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  • Understanding sex differences in cognitive insight across first-and-multiple episode psychosis
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-22
    Danielle Penney; Ridha Joober; Ashok Malla; Martin Lepage

    Objective Cognitive insight represents the capacity to self-reflect and consider external feedback when re-evaluating faulty beliefs. It is associated with specific cognitive capacities such as verbal memory, of which there is substantial evidence for sex differences in psychotic disorders. Like more general cognitive capacities, cognitive insight might too be modulated by sex differences. Method One hundred and seventy-one first episode psychosis (FEP; 123 males, 48 females), and 203 multiple episode psychosis (MEP; 147 males, 56 females) participants completed the Beck Cognitive Insight Scale (BCIS). A two-way MANOVA was conducted on the three BCIS measures (self-reflectiveness, self-certainty, composite index) with sex (male, female) and illness stage (FEP, MEP) as factors, followed by two-way ANOVAs and a post hoc test of simple effects. Results The only significant interaction to emerge was between sex and illness stage in self-certainty (F(1, 373) = 5.88, p = .016). A test of simple effects revealed that self-certainty group means were significantly different for males and females in FEP, where females had lower self-certainty than males (p = .053) but not during MEP (p = .119). Conclusion Sex differences do not modulate cognitive insight in MEP, which may be attributable to females having greater positive symptom severity than males. In FEP however, results revealed that females were significantly less self-certain than males. Lower self-certainty relative to self-reflectiveness predicts treatment response in psychological interventions, and as such future FEP studies should explore sex differences in psychological interventions.

  • Parsing components of risk of premature mortality in the children of mothers with severe mental illness
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-21
    Patsy Di Prinzio; Kathryn M. Abel; Taryn L. Ambrosi; Assen Jablensky; Maxine Croft; Sonal Shah; Thomas F. McNeil; Matthias Pierce; Vera A. Morgan

    Introduction Children of mothers with severe mental illness are at increased risk of premature death including in infancy and early childhood. Importantly, these children are also more likely to be exposed to adverse socio-demographic risk factors and serious obstetric complications which, of themselves, may increase risk for childhood mortality. We examined mortality outcome at different ages up to 5 years taking account of these risks. Method We used linked data across Western Australian whole-population psychiatric, inpatient, death, and midwives' registers to identify 15,486 births to mothers with severe mental illness and 452,459 births to mothers with no mental illness. Multivariable models were adjusted for exposure to adverse socio-demographic risk factors and serious obstetric complications. Results Overall risk of premature death was increased amongst children of mothers with severe mental illness (2.3%, 354 deaths) compared with children of mothers with no mental illness (1.4%, 6523 deaths); the same was true for specific risk of stillbirth, neonatal, post‑neonatal and early childhood deaths. Risk was substantially attenuated after adjustment for adverse socio-demographic exposures, and further still after adjustment for exposure to serious obstetric complications. We observed no effects for the timing of maternal illness diagnosis. Conclusions To minimise the risk of premature mortality in the children of mothers with severe mental illness, priority should be given to the prompt diagnosis of maternal mental illness with targeted delivery of high quality antenatal and psychiatric care, as well as social and structural supports for affected families that continue after birth.

  • Experiential negative symptoms are more predictive of real-life functional outcome than expressive negative symptoms in clinical high-risk states
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-21
    Louise Birkedal Glenthøj; Tina Dam Kristensen; Christina Wenneberg; Carsten Hjorthøj; Merete Nordentoft

    Background Negative symptoms are key features of psychosis-spectrum disorders linked to psychosis development and functional impairments. This study investigated the predictive strength of negative symptoms domains on multiple aspects of real-life functional outcome in individuals at clinical high-risk (CHR) for psychosis. Methods A total of 146 UHR individuals were enrolled in a randomized, clinical trial (RCT), with this being analyses secondary to the RCT. The participants were assessed at baseline with the Scale for the Assessment of Negative Symptoms (SANS) encompassing the four domains of affect, alogia, avolition, and anhedonia. Functioning measures, encompassing overall-, social-, and role functioning, self-report social functioning, and quality of life, were obtained at 12-month follow-up. Regression analyses elucidated on the relationship between the four negative symptom domains and functional outcomes. Results Anhedonia and avolition were the aspects of negative symptoms most predictive of real-life functioning at 12-month follow-up explaining 7–20% of the variance on the outcome measures. Alogia was predictive of social functioning. These findings were maintained when controlling for the effect of neurocognition, antipsychotic medication, and depressive symptoms. Discussion Our findings show experiential negative symptoms to predict multiple areas of real-life functioning and quality of life, while expressive negative symptoms exert a modest influence on the functional prognosis of CHR individuals. Experiential negative symptoms may therefore constitute an important treatment target in intervention approaches aimed at enhancing the functional outcome of CHR individuals.

  • Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-21
    Fernando Carreño; Victória Etges Helfer; Keli Jaqueline Staudt; Karina Paese; Fabíola Schons Meyer; Ana Paula Herrmann; Sílvia Stanisçuaski Guterres; Stela Maris Kuze Rates; Teresa Dalla Costa

    Lipid core nanocapsules (LNC) have been extensively studied as a new treatment strategy to improve therapeutic effects of antipsychotic drugs. We investigated the efficacy of quetiapine LNCs (QLNCs) on the poly(i:c) model of schizophrenia in both male and female rats using the pre-pulse inhibition of startle response (PPI) test paradigm after evaluating the outcomes of three different poly(i:c) doses administered to pregnant damns at GD15 on neurodevelopmental outcomes of maternal immune activation (MIA) in adult offspring. QTP solution was not capable of producing a reversal in the sensorimotor gating-disruptive effect caused by the prenatal poly(i:c) exposure. The same dose of QTP given as QLNCs significantly improved PPI-impairment. This is the first study reporting the restoration of the PPI deficits in a neurodevelopmental model of SCZ using LNCs. This is a promising delivery system strategy to improve antipsychotic effects contributing to the development of better SCZ pharmacological treatments.

