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Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders. Study Design We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network. Study Results DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively. Conclusions DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders. [ABSTRACT FROM AUTHOR]

There are communities in which hearing voices frequently is common and expected, and in which participants are not expected to have a need for care. This paper compares the ideas and practices of these communities. We observe that these communities utilize cultural models to identify and to explain voice-like events—and that there are some common features to these models across communities. All communities teach participants to "discern," or identify accurately, the legitimate voice of the spirit or being who speaks. We also observe that there are roughly two methods taught to participants to enable them to experience spirits (or other invisible beings): trained attention to inner experience, and repeated speech to the invisible other. We also observe that all of these communities model a learning process in which the ability to hear spirit (or invisible others) becomes more skilled with practice, and in which what they hear becomes clearer over time. Practice—including the practice of discernment—is presumed to change experience. We also note that despite these shared cultural ideas and practices, there is considerable individual variation in experience—some of which may reflect psychotic process, and some perhaps not. We suggest that voice-like events in this context may be shaped by cognitive expectation and trained practice as well as an experiential pathway. We also suggest that researchers could explore these common features both as a way to help those struggling with psychosis, and to consider the possibility that expectations and practice may affect the voice-hearing experience. [ABSTRACT FROM AUTHOR]

While reports of twin pairs concordant for insanity began to appear in the 19th century, the first modern psychiatric twin study that fulfilled Galton's 1875 promise of the value of the twin method was published by the German Psychiatrist and Geneticist Hans Luxenburger in 1928. Luxenburger introduced four major methodological advances: the use of representative sampling, proband-wise concordance, rigorous zygosity diagnoses, and age correction. He used a narrow Kraepelinian diagnostic approach diagnosis and ascertained twins hospitalized, on a specific day, in all large Bavarian asylums. We include a brief biography of Luxenburger, summarize the findings of his paper and provide a full English translation in the appendix. Luxenburger presents evidence that the frequency of twinning in those with severe mental illness were as expected and reports proband-wise concordance for probable and definite dementia praecox (MZ—76%, DZ—0%) and manic-depressive insanity (MZ—75%, DZ—0%). He also examined eccentricity and hyperthymic or hypothymic personality in the dementia praecox and manic-depressive pairs, respectively. Luxenburger's substantial contributions to the history of psychiatric genetics should be considered in the context of his intimate but ambivalent relationship with the racial-hygiene policy of the German National Socialists. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Impaired insight into one's illness is common in first episode psychosis (FEP), is associated with worse symptoms and functioning, and predicts a worse course of illness. Despite its importance, little research has examined the effects of early intervention services (EIS) on insight. Designs This paper evaluated the impact of EIS (NAVIGATE) on insight compared to usual community care (CC) in a large cluster randomized controlled trial. Assessments were conducted at baseline and every 6 months for 2 years. Results A multilevel regression model including all time points showed a significant time by treatment group interaction (P <.001), reflecting greater improvement in insight for NAVIGATE than CC participants. Impaired insight was related to less severe depression but worse other symptoms and functioning at baseline for the total sample. At 6 months, the same pattern was found within each group except insight was no longer associated with depression among NAVIGATE participants. Impaired insight was more strongly associated with worse interpersonal relationships at 6 months in NAVIGATE than in CC, and changes in insight from baseline to 6 months were more strongly correlated with changes in relationships in NAVIGATE than CC. Conclusions The NAVIGATE program improved insight significantly more than CC. Although greater awareness of illness has frequently been found to be associated with higher depression in schizophrenia, these findings suggest EIS programs can improve insight without worsening depression in FEP. The increased association between insight and social relationships in NAVIGATE suggests these 2 outcomes may synergistically interact to improve each other in treatment. [ABSTRACT FROM AUTHOR]

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562. [ABSTRACT FROM AUTHOR]

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P <.001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature. [ABSTRACT FROM AUTHOR]

Despite the accepted link between childhood abuse and positive psychotic symptoms, findings between other adversities, such as neglect, and the remaining dimensions in people with psychosis have been inconsistent, with evidence not yet reviewed quantitatively. The aim of this study was to systematically examine quantitatively the association between broadly defined childhood adversity (CA), abuse (sexual/physical/emotional), and neglect (physical/emotional) subtypes, with positive, negative, depressive, manic, and disorganized dimensions in those with psychosis. A search was conducted across EMBASE, MEDLINE, PsychINFO, and Cochrane Libraries using search terms related to psychosis population, CA, and psychopathological dimensions. After reviewing for relevance, data were extracted, synthesized, and meta-analyzed. Forty-seven papers were identified, including 7379 cases across 40 studies examining positive, 37 negative, 20 depressive, 9 disorganized, and 13 manic dimensions. After adjustment for publication bias, general adversity was positively associated with all dimensions (ranging from r = 0.08 to r = 0.24). Most forms of abuse were associated with depressive (ranging from r = 0.16 to r = 0.32), positive (ranging from r = 0.14 to r = 0.16), manic (r = 0.13), and negative dimensions (ranging from r = 0.05 to r = 0.09), while neglect was only associated with negative (r = 0.13) and depressive dimensions (ranging from r = 0.16 to r = 0.20). When heterogeneity was found, it tended to be explained by one specific study. The depressive dimension was influenced by percentage of women (ranging from r = 0.83 to r = 1.36) and poor-quality scores (ranging from r = −0.21 and r = −0.059). Quality was judged as fair overall. Broadly defined adversity and forms of abuse increase transdimensional severity. Being exposed to neglect during childhood seems to be exclusively related to negative and depressive dimensions suggesting specific effects. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Psychotic experiences (PEs) are associated with increased risk for mental disorders, in particular persistent PEs. PEs therefore might be useful within intervention research. We sought to systematically determine the incidence and persistence of PEs in the general population. Study Design A double-blind search of databases (Embase, Pubmed PMC, Psychinfo, Medline, and Web of Science) from inception to January 2023 and data extraction, were conducted. Study quality was assessed using the NIH assessment tool. Random effects models were conducted to calculate pooled incidence rate per person-year and proportion of persistent PEs per year. Age and study design were all examined using subgroup analyses. Demographic, risk factors, and outcomes for incidence and persistence of PEs were reported in a narrative synthesis. Study Results Using a double-blind screening method for abstract (k = 5763) and full text (k = 250) were screened. In total 91 samples from 71 studies were included, of which 39 were included in a meta-analysis (incidence: k = 17, n = 56 089; persistence: k = 22, n = 81 847). Incidence rate was 0.023 per person-year (95% CI [0.0129;0.0322]). That is, for every 100 people, 2 reported first onset PEs in a year. This was highest in adolescence at 5 per 100(13–17 years). The pooled persistence rate for PEs was 31.0% (95% CI [26.65,35.35]) This was highest in adolescence at 35.8%. Cannabis was particularly associated with incidence of PEs, and persistence of PEs were associated with multiple mental disorders. Conclusions Each year incidence of PEs is 2 of every 100 people, and persists each year in 31% of cases, this risk is highest in adolescents. [ABSTRACT FROM AUTHOR]

