosis is made, and is focussed on antagonising striatal dopamine receptors. These drugs are only partially effective, have serious side effects, fail to alleviate the negative and cognitive symptoms of the disorder, and are not useful as a preventive treatment. In recent years, attention has turned to upstream brain regions that regulate striatal dopamine function, such as the hippocampus. This review draws together these recent data to discuss why the hippocampus may be especially vulnerable in the pathophysiology of psychosis. First, we describe the neurodevelopmental trajectory of the hippocampus and its susceptibility to dysfunction, exploring this region’s proneness to structural and functional imbalances, metabolic pressures, and oxidative stress. We then examine mechanisms of hippocampal dysfunction in psychosis and in individuals at high-risk for psychosis and discuss how and when hippocampal abnormalities may be targeted in these groups. We conclude with future directions for prospective studies to unlock the discovery of novel therapeutic strategies targeting hippocampal circuit imbalances to prevent or delay the onset of psychosis.

Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls, using the log coefficient of variation ratio (CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data using Hartigan’s unimodality dip test. MEDLINE and EMBASE databases were searched from inception to October 2021 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia patients compared to controls. 116 studies reporting on 7,844 patients and 7,305 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p