  • Early-life stressful events and suicide attempt in schizophrenia: Machine learning models
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-20
    Samia Tasmim; Oluwagbenga Dada; Kevin Z Wang; Ali Bani-Fatemi; John Strauss; Christopher Adanty; Ariel Graff; Philip Gerretsen; Clement Zai; Carol Borlido; Vincenzo De Luca

    Childhood abuse and neglect predicts suicide attempt. Furthermore, other early-life stressful events may predict lifetime suicide attempt in psychiatric disorders. We assessed 189 schizophrenics for suicide attempt and stressful life events. Early-life stressful events were used as predictors of lifetime suicide attempt in three machine learning models. In our sample, 38% of the schizophrenics had at least one suicide attempt lifetime. The machine learning models provided an overall significant prediction (accuracy range: 62–69%). Childhood sexual molestation and mental illness were important predictors of suicide attempt. Early-life stressful events should be included in models aiming at predicting suicide attempt in schizophrenia.

  • Depressive symptoms during first episode psychosis and functional outcome: A systematic review and meta-analysis
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-20
    Jessica McGinty; Rachel Upthegrove

    Objectives First episode psychosis (FEP) is associated with functional decline. Existing evidence was synthesised to explore the influence of depressive symptoms during FEP on future social, occupational and global functioning. Methods Medline, Embase, PsychINFO, Cochrane Library, Open Grey, NICE Evidence and Web of Science were searched from inception to May 2018. Longitudinal studies of FEP patients were included. Study quality was assessed using the Downs and Black instrument. Two meta-analyses were performed using random effect models. The first meta-analysis correlates depressive symptoms during FEP with follow-up Global Assessment of Functioning (GAF) scores. The second meta-analysis shows the odds of long-term functional remission if depressive symptoms are present during FEP. Results 4751 unique abstracts were found. 36 articles were included. The first meta-analysis included 7 studies (932 participants) and showed depressive symptoms during FEP were negatively correlated with follow-up GAF scores (r = −0.16, 95% CI: −0.24 to −0.09, p < 0.001). The second meta-analysis of 9 studies (2265 participants) showed weak evidence of an association between the presence of depressive symptoms in FEP and reduction in functional remission (OR = 0.87, 95% CI: 0.68 to 1.13, p = 0.294). Conclusion Depressive symptoms during FEP are associated with poorer long-term global functioning and may be associated with a reduced chance of achieving functional remission. Clinical trials are needed to identify efficacious management of depressive symptoms in early psychosis.

  • Slow your role: How slowing clozapine titration can prevent recurrent NMS
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-20
    Rohn Nahmias; David Pison; Areef Kassam; Dennis Anderson

    Ms. D. was a 57-year-old Caucasian female with a past psychiatric history of schizoaffective disorder bipolar type and unspecified anxiety disorder. She presented to the psychiatric unit with cognitive blunting, poverty of thought content, looseness of associations, and inability to respond to questions with meaningful responses. In addition, the patient presented with medical symptoms including rigidity, acute rhabdomyolysis, and elevated liver function tests (LFTs). She was transferred to the inpatient medical unit for stabilization. After acute stabilization, she was transferred back to the psychiatric unit for treatment. A thorough review of the patient's history revealed she had prior episodes of atypical NMS with trials of multiple typical and atypical antipsychotics at therapeutic doses and with clinically appropriate titration schedules. These trials included clozapine, which is known to have decreased likelihood of NMS symptoms. The patient was stabilized during admission, but later decompensated and required re-admission in the months following. At that time, clozapine was reinstituted at very low doses and with a slower titration schedule. This approach was successful in ameliorating the patient's symptoms and without recurrence of NMS. In this case report, we discuss the importance of identifying atypical NMS in patients treated with typical and atypical antipsychotics, and propose that successful treatment of these patients may be possible with slower and gradual titration of clozapine.

  • The placement of anomalous self-experiences within schizotypal personality in a nonclinical sample
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-20
    David C. Cicero; Łukasz Gawęda; Barnaby Nelson

    Anomalous self-experiences are disturbances in the subjective experience of the self and have been shown to be related to the premorbid, prodromal, acute, and chronic phases of schizophrenia-spectrum disorders. Despite having a long history in psychopathology research, anomalous self-experiences are not explicitly represented in any major nosology of mental disorders. Previous research suggests that anomalous self-experiences are correlated, but distinct from other aspects of schizotypal personality, but this has not been examined with confirmatory factor analysis. The current research aimed to examine where anomalous self-experiences fit within the structure of schizotypal personality including cognitive-perceptual, interpersonal, disorganized, and paranoid factors. It also examined the measurement invariance of the factor structure across ethnicity and between sexes. Seven hundred forty-four participants completed multiple measures of anomalous self-experiences and schizotypal personality. The best fitting model was a five-factor model with anomalous self-experiences, cognitive-perceptual, interpersonal, disorganized, and paranoid factors. This model fit better than models with anomalous self-experiences loading on any of the four schizotypal personality factors. The structure had configural, metric, and scalar invariance across race/ethnicities, but lacked scalar invariance between sexes. Anomalous self-experience scores did not differ among race/ethnicity or between sexes. These results suggest that anomalous self-experiences are highly correlated with but distinct from other facets of schizotypal personality. Future research may examine whether anomalous self-experiences should be added to nosologies of psychotic-spectrum disorders.

  • Cardiac left ventricular ejection fraction in men and women with schizophrenia on long-term antipsychotic treatment
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-18
    Dimitrios Andreou; Peter Saetre; Björn Milesson Fors; Björn Mikael Nilsson; Joel Kullberg; Erik Gunnar Jönsson; Charlotte Ebeling Barbier; Ingrid Agartz

    Patients with schizophrenia exhibit a higher cardiovascular mortality compared to the general population which has been attributed to life-style factors, genetic susceptibility and antipsychotic medication. Recent echocardiographic studies have pointed to an association between clozapine treatment and reduced left ventricular ejection fraction (LVEF), a measure that has been inversely associated with adverse outcomes including all-cause mortality. Cardiovascular magnetic resonance (CMR) is considered the reference method for LVEF measurement. The aim of the present study was to investigate the LVEF in patients with schizophrenia on long-term treatment with antipsychotics and healthy controls. Twenty-nine adult patients with schizophrenia on long-term medication with antipsychotics and 27 age-, sex- and body mass index-matched healthy controls (mean ages 44 and 45 years, respectively) were recruited from outpatient psychiatric clinics in Uppsala, Sweden. The participants were interviewed and underwent physical examination, biochemical analyses, electrocardiogram and CMR. Men with schizophrenia on long-term antipsychotic treatment showed significantly lower LVEF than controls (p = 0.0076), whereas no such difference was evident among women (p = 0.44). Specifically, clozapine-treated male patients had 10.6% lower LVEF than male controls (p = 0.0064), whereas the LVEF was 5.5% below that of controls among male patients treated with non-clozapine antipsychotics (p = 0.047). Among medicated men with schizophrenia, we found significantly lower LVEF compared to healthy individuals, suggesting the need of routine cardiac monitoring in this patient group. This is the first study showing a significant negative association between treatment with non-clozapine antipsychotics and LVEF.