While the roots of mania and melancholia can be traced to the 18th century and earlier, we have no such long historical narrative for dementia praecox (DP). I, here, provide part of that history, beginning with Kraepelin's chapter on Verrücktheit for his 1883 first edition textbook, which, over the ensuing 5 editions, evolved into Kraepelin's mature concepts of paranoia and paranoid DP. That chapter had 5 references published from 1865 to 1879 when delusional-hallucinatory syndromes in Germany were largely understood as secondary syndromes arising from prior episodes of melancholia and mania in the course of a unitary psychosis. Each paper challenged that view supporting a primary Verrücktheit as a disorder that should exist alongside mania and melancholia. The later authors utilized faculty psychology, noting that primary Verrücktheit resulted from a fundamental disorder of thought or cognition. In particular, they argued that, while delusions in mania and melancholia were secondary, arising from primary mood changes, in Verrücktheit, delusions were primary with observed changes in mood resulting from, and not causing, the delusions. In addition to faculty psychology, these nosologic changes were based on the common-sense concept of understandability that permitted clinicians to distinguish individuals in which delusions emerged from mood changes and mood changes from delusions. The rise of primary Verrücktheit in German psychiatry in the 1860–1870s created a nosologic space for primary psychotic illness. From 1883 to 1899, Kraepelin moved into this space filling it with his mature diagnoses of paranoia and paranoid DP, our modern-day paranoid schizophrenia. [ABSTRACT FROM AUTHOR]

The rapid embracing of artificial intelligence in psychiatry has a flavor of being the current "wild west"; a multidisciplinary approach that is very technical and complex, yet seems to produce findings that resonate. These studies are hard to review as the methods are often opaque and it is tricky to find the suitable combination of reviewers. This issue will only get more complex in the absence of a rigorous framework to evaluate such studies and thus nurture trustworthiness. Therefore, our paper discusses the urgency of the field to develop a framework with which to evaluate the complex methodology such that the process is done honestly, fairly, scientifically, and accurately. However, evaluation is a complicated process and so we focus on three issues, namely explainability, transparency, and generalizability, that are critical for establishing the viability of using artificial intelligence in psychiatry. We discuss how defining these three issues helps towards building a framework to ensure trustworthiness, but show how difficult definition can be, as the terms have different meanings in medicine, computer science, and law. We conclude that it is important to start the discussion such that there can be a call for policy on this and that the community takes extra care when reviewing clinical applications of such models.. [ABSTRACT FROM AUTHOR]

There is mounting evidence that the social determinants of psychosis operate via a long and circuitous route. Here, we comment on the striking findings from a recent study by Ku et al. that area-level social environmental factors yield social disability and increased risk for schizophrenia through intervening variables and over a long time course. We discuss the relevance of animal models of social isolation to understand how environmental factors interrelate with individual-level mechanisms. We also discuss treatment implications, including the search for novel psychopharmacological treatments for reduced social motivation, and the need for a comprehensive prediction and prevention model. [ABSTRACT FROM AUTHOR]

In his 1933 article, Bruno Schulz reported a follow-up and reanalysis of the schizophrenic probands and their relatives first studied by Rüdin 20 years earlier that sought to clarify whether schizophrenia was a valid "unit-character" for Mendelian genetic analysis. He proposed a range of subgroupings of probands, particularly traditional subtyping, presence or absence of identifiable causal influences, and outcome. He then compared those subgroupings in several ways, most commonly by the risk for schizophrenia in their siblings and by the level of resemblance among proband-sibling affected pairs. Of his many findings, those of greatest interest included (1) probands with possible and probable physical causes, particularly those with head trauma, had substantially lower risk of illness in siblings, (2) probands with a hebephrenic subtype had a striking elevation of risk for schizophrenia in siblings, (3) probands with psychological causes had higher rates of good outcome, (4) proband-sibling pairs resembled one another for the classical schizophrenic subtypes, and (5) an absence of any cases of schizophrenia in siblings of a small group of schizophrenic probands with birth complications, convulsions, and skull deformities. Schulz used this sample in a fundamentally different way than Rüdin. Rather than seeking for Mendelian transmission patterns, Schulz used family data to evaluate hypothesis about clinical/etiological heterogeneity, thereby presaging many subsequent family studies of psychiatric disorders. While Schulz did not claim to have proved the etiologic heterogeneity of schizophrenia, he raised important questions, still unanswered, about whether schizophrenia is a legitimate "unit-character" appropriate for genetic analysis. [ABSTRACT FROM AUTHOR]