  • Altered functional connectivity of the thalamus induced by modified electroconvulsive therapy for schizophrenia
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-17
    Junjie Wang; Yuchao Jiang; Yingying Tang; Mengqing Xia; Adrian Curtin; Jin Li; Jianhua Sheng; Tianhong Zhang; Chunbo Li; Li Hui; Hongliang Zhu; Bharat B. Biswal; Qiufang Jia; Cheng Luo; Jijun Wang

    Background Electroconvulsive therapy (ECT) has been shown to be effective in schizophrenia (SZ), particularly in drug-refractory cases or when rapid symptom relief is needed. However, its precise mechanisms of action remain largely unclear. To clarify the mechanisms underlying modified electroconvulsive therapy (mECT) for SZ, we conducted a longitudinal cohort study evaluating functional connectivity of the thalamus before and after mECT treatment using sub-regions of thalamus as regions of interest (ROIs). Methods Twenty-one SZ individuals taking only antipsychotics (DSZ group) for 4 weeks and 21 SZ patients receiving a regular course of mECT combining with antipsychotics (MSZ group) were observed in parallel. All patients underwent magnetic resonance imaging scans at baseline (t1) and follow-up (t2, ~4 weeks) time points. Data were compared to a matched healthy control group (HC group) consisting of 23 persons who were only scanned at baseline. Group differences in changes of thalamic functional connectivity between two SZ groups over time, as well as in functional connectivity among two SZ groups and HC group were assessed. Results Significant interaction of group by time was found in functional connectivity of the right thalamus to right putamen during the course of about 4-week treatment. Post-hoc analysis showed a significantly enhanced functional connectivity of the right thalamus to right putamen in the MSZ group contrasting to the DSZ group. In addition, a decreased and an increased functional connectivity of the thalamus to sensory cortex were observed within the MSZ and DSZ group after 4-week treatment trial, respectively. Conclusion Our findings suggest that changes in functional connectivity of the thalamus may be associated with the brain mechanisms of mECT for schizophrenia.

  • A symptom combination predicting treatment-resistant schizophrenia – A strategy for real-world clinical practice
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-16
    Bruno B. Ortiz; Cinthia H. Higuchi; Cristiano Noto; Dan W. Joyce; Christoph U. Correll; Rodrigo A. Bressan; Ary Gadelha

    Early identification of symptoms that can predict treatment-resistant schizophrenia (TRS) could help clinicians to avoid delays in clozapine therapy. This study aims to investigate symptom patterns that could predict TRS using a discovery/replication study design. First, we followed a cohort of inpatients with schizophrenia (n = 164) in which the most discriminative items at baseline of the Positive and Negative Syndrome Scale (PANSS) were determined using logistic regression with TRS status as an outcome. Using Receiver Operating Characteristic (ROC) curves, we tested the prediction performance of multiple combinations of the identified items. The same items' combination was tested in an independent replication sample of (n = 207) outpatients with schizophrenia. In the discovery sample, the best combination to predict TRS at the discharge was the sum of three baseline PANSS items – conceptual disorganization (P2), difficulty in abstract thinking (N5), and unusual thought content (G9). The P2 + N5 + G9 model yielded an area under the curve (AUC) of 0.881, a sensitivity of 77.8%, and a specificity of 83.3%. In the outpatient sample, the model P2 + N5 + G9 predictive accuracy for TRS was only in the range of “acceptable” with an AUC of 0.756 and sensitivity of 72.3% and a specificity of 74.4%. Overall, the P2 + N5 + G9 model corresponds to the construct of formal thought disorder composed of disorganized thinking, concrete thinking, and bizarre-idiosyncratic thinking. Pronounced levels of these symptoms are easily identifiable in clinical practice and may be a feasible strategy in TRS. Replicating in first-episode cohorts is desirable to understand the likely clinical utility.

  • Effects of risperidone monotherapy on the default-mode network in antipsychotic-naïve first-episode schizophrenia: Posteromedial cortex heterogeneity and relationship with the symptom improvements
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-15
    Xujun Duan; Maolin Hu; Xinyue Huang; Xia Dong; Xiaofen Zong; Changchun He; Jinming Xiao; Jinsong Tang; Xiaogang Chen; Huafu Chen

    The default mode network (DMN) has been consistently detected abnormally in schizophrenia. However, the effects of antipsychotics on this network are still under debate, and inconsistent findings may be due to the functional heterogeneity within the DMN, especially in the component regions of the posteromedial cortex (PMC). Here, we conducted a longitudinal research on the resting-state functional connectivity of the PMC subdivisions on 33 treatment-naive first-episode patients with schizophrenia at baseline and after 8 weeks of risperidone treatment through resting-state functional magnetic resonance imaging. At baseline, the patients demonstrated decreased connectivity of the three PMC seeds with several brain regions (target regions) compared with healthy controls. We then tested the effect of antipsychotic treatment on the functional connectivity between the three seeds and the target regions. We found that, one of the three seeds encompassed in PMC, namely, posterior cingulate cortex (PCC), was observed to have increased functional connectivity with the bilateral thalamus and the left lingual gyrus (LG). On the contrary, the functional connectivity between the target regions and the two remaining seeds, namely, the retrosplenial cortex and precuneus, was unaffected by risperidone treatment. Correlation analysis revealed a positive correlation between longitudinal change of PCC-LG connectivity and symptom improvement. These findings indicated the heterogeneity of the PMC in response to antipsychotic treatment and suggested the role of PCC as a treatment biomarker for schizophrenia.