Background Treatment adherence in patients with psychotic disorders is an important challenge for physicians and caregivers, and various methods have been suggested in order to improve this parameter. Therapeutic adherence is defined as the extent to which the patient's behavior corresponds to the agreement between him or her and the prescribing physician. Monitoring this parameter is essential, because of its implications for the patient's prognosis, evolution, risk of relapse, quality of life, and overall functioning. A large number of factors have been associated with the ability to influence therapeutic adherence, e.g. frequency of administration and number of daily medications, adverse events related to antipsychotics, lack of insight or partial insight. Finding new ways to improve therapeutic adherence may be of considerable help for clinicians and may improve patients' functional prognosis. Methods Main electronic databases (PubMed, CINAHL, PsychInfo, Cochrane, EMBASE, Thomson Reuters/Web of Science) were searched using as keywords "therapeutic adherence", "treatment adherence", combined with "schizophrenia", "schizoaffective disorder", and "psychotic disorders". All papers published between 1988 and 2018 were included in the review. RCTs, as well as meta-analyses, systematic reviews and narrative reviews, case reports, case series, and letters to the editor were included. Papers without specified diagnoses of psychotic disorders, which included poorly specified interventions, or which included patients under 18 years old were excluded from this review. Results A number of 288 papers were found after the primary search, and 41 remained after filtering out the rest of studies based on inclusion and exclusion criteria. Adherence therapy based on motivational interview, and psycho-educational approaches were the most reported psychological interventions. Adherence therapy was associated with lower duration of re-hospitalization, improvements in severity of the main symptoms, and better functioning. Good-quality data about the efficacy of nursing techniques for improving therapeutic adherence are not available. Assertive community treatment is useful in patients with schizophrenia, because it improved the general psychopathology, functioning, quality of life, and decreased the re-hospitalization rates. Long-acting injectable atypical antipsychotics were also evaluated for patients with low adherence and this formulation decreased the number of re-hospitalization and treatment discontinuation rate. Aripiprazole tablets with sensor represent the newest addition in the clinician's toolkit for improving therapeutic adherence, but data derived from independent trials about the effects of this formulation over patients' rate of re-hospitalization and antipsychotic discontinuation rate are still lacking. Discussion Psychological and pharmacological interventions focused on treatment adherence augmentation have impact over patients' functionality, several aspects of the general psychopathology, re-hospitalization and treatment discontinuation rates. Data about superiority of one therapeutic adherence- focused intervention over another are not available, so the decision about what method should be used depends mostly on the clinician's judgment. [ABSTRACT FROM AUTHOR]

Background: Behavioural findings suggest that the emotion processing abnormalities typically observed in established schizophrenia are already present in patients with a first episode of psychosis (FEP). Evidence has been less consistent in people at clinical high risk for psychosis (CHRp). While several studies have reported unaltered behavioural performance on emotion identification in people at CHRp compared to healthy controls, some studies have shown poorer negative emotion recognition. A growing number of functional magnetic resonance (fMRI) studies have investigated brain response to emotion processing to elucidate the mechanisms underlying these processes in FEP patients and CHRp individuals. Despite the marked expansion of this field over the last two decades, to date, no systematic review or meta-analysis has attempted to synthesise the evidence on the neural bases of emotion processing in these groups as potential markers of psychosis vulnerability and expression. Methods: The PubMed and Ovid MEDLINE databases were searched for published English-language articles applying an emotion processing task during fMRI in a FEP and/or a CHRp sample compared to healthy controls. References of included papers were also screened. For CHRp studies, only those including participants by the basic or attenuated symptom presentation criteria were included. Individual study methodology and results were extracted and systematically reviewed. In addition, at present, statistical parametric mapping contrast maps (‘T-maps’) are being collected from study authors and will be meta-analysed using the Seed-based d Mapping method. The contrasts meta-analysed will be the ones most commonly reported in the studies identified, i.e., of all emotion over comparison conditions and of negative emotion over neutral conditions. These will be meta-analysed separately, as behavioural evidence suggests that emotion recognition performance in these populations might be valence specific. Results: For the systematic review, 4,389 papers were identified through the search. 19 relevant fMRI papers were identified and their references were screened. 17 articles were included after full-text screening. Six out of twelve fMRI studies in the FEP population reported lower brain activation to emotion processing tasks compared to healthy controls. Four articles reported region-specific hyper- and hypoactivations and two studies found no significant difference. Of the seven studies in the CHRp population, one study reported lower brain response to emotion relative to healthy controls, two studies found hyperactivations, one study found region-specific increases and decreases, and two studies reported no significant difference. The most consistent finding across studies was lower amygdala activation in FEP participants (n=6). Conversely, in the CHRp population one article found an increase in amygdala response to emotion with age, consistently with one other article but contrasting with another study showing activity decreases in this region. Discussion: To our knowledge, no previous systematic review or metaanalysis has synthesised the fMRI findings of emotion processing in both people at CHRp and a FEP. The present systematic review shows that while more consistent hypoactivations are found in the FEP population, results are less consistent in CHRp studies. The undergoing meta-analysis will quantitatively synthesise these findings. Elucidating the nature of emotion processing aberrances in early psychosis may help understand the functional changes across both vulnerability and symptom emergence phases and inform molecular investigations into its underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairments are a core feature of schizophrenia. Although cognitive impairments have consistently shown to have negative impacts on functional outcomes among individuals with schizophrenia, assessing and treating these symptoms in clinical settings remains a difficult challenge. Interestingly, the growing potential of new digital technologies, such as smartphone applications and virtual reality, hold great promise in alleviating these impairments. Methods: This presentation will introduce results from two recent studies using digital technologies to assess and treat cognitive symptoms in schizophrenia. In the first study, smartphone versions of the pen-and-paper Trail Making Tests A and B were developed. These cognitive tests measure speed of processing and cognitive flexibility. We assessed the validity of the smartphone versions of both Trail Making Tests in measuring these cognitive domains in in 37 healthy controls and 26 individuals with schizophrenia. Following the initial assessment, participants were asked to complete the two smartphone cognitive tests once a week for three months. This served as a measure of cognitive performance over time Results: Results showed that it was feasible to measure cognition using a smartphone application in schizophrenia. Performances on both smartphone cognitive tests were significantly and positively correlated with the pen-and-paper versions (Parts A: r = 0.65, p < .001; Parts B: r= 0.44, p= .01). Additionally, significant differences were observed between controls and individuals with schizophrenia on both smartphone tests (Part A: t = -3.88, p = .004; Part B: t = -3.29, p = .002). Moreover, longitudinal results showed no significant effect of practice over time on the smartphone cognitive tests. Discussion: Digital technologies have the potential to optimize cognitive assessments, monitoring, and care in schizophrenia. Our findings support the feasibility and efficacy of using digital technologies to measure and treat cognitive impairments in schizophrenia. Our research also highlights the importance of including scientists, clinicians, and content experts with schizophrenia in the development of these tools to ensure their validity and facilitate clinical implementation. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic (AP) medication is associated with metabolic dysregulation, increasing the risk for weight gain. Previously, we showed that all antipsychotics are related with body weight gain and there was a time effect, the longer the AP was taken the more the weight gain was (Bak, Fransen, Janssen, van Os, & Drukker, 2014). This study included data from 1999–2013. The aim of this study is to up-date the previous study on weight gain by extending the search from 1960 – July 2019. So, older studies of before 2000 were in included as well as studies on AP’s after 2014. The differences in weight change between the various AP’s were calculated. Methods: A systematic search was performed using the databases PubMed and EMBASE. Eligible RCTs were identified and no restriction was made regarding diagnosis or publication date. Statistical analysis was based on a random effects model from which forest plots were generated. Effect sizes were reported as the standardized mean difference (SMD) with 95% confidence intervals (CI). Results were presented stratified by four exposure categories, namely < 6 weeks, 6–16 weeks, 16–38 weeks, and ≥ 38 weeks. Furthermore, that results are divided in AP naive patients (patients who had no AP previously) and patient in whom AP were switched from at least one other AP. Patients >17 years of age were excluded and all diagnostic categories were included. Results: In total 3488 papers were found. Following PRSIMA guidelines in total 472 papers were eligible for inclusion. Preliminary results. For the longer term 16–38 & >38 wks all AP-naive patients showed an increase in weight of > 5 kg, except for aripiprazole (< 6wks, 0.46kg; 6-16wks, 2.04kg; 16-38wks, 4.5kg; >38 wks, 3.31kg), paliperidone (< 6wks, 1.24kg; 6-16wks, 1.69kg; 16-38wks, -0.3kg; >38wks 0.2kg), quetiapine (< 6wks, 2.51kg; 6-16wks, 2.69kg; 16-38wks, 3.02kg; >38wks 6.14kg) and ziprasidone (< 6wks, 0.06kg; 6-16wks, 0.32kg; 16-38wks, 0.51kg; >38wks 2.18kg). The result of the switch studies shows that clozapine and olanzapine result in most weight gain after switch. Other AP result in modest weight gain to weight loss over the various time periods: amisulpride (range -0.76 and 1.40), aripriprazole (range -0.81 and 0.81), asenapine (-0.99 – 1.14), haloperidol (0.49 – 1.31) and ziprasidone (-1.18 – -0.38). During SIRS final results will be presented. Discussion: The number of studies in AP naif patients is limited. Most RCT’s discuses medication evaluation after switch into a new compound. Here, metabolic changes may interact with evaluation of changes in weight. However, switching an AP because after severe weight gain needs to be considered with caution as it does not result in considerable weight loss. The AP-naive show that all AP lead to weight gain. Given only patient older than 17years were included, this might explain the limited number of available studies. However, younger age seems to be associated were an increased risk of weight gain. [ABSTRACT FROM AUTHOR]

Background: Despite the progress in treatment and clinical outcomes, schizophrenia remains a highly stigmatized disease and imposes a challenge to families and patients towards recovery. Stigma can debilitate individuals as much as the disease itself, representing one of the most relevant obstacles to overcome the illness: it hinders the pursuit of autonomy and achievement of life goals. Stigma is complex and multilayered and its research usually focus on patients and society, but a lower number of studies address health professionals stigma. Even fewer investigate stigma of researchers. Thus, our objective is to analyze how the most cited research papers published in 2018 addressing schizophrenia depict the disease to identify putative stigma among researchers. Methods: In this exploratory study, we conducted a search using Web of Science (WoS) with the following terms: (“patients with schizophrenia”) OR (“schizophrenia patients”). We restricted the search to articles published in 2018 and selected the 20 studies with the highest total number of citations. We identified how the authors defined schizophrenia and then categorized the definition in three groups: (1) negative perspective, in which depreciative words were used to define the disease; (2) neutral definition, in which emphasis is given to the description of epidemiological data; and (3) neutral to positive definition, when negative outcomes were listed as possibilities, not certainties. Two independent authors (G.K. and M.M.) categorized each article and eventual conflicts were solved by a third author (A.G.) Results: 25% of the studies depicted a clearly negative perspective of schizophrenia. In these studies, the disease was described with words such as “devastating” and “highly disabling”. Most studies (60%) were coded as neutral, being mainly descriptive of current epidemiological data. Only 3 studies (15%) were identified as more favorable, since they acknowledged the possibility of better outcomes among patients with schizophrenia. Discussion: In the current schizophrenia scientific literature, negative views of the disease are still largely common. Considering the role of highly cited papers as opinion formers, we suggest that as occurred in other fields, such as the change in address of suicide by the media, some orientation should be adopted to avoid further contributions to the schizophrenia stigma. [ABSTRACT FROM AUTHOR]

This paper discusses the current evidence from animal and human studies for a central role of inflammation in schizophrenia. In animal models, pre- or perinatal elicitation of the immune response may increase immune reactivity throughout life, and similar findings have been described in humans. Levels of pro-inflammatory markers, such as cytokines, have been found to be increased in the blood and cerebrospinal fluid of patients with schizophrenia. Numerous epidemiological and clinical studies have provided evidence that various infectious agents are risk factors for schizophrenia and other psychoses. For example, a large-scale epidemiological study performed in Denmark clearly showed that severe infections and autoimmune disorders are such risk factors. The vulnerability-stress-inflammation model may help to explain the role of inflammation in schizophrenia because stress can increase pro-inflammatory cytokines and may even contribute to a chronic pro-inflammatory state. Schizophrenia is characterized by risk genes that promote inflammation and by environmental stress factors and alterations of the immune system. Typical alterations of dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission described in schizophrenia have also been found in low-level neuroinflammation and consequently may be key factors in the generation of schizophrenia symptoms. Further support for the relevance of a low-level neuroinflammatory process in schizophrenia is provided by the loss of central nervous system volume and microglial activation demonstrated in neuroimaging studies. Last but not least, the benefit of anti-inflammatory medications found in some studies and the intrinsic anti-inflammatory and immunomodulatory effects of antipsychotics provide further support for the role of inflammation in this debilitating disease. [ABSTRACT FROM AUTHOR]