  • An investigation of retinal layer thicknesses in unaffected first-degree relatives of schizophrenia patients
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-14
    Ayse Kurtulmus; Ahmet Elbay; Fatma Busra Parlakkaya; Tezer Kilicarslan; Mehmet Hakan Ozdemir; Ismet Kirpinar

    Introduction A large number of studies using different neuroimaging methods showed various structural changes both in patients and their unaffected first-degree relatives (FDRs) over the past years. Optical coherence tomography (OCT) is a relatively new, non-invasive imaging method used to obtain high-resolution cross-sectional images of the retina. A growing body of evidence reports thinning of retinal layers in patients with schizophrenia which is considered as a proxy for CNS alterations. We hypothesized that retinal layer changes would be observed in FDRs, in parallel with those seen in patients, as a potential endophenotype candidate. Methods Thirty-eight schizophrenia patients, 38 FDRs of schizophrenia and 38 age and gender-matched healthy subjects with no family history (HCs) were recruited to this study. OCT measurements were performed and peripapillary retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL) and macular thicknesses were measured. Results The groups did not differ on RNFL, macular or GCL thickness. However, IPL thickness was significantly lower in both patients and FDRs than HCs (p = .025 and p = .041, respectively). The difference between groups remained significant after controlling for confounders such as age, gender, smoking status, comorbid medical diseases and BMI (p = .016 patients vs HCs and p = .014 FDRs vs HCs). Conclusion Our findings suggest that IPL thinning may hold promise as a useful endophenotype for genetic and early detection studies. The evaluation of this area could provide an important avenue for elucidating some of the neurodevelopmental aberrations in the disorder.

  • Associations between physiological responses to social-evaluative stress and daily functioning in first-episode schizophrenia
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-14
    Alexandra C. Reed; Junghee Lee; Michael F. Green; Holly K. Hamilton; Gregory A. Miller; Kenneth L. Subotnik; Joseph Ventura; Keith H. Nuechterlein; Cindy M. Yee

    Schizophrenia (SZ) is associated with impaired adaptive functioning, including difficulties managing the demands of independent living, work, school, and interpersonal relationships. Prior studies have linked the physiological stress response with less effective coping in daily life. Differences in stress-response tendencies may also support heterogeneity in daily functioning in SZ. The present study examined two established measures of the stress response in patients with first-episode SZ. Salivary cortisol was included as an index of hypothalamic–pituitary–adrenal response. Vagal suppression (VS), a measure of stress-related reduction in heart rate variability, was used to assess parasympathetic flexibility. Greater cortisol response and VS to social-evaluative stress were predicted to be associated with better functioning in SZ over and above relationships with social cognition and neurocognition, two well-established predictors of functional outcome. Thirty-eight first-episode SZ outpatients and 29 healthy comparison subjects (HC) provided social cognitive, neurocognitive, and physiological measurements before and after the Trier Social Stress Test (TSST). Although SZ and HC did not differ on VS to the TSST, patients exhibited significant associations between VS and functioning across all four domains of the Role Functioning Scale. Furthermore, greater VS predicted more effective functioning with friends, beyond the contributions associated with social cognition and neurocognition, and strengthened the positive effects of higher levels of social cognition on independent living/self-care. VS elicited by social-evaluative stress in the laboratory may reflect stress-response tendencies in daily life that are relevant for daily functioning in first-episode SZ.

  • Gut microbial changes of patients with psychotic and affective disorders: A systematic review
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-14
    Nina Vindegaard; Helene Speyer; Merete Nordentoft; Simon Rasmussen; Michael Eriksen Benros

    Background Many diverse inflammatory pathophysiologic mechanisms have been linked to mental disorders, and through the past decade an increasing interest in the gut microbiota and its relation to mental health has been arising. We aimed to systematically review studies of alterations in gut microbiota of patients suffering from psychotic disorders, bipolar disorder or depression compared to healthy controls. Methods We systematically searched the databases CENTRAL, PubMed, EMBASE, PsycINFO and LILACS. Primary outcome was to compare the gut microbiota of patients suffering from psychotic disorders, bipolar disorder or depression with healthy controls. Results We identified 17 studies, covering 744 patients and 620 healthy controls. The most consistent microbiota changes were a tendency towards higher abundance of Actinobacteria and lower abundance of Firmicutes at the phylum level, lower abundance of Lachnospiraceae at family level and lower abundance of Faecalibacterium at genus level for the mental disorders overall. However, we found that all studies had risk of bias and that the included studies displayed great variability in methods of storage, analysis of the fecal samples, reporting of results and statistics used. Conclusion Due to the many limitations of the included studies the findings should be interpreted with caution. Larger studies (especially of schizophrenia and major depressive disorder) are needed, but it is also of great importance to gather information of and control for factors that influence the result of a microbiota analysis including body mass index (BMI), smoking, alcohol consumption, diet habits, antibiotics, sample handling, wet laboratory methods and statistics.

  • Neighborhood-level predictors of age at onset and duration of untreated psychosis in first-episode psychotic disorders
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-14
    Benson S. Ku; Luca Pauselli; Marc Manseau; Michael T. Compton

    Objective Recent years have witnessed growing interest in the role of the social environment in the development and outcomes of schizophrenia. We investigated whether neighborhood characteristics are associated with two important prognostic factors in early-course psychosis, age at onset of psychosis (AOP) and duration of untreated psychosis (DUP). Methods Data were collected from patients admitted to the hospital for first-episode schizophrenia-spectrum disorder. We collected data on perceived neighborhood disorder during childhood/adolescence and extracted data on 13 neighborhood characteristics from the American Community Survey based upon individual addresses. Four neighborhood-level factors were derived from factor analysis. Multiple logistic regression analyses assessed the association between specific neighborhood characteristics and the two prognostic factors (earlier AOP and longer DUP) in early-course psychosis. Results 143 participants had valid addresses geo-coded. Neighborhood-level residential instability was associated with an earlier AOP (OR = 1.760; p = 0.022) even after controlling for known risk factors (OR = 2.026; p = 0.020) and also after controlling for individual-level residential instability (OR = 1.917; p = 0.037). The general socioeconomic status neighborhood factor (OR = 1.119; p = 0.019) and perceived neighborhood disorder (OR = 1.075; p = 0.005) were associated with a longer DUP. But only perceived neighborhood disorder (OR = 1.146; p = 0.011) remained significant, and general socioeconomic status was close to significant (OR = 1.215; p = 0.062), after controlling for individual-level predictors and socioeconomic status. Conclusions This study found evidence that neighborhood-level characteristics (in this case, residential instability) may be associated with earlier AOP, and perceptions of neighborhood disorder are associated with a longer treatment delay. Socioenvironmental factors should be more consistently considered going forward in research on early psychotic disorders.