Sex is considered an understudied variable in health research. Schizophrenia is a brain disorder with known sex differences in epidemiology and clinical presentation. We systematically reviewed the literature for sex-based differences of diffusion properties of white matter tracts in schizophrenia. We then conducted a meta-analysis examining sex-based differences in the genu and splenium of the corpus callosum in schizophrenia. Medline and Embase were searched to identify relevant papers. Studies fulfilling the following criteria were included: (1) included individuals with a diagnosis of schizophrenia, (2) included a control group of healthy individuals, (3) included both sexes in the patient and the control groups, (4) used diffusion tensor imaging, and (5) involved analyzing metrics of white matter microstructural integrity. Fractional anisotropy (FA) was used as the measure of interest in the meta-analysis. Of 730 studies reviewed, 75 met the inclusion criteria. Most showed no effect of sex, however, those that did found either that females have lower FA than males, or that the effect of disease in females is larger than that in males. The findings of the meta-analysis in the corpus callosum supported this result. There is a recognized need for studies on schizophrenia with a sufficient sample of female patients. Lack of power undermines the ability to detect sex-based differences. Understanding the sex-specific impact of illness on neural circuits may help inform development of new treatments, and improvement of existing interventions. [ABSTRACT FROM AUTHOR]

Background: Sexual dysfunction is one of the most frequently occurring side-effects of antipsychotic medication, impacting both quality of life and adherence to treatment. Despite this, limited evidence-based guidance on treatment options is available. The aim of this systematic review was to synthesize and analyze the evidence on the management of antipsychoticrelated sexual dysfunction, specifically taking note of the more recently developed antipsychotics that have been incorporated Methods: EMBASE, Medline, and PsychINFO databases were searched using search terms related to sexual or erectile dysfunction, treatments, and antipsychotics. 2 reviewers independently assessed papers for the inclusion criteria for randomized controlled trials (RCTs) of treatments for antipsychotic-related sexual dysfunction, including adjunctive medications and a switch of antipsychotic. Studies were excluded if participants did not have recorded sexual dysfunction at baseline. Results: The primary outcome measure was any change in sexual function. Results 6 RCTs were identified, all of which investigated different interventions; hence, it was not possible to synthesize the data quantitatively. Results were overall limited by small sample size, brief treatment duration, and the potential for bias. 2 studies, one assessing adjunctive sildenafil and the other adjunctive aripiprazole, reported a reduction in antipsychotic-related sexual dysfunction. Discussion: Due to the lack of high-quality data, no clinical recommendations can be made. Our findings highlight the paucity of high-quality research in this area, and conjecture that it may be difficult to recruit participants with antipsychotic-related sexual dysfunction. Future research may be necessary to unlock and address these difficulties. Furthermore, fully powered future studies should focus on the management of sexual dysfunction rather than the surrogate marker of hyperprolactinemia. [ABSTRACT FROM AUTHOR]

Background Long-acting injectable antipsychotics (LAIs) are recommended to decrease relapse in SZ and their relevance is acknowledged in every treatment guideline available internationally. Yet their rate of use is reported to be very low (6%) in Canada, based on a paper by Williams et al. It could be hypothesized that the fact that second generation LAIs (SGA-LAIs) had just become available might have accounted for these modest rates of use, given the strong inclination of clinicians to prefer prescribing SGAs, that had been previously available only in an oral form. However, this paper dates were published in 2006, and we are unaware from any other data on possible changes in LAI used that could have occurred following the increasing availability of new second-generation LAIs or after the publication of Québec and Canada recommendations of experts. The present report examines the changes in rates of LAIs in Québec from 2003 until 2017. Methods We obtained from the number of LAIs prescriptions reimbursed for each month from 2003 to 2017 by the provincial public insurance system that provides coverage to more than 90% of people suffering from a psychotic disorder. As this data set was obtained from a commercial entity (IMS), it did not include any information on the individuals receiving this LAIs. Hence, we computed their rate of use per 1000,000 people, taking into account the increase in Québec population over that period. In the absence of any diagnostic information, change in number of prescription might reflect changes in their use in diagnostic categories other that SZ and related psychotic disorder. To address this, we performed sensitivity analyses that will be detailed below. Results Over the studied period, the rate of use of LAIs more than tripled, going from 32,4/100 000 in 2003 to 99,6 per 100 000 in 2016. The use of first-generation LAIs decreased from 33,6 per 100 000 in 2003 to 24,5 per 100 000 in 2017. The use of second-generation LAIs (SGA-LAIs), first introduced in 2003 (Risperidone-Consta), reached 75,1/100,000 in 2017. Further analyses of changes in rates of use started in 2004, a few months after the introduction of the first SGA-LAI and increased in a linear pattern over the period of the study, without any significant inflection point over that period. Discussion These data show that LAI use in Québec has increased steadily since 2004, and that this use seems to coincide with the introduction of the first SGA-LAI, without further increase co-occurring with the publication and dissemination of expert recommendations. This supports the hypothesis that the modest rates of use of LAIs that was previously reported in Québec and Canada might have resulted from the fact that only FGA were available in the LAI form while SGAs had become the mainstay in pharmacological treatment of psychotic disorders. However, the lack of diagnostic information on the persons who have used these LAIs prevent concluding about their current rates of use in people suffering from SZ and related psychotic disorders as well as on the variations of these rates over the study period. To address these limitations, we are currently planning further analyses based on the public health care system that will combine information of medication use and diagnostic information on the people with whom these medications are used. [ABSTRACT FROM AUTHOR]

A number of influences have converged that make this Special Theme Issue timely: “A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia”. These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved. [ABSTRACT FROM AUTHOR]

The “Kraepelinian dichotomy” between schizophrenia (SZ) and bipolar disorder (BD) has been a dominant force in our thinking on the classification of these mental disorders. Emerging evidence indicates that these 2 disorders overlap significantly with regard to epidemiology, clinical presentation, genetic susceptibility, structural neuroanatomy, and treatment. Prenatal infection and immunologic dysfunction appear to be risk factors for both SZ and BD; some of these gestational exposures are present in both disorders while others may be specific to 1 or the other of the 2 syndromes. In this paper, we shall review prior studies of prenatal infections and immunologic insults in schizophrenia and BD, including exposures which overlap and which differ between these disorders, discuss the potential utility of maternal infection as one strategy toward developing a more biologically meaningful diagnostic classification system, and propose new recommendations for future research aimed at dissecting these 2 disorders from one another at the etiologic level. [ABSTRACT FROM AUTHOR]

The aim of this paper is to show that the dynamic effects of emotions in schizophrenia are underestimated and partly misunderstood. This may be related to an insufficient consideration for certain key properties of emotions, especially their energizing effects. After introductory remarks on current notions on emotions in schizophrenia, I present an alternative view based on my concept of affect-logic and discuss some of its therapeutic implications. [ABSTRACT FROM PUBLISHER]

Several contributions have reported an altered expression of pseudoneglect in psychiatric disorders, highlighting the existence of an anomalous brain lateralization in affected subjects. Surprisingly, no studies have yet investigated pseudoneglect in first-degree relatives (FdR) of psychiatric patients. We investigated performance on “paper and pencil” line bisection (LB) tasks in 68 schizophrenic patients (SCZ), 42 unaffected FdR, 41 unipolar depressive patients (UP), and 103 healthy subjects (HS). A subgroup of 20 SCZ and 16 HS underwent computerized LB and mental number line bisection (MNL) tasks requiring judgment of prebisected lines and numerical intervals. Moreover, we evaluated, in a subgroup of 15 SCZ, performance on LB and MNL before and after parietal transcranial direct current stimulation (tDCS). In comparison to HS and UP, SCZ showed a systematic rightward bias on LB, partially corrected by selective right posterior parietal tDCS. Interestingly, even FdR showed a lack of pseudoneglect on LB, expressing a mean error lying in the middle between those of HS and SCZ. On the other hand, our results showed no significant difference between the performance of SCZ and HS on MNL. Both groups showed a comparable leftward bias that could not be significantly altered after left or right parietal tDCS. These findings confirm the existence of reduced lateralization in SCZ, suggesting specific impaired functioning of the right parietal lobule. Notably, we report a lack of pseudoneglect not only in SCZ but also in FdR, raising the hypothesis that an inverted laterality pattern may be considered a concrete marker of schizotypal traits. [ABSTRACT FROM PUBLISHER]

Visual masking provides several key advantages for exploring the earliest stages of visual processing in schizophrenia: it allows for control over timing at the millisecond level, there are several well-supported theories of the underlying neurobiology of visual masking, and it is amenable to examination by electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI). In this paper, we provide an overview of the visual masking impairment schizophrenia, including the relevant theoretical mechanisms for masking impairment. We will discuss its relationship to clinical symptoms, antipsychotic medications, diagnostic specificity, and presence in at-risk populations. As part of this overview, we will cover the neural correlates of visual masking based on recent findings from EEG and fMRI. Finally, we will suggest a possible mechanism that could explain the patterns of masking findings and other visual processing findings in schizophrenia. [ABSTRACT FROM PUBLISHER]

As an epilogue to the themed papers on “Theories of Schizophrenia” in this issue of Schizophrenia Bulletin, this article reviews some basic philosophy of science principles in regard to the role of theories in the evolving state of a natural science discipline. While in early phases inductive and abductive logic are the primary vehicles for organizing observations and developing models, when a critical set of “facts” have been elucidated which can be explained by competing theoretical perspectives, hypothetico-deductive logic provides a more robust and efficient approach to scientific progress. The key principle is to determine where two or more theories predict different observations and then to devise studies that collect critical observations—correlations or experimental outcomes that are predicted differentially by the competing theories. To a large extent, current theories of schizophrenia (eg, focusing on aberrant dopaminergic signaling, neural dysconnectivity, and disrupted neural development) are not (and are not intended by their authors to be) mutually exclusive of each other. Rather, they provide explanations that differ in relative emphases, eg, on distal vs proximal causes and on broad vs narrow behavioral end points. It is therefore possible for all of them to be “right” at least in a general sense. This non-exclusivity is problematic when considered in light of the strong inferences principles characteristic of a mature natural science discipline. The contrast points are likely to be found in constructions that integrate influences across different levels of analysis, as in additive vs interactive models, direct effects vs mediation models, and developmental vs deteriorative models. [ABSTRACT FROM PUBLISHER]

This Special Theme issue presents a series of related papers describing fMRI data collected as part of a multi-site brain imaging consortium, the Functional Imaging Biomedical Informatics Research Network (FBIRN) on the same subject population (∼125 patients and ∼125 controls), a larger sample than would have been possible from a single-site, and from a broader clinical and demographic range of patients. Potkin et al observe cortical inefficiency during retrieval of items from memory but not during encoding of those items; Brown et al showed that the lawful relationship between memory retrieval time and neural activation is decoupled in patients with schizophrenia. Wible et al analyzed the same memory data and report activations of left auditory and parietal cortices are especially abnormal in patients who tend to hallucinate. Using an auditory target detection task, Ford et al report abnormal activation of left primary auditory cortex in the hallucinators. A multivariate analysis of those auditory data by Kim et al found differences in connectivity in patients and controls. These studies on the same patient sample suggest that abnormal circuitry characterizes schizophrenic performance in both auditory target detection and memory retrieval, and that patients who hallucinate have reduced left auditory cortical activation on both tasks. Segall et al report anatomical differences between patients and controls in the largest sample yet published. Finally, Potkin et al. identified six genes that influence DLPFC activation and have functions related to forebrain development and stress responses in schizophrenia. These related publications indicate the power of multisite neuroimaging. [ABSTRACT FROM PUBLISHER]