  • Reward anticipation in schizophrenia: A coordinate-based meta-analysis
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-14
    Arnaud Leroy; Ali Amad; Fabien D'Hondt; Delphine Pins; Nematollah Jaafari; Pierre Thomas; Renaud Jardri

    Reward processing impairments have been linked with positive and negative symptoms of schizophrenia. Here, we performed a coordinate-based meta-analysis that combined eleven BOLD-fMRI studies comparing reward anticipation signals between schizophrenia patients and healthy controls. We observed a reduced difference in activation in schizophrenia patients within a frontal-striatal network. Meta-regressions revealed that this functional signature was linked to the severity of psychotic symptoms and persisted even after controlling for the dose of antipsychotic medications.

  • Screening for cognitive impairment in non-affective psychoses: A comparison between the SCIP and the MoCA
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-13
    Martino Belvederi Murri; Federica Folesani; Silvia Costa; Bruno Biancosino; Cristina Colla; Luigi Zerbinati; Rosangela Caruso; Maria Giulia Nanni; Scot E. Purdon; Luigi Grassi

    Background Neuropsychological performance has a strong impact on real-life functioning and clinical outcomes in psychosis. However, conducting lengthy cognitive assessments may not be feasible in routine clinical practice. Brief, reliable and cost-effective tools are highly needed, but few studies are available to guide clinician choice. Methods The purpose of this study was to compare the performance of two widely used, short instruments: the Screen for Cognitive Impairment in Psychiatry (SCIP) and the Montreal Cognitive Assessment (MoCA). These instruments were validated in a sample of patients with psychotic disorders and healthy controls, using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and other instruments to assess executive functions, as comparators. Results Patients fared worse than controls across almost all cognitive domains, with effect sizes ranging from 0 (MoCA naming) to 2.08 (SCIP total). Receiver Operator Curve analysis of patient and control performance suggested a better convergent validity for the SCIP (total score AUC: 0.85; 95%CI: 0.79–0.90; Se: 76%, Sp: 83%, PPV: 85%, NPV: 73%) than the MoCA (AUC: 0.78; 95%CI: 0.72–0.85; Se: 69%, Sp: 76%, PPV: 78.7%, NPV 66%). Conclusions The Screen for Cognitive Impairment in Psychiatry seems to be a more sensitive and specific screening tool than the MoCA to identify cognitive impairment among patients with psychotic disorders.

  • Anatomical integrity within the inferior fronto-occipital fasciculus and semantic processing deficits in schizophrenia spectrum disorders
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-13
    Werner Surbeck; Jürgen Hänggi; Felix Scholtes; Petra V. Viher; André Schmidt; Katharina Stegmayer; Erich Studerus; Udine E. Lang; Anita Riecher-Rössler; Werner Strik; Erich Seifritz; Stefan Borgwardt; Boris B. Quednow; Sebastian Walther

    The core symptoms of schizophrenia spectrum disorders (SSD) include abnormal semantic processing which may rely on the ventral language stream of the human brain. Thus, structural disruption of the ventral language stream may play an important role in semantic deficits observed in SSD patients. Therefore, we compared white matter tract integrity in SSD patients and healthy controls using diffusion tensor imaging combined with probabilistic fiber tractography. For the ventral language stream, we assessed the inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus, and uncinate fasciculus. The arcuate fasciculus and corticospinal tract were used as control tracts. In SSD patients, the relationship between semantic processing impairments and tract integrity was analyzed separately. Three-dimensional tract reconstructions were performed in 45/44 SSD patients/controls (“Bern sample”) and replicated in an independent sample of 24/24 SSD patients/controls (“Basel sample”). Multivariate analyses of fractional anisotropy, mean, axial, and radial diffusivity of the left IFOF showed significant differences between SSD patients and controls (p(FDR-corr) < 0.001, ηp2 = 0.23) in the Bern sample. Axial diffusivity (AD) of the left UF was inversely correlated with semantic impairments (r = −0.454, p(FDR-corr) = 0.035). In the Basel sample, significant group differences for the left IFOF were replicated (p < .01, ηp2 = 0.29), while the correlation between AD of the left IFOF and semantic processing decline (r = −0.376, p = .09) showed a statistical trend. No significant effects were found for the dorsal language stream. This is direct evidence for the importance of the integrity of the ventral language stream, in particular the left IFOF, in semantic processing deficits in SSD.

  • Suicidal thoughts and behavior (STB) and psychosis-risk symptoms among psychiatrically hospitalized adolescents
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-13
    Elizabeth Thompson; Anthony Spirito; Elisabeth Frazier; Alysha Thompson; Jeffrey Hunt; Jennifer Wolff

    Background Individuals in the early stages of psychosis have a markedly high risk for suicidal thoughts and behavior (STB). It is not well understood if STB among those with psychosis-risk symptoms is accounted for by co-occurring psychopathology (e.g., depression), unique experiences specific to psychosis-spectrum symptomatology (e.g., hallucinations, delusions), or combined effects of different factors. This cross-sectional study explored the link between psychosis-spectrum symptoms, co-occurring disorders, and STB. Methods This record review included 569 adolescents (mean age = 14.83) admitted to a psychiatric inpatient hospital due to exhibiting behavior indicating they were an imminent threat to themselves or others. Upon intake to the hospital, participants completed a diagnostic interview and self-report measures of suicidal ideation, suicide attempt history, and psychosis-spectrum symptoms. The primary analysis used linear regression to predict suicidal ideation from psychosis-spectrum symptom scores, controlling for known characteristics associated with STB including specific psychiatric disorders (i.e. depressive, anxiety, post-traumatic stress, and psychotic disorders), biological sex, and race. Results Psychosis-spectrum symptoms predicted suicidal ideation above and beyond the significant effects of a depressive disorder diagnosis and sex, as well as the non-significant effects of anxiety, PTSD, full-threshold psychosis, and race. Item-level correlations demonstrated that several psychosis-spectrum symptoms were significantly associated with ideation and lifetime suicide attempts. Conclusions Results indicate that within this sample of psychiatrically hospitalized youth, psychosis-risk symptoms were uniquely linked to STB. These findings suggest that attention to psychosis-spectrum symptoms, including several specific psychosis-risk experiences, may be clinically important for better assessment and treatment of suicidal youth.