Objective: The effects of estrogen on comprehension of metaphoric speech, word fluency, and verbal ability were investigated in women suffering from schizophrenia. The issue of estrogen-dependent neuropsychological performance could be highly relevant because women with schizophrenia frequently suffer from hypoestrogenism. Method: A placebo-controlled, double-blind, crossover study using 17β-estradiol for replacement therapy and as an adjunct to a naturalistic maintenance antipsychotic treatment was carried out over a period of 8 months. Nineteen women (mean age = 38.0 years, SD = 9.9 years) with schizophrenia were included in the study. Comprehension of metaphoric speech was measured by a lexical decision paradigm, word fluency, and verbal ability by a paper-and-pencil test. Results: Significant improvement was seen for the activation of metaphoric meaning during estrogen treatment (P = .013); in contrast, no difference was found for the activation of concrete meaning under this condition. Verbal ability and word fluency did not improve under estrogen replacement therapy either. Conclusions: This is the very first study based on estrogen intervention instead of the physiological hormone changes to examine the estrogen effects on neuropsychological performance in women with schizophrenia. In addition, it is the first time that the effect of estrogen on metaphoric speech comprehension was investigated in this context. While in a previous study estrogen therapy as adjunct to a naturalistic maintenance treatment with antipsychotics did not show an effect on psychopathology measured by a rating scale, a significant effect of estrogen on the comprehension of metaphoric speech and/or concretism, a main feature of schizophrenic thought and language disturbance, was found in the present study. Because the improvement of formal thought disorders and language disturbances is crucial for social integration of patients with schizophrenia, the results may have implications for the treatment of these individuals. [ABSTRACT FROM PUBLISHER]

Endophenotypes represent intermediate phenotypes on the putative causal pathway from the genotype to the phenotype. They offer a potentially valuable strategy to examine the molecular etiopathology of complex behavioral phenotypes such as schizophrenia. Neurocognitive and neurophysiological impairments that suggest functional impairments associated with schizophrenia have been proposed as endophenotypes. However, few studies have examined the structural variations in the brain that might underlie the functional impairments as useful endophenotypes for schizophrenia. Over the past three decades, there has been an impressive body of literature supporting brain structural alterations in schizophrenia. We critically reviewed the extant literature on the neuroanatomical variations in schizophrenia in this paper to evaluate their candidacy as endophenotypes and how useful they are in furthering the understanding of etiology and pathophysiology of schizophrenia. Brain morphometric measures meet many of the criteria set by different investigators, such as being robustly associated with schizophrenia, heritable, quantifiable, and present in unaffected family members more frequently than in the general population. We conclude that the brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Some caveats for the utility of endophenotypes are discussed. A proposal to combine more than one endophenotype (“extended endophenotype”) is suggested. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders. [ABSTRACT FROM PUBLISHER]

Cognitive enhancement has become an important target for drug therapies in schizophrenia. Treatment development in this area requires assessment approaches that are sensitive to procognitive effects of antipsychotic and adjunctive treatments. Ideally, new treatments will have translational characteristics for parallel human and animal research. Previous studies of antipsychotic effects on cognition have relied primarily on paper-and-pencil neuropsychological testing. No study has directly compared neurophysiological biomarkers and neuropsychological testing as strategies for assessing cognitive effects of antipsychotic treatment early in the course of schizophrenia. Antipsychotic-naive patients with schizophrenia were tested before treatment with risperidone and again 6 weeks later. Matched healthy participants were tested over a similar time period. Test-retest reliability, effect sizes of within-subject change, and multivariate/univariate analysis of variance were used to compare 3 neurophysiological tests (visually guided saccade, memory-guided saccade, and antisaccade) with neuropsychological tests covering 4 cognitive domains (executive function, attention, memory, and manual motor function). While both measurement approaches showed robust neurocognitive impairments in patients prior to risperidone treatment, oculomotor biomarkers were more sensitive to treatment-related effects on neurocognitive function than traditional neuropsychological measures. Further, unlike the pattern of modest generalized cognitive improvement suggested by neuropsychological measures, the oculomotor findings revealed a mixed pattern of beneficial and adverse treatment-related effects. These findings warrant further investigation regarding the utility of neurophysiological biomarkers for assessing cognitive outcomes of antipsychotic treatment in clinical trials and in early-phase drug development. [ABSTRACT FROM PUBLISHER]

The DSM V planning process is currently underway and it has once again ignited the debate about the validity of the schizophrenia diagnosis. In this paper, we review the psychometric literature examining the evidence for discontinuity between schizophrenia and normality and the distinction between schizophrenia and other psychotic disorders. We conclude by proposing potential alternative approaches to refining the classification of psychosis. [ABSTRACT FROM PUBLISHER]

Background: Smartphone technology has seen expanding interest across nearly all areas of medicine, including psychiatry, where app-based technologies frequently function as proxies for digitized behavioural phenotypes (Firth and Torous 2015). In the area first episode psychosis especially, there has been a rising interest in the use of digital platforms for patient self-management as well as for assessment of symptom domains (Ben-Zeev et al. 2014; Bell et al. 2018). Methods: This paper discusses findings from a 3 year-long ethnographic study carried out within a first episode psychosis program in Toronto, Canada, in combination with a discourse analysis of the clinical and research literature relating to the use of self-monitoring technologies within first episode psychosis contexts. The qualitative data consists of formal and informal interviews with psychiatric service users, family members, and clinicians (n=45 interviews), in addition to observational field work within the clinical setting. Data were analyzed thematically within an interpretivist-constructivist frame, and triangulated through reflexive field notes, member-checking, and the authors’ clinical experience within the field. Themes were reviewed with senior clinicians in the first episode clinic setting as well as psychiatric service users for reliability and fidelity. Results: Self-monitoring technologies are increasingly used in both research and clinical care settings, most frequently related to the management of medication side effects and the tracking of the phenomenological aspects of psychotic and psychotic-like experiences. The uptake of these technologies by psychiatric service users in this setting was varied: at times, symptom and side effect tracking faciliated conversations about uncomfortable topics such as sexual side effects of antipsychotics, while in other instances the use of self-monitoring technologies was intrusive. Challenges with self-monitoring were likely to arise when issues relevant to understanding complex phenomena such as medication adherence were prematurely narrowed or when experiential narratives were foreclosed by the structure imposed by the technologies themselves. Resistance to self-monitoring arose in novel and interesting ways. Discussion: Engaging in self-monitoring, whether for side effect tracking or phenomenological analysis of moment-to-moment experiences have significant material effects on those engaged in such practices. When we consider the study findings through the lens of contemporary mental health ethics, we can appreciate how such technologies carry with them a potential for what has been termed “epistemic injustice” (Medina 2013; Fricker 2007), even at the same time as they offer potentially novel, meaningful forms of health care engagement. Grappling with this tension is of critical importance in light of the expansion of such platforms in both clinical and research environments. [ABSTRACT FROM AUTHOR]