  • Expressive deficits and amotivation as mediators of the associations between cognitive problems and functional outcomes: Results from two independent cohorts
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-13
    Edith J. Liemburg; Stefanie Enriquez-Geppert; Klaas J. Wardenaar; Richard Bruggeman; André Aleman

    Many individuals with severe mental disorders have difficulties in vocational and social functioning, which are regarded the most important outcomes, together with clinical symptoms. To understand the underlying mechanisms, research is increasingly focused on factors influencing functional outcomes. One established association has been shown between cognition and community functioning with negative symptoms as a possible mediator. Although it has been shown that negative symptoms consist of two subdomains, thus far negative symptoms have been assessed as one unitary construct. This study considers for the first time subdomains of negative symptoms as putative mediators (expressive deficits, amotivation) of the association between cognition (neuro- and social cognition) and functional outcome (living situation, occupation, social functioning). We expected that specific subdomains of negative symptoms (e.g. amotivation) would mediate the effect of cognition on specific functional outcomes (e.g. social functioning) independently from illness duration. To assess this, we included two independent cohorts, consisting of participants with different illness duration. These two independent cohorts consisted of patients with a recent-onset psychotic disorder: PROGR-S (first time treated; N = 1129) and GROUP (illness duration preferably <5 years; N = 1200). Using linear regression, mediation analyses were performed with two cognition domains (neurocognition and social cognition) as predictors, negative symptoms (Expressive deficits and Amotivation as indexed with items from the Positive and Negative Syndrome Scale) as mediators and three measures of functional outcomes (living situation, occupation and social functioning) as outcome measures. The analyses were repeated with the same outcome measures three years later. Three main results were obtained. I) Both in the cross-sectional and longitudinal analyses, the associations of neurocognition (both cohorts) and social cognition (GROUP) with social functioning were mediated by amotivation. II) The association between cognition and living situation was mediated by Expressive deficits in one cohort (GROUP) but not in the cohort assessing first-episode psychosis (PROGR-S). III) The association between cognition and occupation was mediated by Amotivation in PROGR-S and by Expressive deficits in GROUP. Conclusion The current results show a less robust mediating role for specific negative symptom domains regarding the associations of cognition with occupation and living situation that may depend on the duration of psychotic illness. However, Amotivation, mediates the association between cognition and social functioning, which holds true for patients experiencing a first-onset and patients with a longer illness duration alike. The results may have implications for the development of therapeutic approaches focusing on amotivation to improve social functioning. General scientific summary This study stresses the importance of distinguishing subdomains of negative symptoms, cognition and functioning. Our results show that specific negative symptom dimensions mediate the effects of cognition on specific functional outcomes.

  • Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-11
    Margaret Miller; Vance Zemon; Rachel Nolan-Kenney; Laura J. Balcer; Donald C. Goff; Michelle Worthington; Lisena Hasanaj; Pamela D. Butler

    Background Optical coherence tomography (OCT) studies have demonstrated differences between people with schizophrenia and controls. Many questions remain including the agreement between scanners. The current study seeks to determine inter-device agreement of OCT data in schizophrenia compared to controls and to explore the relations between OCT and visual function measures. Methods Participants in this pilot study were 12 individuals with schizophrenia spectrum disorders and 12 age- and sex-matched controls. Spectralis and Cirrus OCT machines were used to obtain retinal nerve fiber layer (RNFL) thickness and macular volume. Cirrus was used to obtain ganglion cell layer + inner plexiform layer (GCL + IPL) thickness. Visual function was assessed with low-contrast visual acuity and the King-Devick test of rapid number naming. Results There was excellent relative agreement in OCT measurements between the two machines, but poor absolute agreement, for both patients and controls. On both machines, people with schizophrenia showed decreased macular volume but no difference in RNFL thickness compared to controls. No between-group difference in GCL + IPL thickness was found on Cirrus. Controls showed significant associations between King-Devick performance and RNFL thickness and macular volume, and between low-contrast visual acuity and GCL + IPL thickness. Patients did not show significant associations between OCT measurements and visual function. Conclusions Good relative agreement suggests that the offset between machines remains constant and should not affect comparisons between groups. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device.

  • Systematic review and meta-analysis of the relationship between genetic risk for schizophrenia and facial emotion recognition
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-11
    David Martin; Jazz Croft; Alice Pitt; Daniela Strelchuk; Sarah Sullivan; Stan Zammit

    Background Recent research has highlighted that facial emotion recognition deficits are more common in people with schizophrenia, but the reason for this association is not well understood. Comparing facial recognition deficits in unaffected individuals at higher genetic risk for schizophrenia with individuals at lower genetic risk could increase our understanding of this relationship. Methods We systematically reviewed studies reporting on the relationship between genetic risk of schizophrenia and facial emotion recognition deficits. Meta-analyses were performed where sufficient data were available, otherwise we conducted narrative summaries. Meta-analyses were performed both for generalised and specific facial emotion recognition deficits. Results 34 studies were included in this review with 23 included in meta-analyses. Meta-analysis indicated strong evidence of a deficit in facial emotion recognition in first-degree relatives of people with schizophrenia compared with controls (SMD 0.38 95% CI 0.26 to 0.51, p ≤ 0.001). Further meta-analyses demonstrated strong evidence of a deficit in the recognition of negative valence facial expressions (SMD 0.19 CI 0.06 to 0.32, p = 0.004) but no evidence of deficit in the recognition of neutral or positive valance. Conclusions There is strong evidence of facial emotion recognition deficits in first-degree relatives of people with schizophrenia. Our findings suggest that such deficits in people with schizophrenia arise prior to the onset of the disorder, though cannot inform whether that association is causal or due to confounding. Emotion recognition deficits, particularly to negative emotions, might be useful predictors of schizophrenia risk.

  • Neurotrophic factor changes are essential for predict electroconvulsive therapy outcome in schizophrenia
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-10
    Jin Li; Xiaobin Zhang; Xiaowei Tang; Wenhuan Xiao; Fei Ye; Weiwei Sha; Qiufang Jia

    Brain-derived neurotrophic factor (BDNF) plays an important role in the treatment of schizophrenia with electroconvulsive therapy (ECT) or antipsychotic (AP) drugs. However, it is unclear whether BDNF is a mediator; we therefore assumed that baseline BDNF level can mediate the efficacy of ECT−AP treatment. A total of 160 patients with schizophrenia were examined; 80 received AP monotherapy and the other 80 were treated with a combination of ECT and AP. BDNF concentration was measured by enzyme-linked immunosorbent assay using the Emax Immunoassay System kit (Promega, Madison, WI, USA) according to the manufacturer’s instructions.Log-linear analyses were used to examine the relationship between demographic characteristics, BDNF level, and clinical features and response status. The baseline BDNF levels and BDNF level increment were the best predictors of clinical outcome (OR1 = 3.358, P = 0.000; OR2 = 3.243, P = 0.000).The higher baseline BDNF levels and greater BDNF level increment were found to be associated with good outcome.

  • Age dependent association of inbreeding with risk for schizophrenia in Egypt
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-09
    Lora McClain; Hader Mansour; Ibtihal Ibrahim; Lambertus Klei; Warda Fathi; Joel Wood; Chowdari Kodavali; Alina Maysterchuk; Shawn Wood; Farha El-Chennawi; Nahed Ibrahim; Ahmed Eissa; Wafaa El-Bahaei; Hanan El Sayed; Amal Yassein; Salwa Tobar; Hala El-Boraie; Eman El-Sheshtawy; Vishwajit Nimgaonkar

    Background Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. Methods We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. Results Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. Conclusions We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.

  • Odor identification in 7-year-old children at familial high risk of schizophrenia or bipolar disorder - the Danish high risk and resilience study VIA 7
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-08
    Anna Hester Ver Loren van Themaat; Md Jamal Uddin; Camilla Jerlang Christiani; Nicoline Hemager; Ditte Ellersgaard; Birgitte Klee Burton; Katrine Søborg Spang; Aja Greve; Ditte Gantriis; Ole Mors; Anne Amalie Elgaard Thorup; Kerstin Jessica Plessen; Merete Nordentoft; Jens Richardt Møllegaard Jepsen

    Background Odor identification deficits occur in individuals with schizophrenia and their unaffected first-degree relatives, while deficits are less pronounced in individuals with bipolar disorder. We hypothesized that children at familial high-risk for schizophrenia (FHR-SZ) show odor identification deficits compared to population-based controls and that children at familial high-risk for bipolar disorder (FHR-BP) perform intermediate. Methods Odor identification was assessed at age 7 in 184 children with FHR-SZ, 106 children with FHR-BP, and 186 population-based controls with the Brief Smell Identification Test. Dimensional and predefined categorical outcomes were used in the analyses. Potential relationships with psychopathological, cognitive, and home environmental variables were conducted using hierarchical and logistic multiple regression analyses. Results ANOVA revealed no between-group differences in odor identification. Using the recommended cut-off (below 5), we found a significantly greater proportion of boys at FHR-SZ than population-based boys with an abnormal odor identification (p = .013). However, a supplementary analysis using a Danish-based cut-off (below 4) did not support this. All children showed significant, positive associations of odor identification with female gender, social responsiveness, and verbal working memory. Lower social responsiveness predicted abnormal odor identification in boys at FHR-SZ, only using the recommended cut-off. Conclusions Odor identification efficacy and risk status appear independent in this early developmental phase. Using the recommended threshold, abnormal odor identification is more frequent in young boys at FHR-SZ than in population-based boys and is linked to lower social responsiveness. The validity of these results is questioned by non-significant differences in the rates when using an exploratory Danish-based threshold.

  • Advice weighting as a novel measure for belief flexibility in people with psychotic-like experiences
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-08
    Jakob Scheunemann; Łukasz Gawęda; Klaus-Michael Reininger; Lena Jelinek; Helmut Hildebrandt; Steffen Moritz

    Jumping to conclusions and bias against disconfirmatory evidence are two cognitive biases common in people with psychotic-like experiences and psychosis. However, many participants show comprehension problems doing traditional tasks; new paradigms with additional applied scenarios are thus needed. A large MTurk community sample (N = 1422) was recruited and subdivided into participants with high levels of psychotic-like experiences (at least 2 SD above the mean, n = 79) and participants with low levels of psychotic-like experiences (maximum 0.5 SD above the mean, n = 1110), based on the positive subscale of the Community Assessment of Psychic Experiences (CAPE). In the context of a judge-advisor system, participants made an initial estimate and then received advice that was either confirmatory or disconfirmatory. Participants then gave a new, possibly revised estimate and were allowed to seek additional advice. Participants with high levels of psychotic-like experiences gave their final assessment after receiving significantly less advice and were significantly more confident in their decision than participants with low psychotic-like experiences, in line with previous studies on jumping to conclusions and overconfidence. Contrary to the hypothesis and earlier studies, however, no deficit in belief revision was found. In fact, participants with high psychotic-like experiences weighted advice significantly higher in the condition with disconfirmatory advice, but only for the first advice they received. The increased weighting of a single piece of disconfirmatory advice can be explained by the hypersalience of evidence-hypothesis matches theory, according to which more weight is attached to the most recently available information.