Background: Theory of mind (ToM) is a core feature of the social functioning because it influences the way an individual perceive other people’s mental states, and because responses to social cues are shaped by one’s ToM. Patients diagnosed with schizophrenia spectrum disorders (SSD) often present cognitive symptoms as part of their clinical manifestations, and there is a controversy about the relation of ToM deficiencies and more general cognitive features of schizophrenia and related disorders [1]. In order to find data that may clarify if ToM deficiencies are part of the schizophrenia cognitive dimension, or if they precede the onset of psychosis and simply coexist with other symptoms met in this type of disorders, a literature analysis was conducted. Methods: This review included papers published between January 2000 and August 2019 in the main electronic databases (PubMed, Cochrane, EMBASE, CINAHL). Keywords used for database search were “schizophrenia spectrum disorders”, “schizophrenia”, “schizoaffective disorder”, “delusional disorder”, or “schizophreniform disorder” and “theory of mind”. There was included no age limit, and no exclusion criteria referred to the duration of the disorder. Results: A number of 93 papers resulted after the primary search, but only 17 remained after de-duplication and application of inclusion/exclusion criteria. A study with young adults diagnosed with first episode of schizophrenia and matched controls (n=128) suggested that ToM deficits are partly independent of other cognitive functions [1]. Another study (n=1630 children 11–12 years old) reported specific alterations in ToM may be associated with specific types of psychotic experiences, and exaggerated type of ToM may index risk for developing psychosis and paranoid delusions in particular [2]. Adolescents who were genetically at high risk for schizophrenia had social skills impairments but no ToM deficits in a study [3]. Also, there is evidence for ToM deficits in the healthy relatives of schizophrenics, patients with delusional disorder, and individual with high schizotypy scores [4]. The hyper-connectivity in SSD has been confirmed on functional magnetic resonance imaging and default connectivity is correlated to and predictive of theory of mind performance [5]. A significant number of papers (n=10) did not formulate any clear argument to support the independent versus secondary status of the ToM deficits in relation to the SSD cognitive dimension. Discussion: ToM deficiencies are important elements that have been associated with the social skills and functioning in patients with SSD, although it is not clear if these elements exist independently from other cognitive symptoms. Relatives of patients with SSD may present ToM deficits, and data exist about the correlation between ToM abnormalities and several positive symptoms of the SSD. However, more well designed trials are needed in order to confirm the association between ToM impairments and SSD. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant schizophrenias include a heterogeneous group of patients with significant individual and societal consequences, and a high number of these patients fail to respond to clozapine (almost 50%). Patients who did not respond to the second line antipsychotics are a challenge for their treating physicians and although many augmentation strategies have been tried, including other agents with antipsychotic properties, mood-stabilizers, antidepressants, glutamatergic agents and neuromodulation techniques. Methods: A literature review was conducted in the main electronic databases (PubMed, Cochrane, EMBASE, CINAHL), and papers published between January 2000 and August 2019 were included. The search paradigm was “ultra-resistant schizophrenia” or “clozapine-resistant schizophrenia” or “add-on to schizophrenia” and non-proprietary names of currently marketed antipsychotics, mood stabilizers, antipsychotics, nootropics, “neuromodulation techniques” and “psychotherapy”. Results: A number of 197 papers resulted from the primary search, and 45 papers remained after de-duplication and application of inclusion and exclusion criteria. Electroconvulsive therapy seems to be efficient and the response rate ranges from 37.5 to 100% in cases of ultra-resistant schizophrenia [1]. Transcranial direct-current stimulation (tDCS) lead to meaningful improvement in positive symptoms and overall symptomatology when compared to no standard treatment of the control group, in a 4 weeks trial [2]. A 21-week pragmatic trial did not find any significant lasting effect of the cognitive-behavioral therapy (CBT) on total symptoms of schizophrenia compared to treatment as usual, although improvements were detected [3]. Pharmacological augmentation of clozapine included amisulpride (results were not significant), memantine (positive effects, but the trial included a small number of patients), reboxetine (uncertain efficacy), ziprasidone (possible effective on negative and cognitive symptoms), aripiprazole (uncertain effect based on multiple trials), lamotrigine (not efficient), pimozide (not efficient), sertindole (no benefits detected, possible worsen psychosis in several cases), tetrabenazine (not effective), duloxetine (possible efficacy on negative and general psychopathology, but not on the executive cognitive functions), topiramate (no efficacy), valproic acid (possible efficacy, larger trials needed), risperidone (not efficient), donepezil (not efficient), mirtazapine (possible efficacy), sulpiride (possible efficacy in a subgroup of schizophrenia patients). Discussion: Until now no single pharmacological augmentation strategy to clozapine has been proven superior to other in double-blind randomized, large-scale placebo-controlled data. Electroconvulsive therapy seems to be the only non-pharmacological technique with enough data to support its efficacy in ultra-resistant cases of schizophrenia. Other neuromodulatory techniques, like tDCS, are still in early phase of investigation, and psychotherapy does not have enough evidence to support its efficacy. [ABSTRACT FROM AUTHOR]