  • Reduced sleep spindle density in adolescent patients with early-onset schizophrenia compared to major depressive disorder and healthy controls
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-07
    Miriam Gerstenberg; Melanie Furrer; Noemi Tesler; Maurizia Franscini; Susanne Walitza; Reto Huber

    Objectives During adolescence schizophrenia and major depressive disorder (MDD) increasingly emerge. Overlapping symptomatology during first presentation challenges the diagnostic process. Reduced sleep spindle density (SSD) was suggested as a biomarker in adults, discerning patients with schizophrenia from patients with depression or healthy controls (HC). We aimed to compare SSD in early-onset schizophrenia (EOS), with MDD, and HC, and to analyse associations of SSD with symptomatology and neurocognitive measures. Methods Automatic sleep spindle detection was performed on all-night high-density EEG (128 electrodes) data of 12 EOS, 19 MDD, and 57 HC (age range 9.8–19), allowing an age- and sex-matching of 1:2 (patients vs. HC). Severity of current symptoms and neurocognitive variables were assessed in all patients. Results SSD was defined between 13.75 and 14.50 Hz as within this frequency range SSD differed between EOS vs. HC in bin by bin analyses (12–15 Hz). In EOS, SSD was lower over 27 centro-temporal electrodes compared to HC and over 9 central electrodes compared to MDD. Reduced SSD in EOS compared to MDD and HC was accompanied by a high variability of SSD in all adolescents. SSD did not differ between MDD and HC. In the pooled sample of patients, lower SSD was associated with more severe Positive and Negative Symptoms Scale total score, more impaired memory consolidation and processing speed. Conclusion A high variability of SSD in all adolescents may reflect the evolving character of SSD. The association of reduced SSD with the symptom dimension of impaired cognition cuts across diagnostical entities.

  • Structural and functional alterations in the brain gray matter among first-degree relatives of schizophrenia patients: A multimodal meta-analysis of fMRI and VBM studies
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-07
    Aino I.L. Saarinen; Sanna Huhtaniska; Juho Pudas; Lassi Björnholm; Tuomas Jukuri; Jussi Tohka; Niklas Granö; Jennifer H. Barnett; Vesa Kiviniemi; Juha Veijola; Mirka Hintsanen; Johannes Lieslehto

    Objective We conducted a multimodal coordinate-based meta-analysis (CBMA) to investigate structural and functional brain alterations in first-degree relatives of schizophrenia patients (FRs). Methods We conducted a systematic literature search from electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks than healthy controls. In VBM studies, there were no differences in gray matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. By utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the gray matter.

  • Effect of music listening on P300 event-related potential in patients with schizophrenia: A pilot study
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-07
    Shikha Ahuja; Rajnish Kumar Gupta; Dinakaran Damodharan; Mariamma Philip; Ganesan Venkatasubramanian; Matcheri S. Keshavan; Shantala Hegde

    Reduced amplitude and increased latency of P300 auditory event-related potential (ERP) in patients with schizophrenia (SZ) indicate impairment in attention. Overall arousal level can determine the amount of processing capacity required for attention allocation. Music evokes strong emotions and regulates arousability. Music has been used to modulate P300, especially in normals. This exploratory study examined the effect of music listening on the amplitude and latency of P300 in SZ patients. EEG/ERP was recorded (32-channels) while SZ patients (n = 20; 18–45 years) performed an auditory oddball P300 task after the eyes-closed rest condition (Condition-A) and ten-minute music listening condition (Condition-B) as per the complete counterbalancing design (AB-BA). Patients listened to the researcher chosen, instrumental presentation of raag-Bhoopali in the North-Indian-Classical-Music, for ten-minutes. All patients rated the music excerpt as a relaxing and positively valenced. A significant increase in accuracy score and reaction time during the oddball task after music listening was noted. There was an increase in amplitude at TP7. A trend of increased amplitude was noted across all electrodes in the music condition compared to the rest condition. Mean amplitude in an apriori defined time window of interest (250 to 750 ms) showed significant changes in the frontal and central electrode sites. Power spectral analysis indicated a slight increase in frontal and central alpha and theta activity during music listening. However, this was not statistically significant. Findings add further impetus to examine the effect of music in chronic psychiatric conditions. Need for systematic studies on a larger cohort is underscored.

  • The cognitive training version of the MUSIC® model of motivation inventory: A follow-up validity study
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-07
    Alice M. Saperstein; Brett D. Jones; Marie C. Hansen; Alice Medalia

    Further validation of the MUSIC® Model of Motivation Inventory (MMI) for use in Cognitive Remediation (CR) for schizophrenia is needed. The MMI was compared to the Intrinsic Motivation Inventory - Schizophrenia Research and Perceived Competency Scale following early treatment exposure in a CR clinical trial. MMI Usefulness, Success, and Interest scales were significantly correlated with corresponding comparison scales. The MMI was not correlated with pre-morbid cognitive ability. Higher expectancy for success and perceived usefulness were significantly associated with greater intensity of session attendance. Results support the convergent, divergent, and predictive validity of the MMI for CR research and clinical use.

  • Stressful experiences affect the course of co-occurring obsessive-compulsive and psychotic symptoms: A focus on within-subject processes
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-07
    Frederike Schirmbeck; Max Konijn; Vera Hoetjes; Jentien Vermeulen; Mathias Zink; Jack Dekker; Lieuwe de Haan

    Objective Obsessive-compulsive symptoms (OCS) frequently occur in patients with psychotic disorders and are associated with higher burden and poorer prognosis. This study prospectively investigated the effect of stressful experiences on the severity of OCS and co-occurring psychotic and affective symptoms, with a focus on within-subject processes. Method Monthly assessments over 6 months in patients with a psychotic disorder (n = 56) and unaffected siblings (n = 49) resulted in 309 and 277 observations, respectively. Linear mixed-effects models investigated the disaggregated effects of within-subject changes and between-subject differences in stressful events on OCS, positive, negative and depressive symptoms. Subsequently, moderating effects of coping strategies and dysfunctional metacognitive beliefs were assessed. Mediation analyses investigated direct and indirect effects of stressful events on OCS four weeks later. Results Stressful experiences were associated with severity in almost all symptom domains on the between- and within-subject levels. Dysfunctional coping and metacognitive beliefs moderated these associations. Patients and siblings with a tendency for passive coping showed higher within-subject increase in depressive symptoms, whereas passive coping and dysfunctional beliefs moderated the association between stressful experiences and severity of positive symptoms and OCS on the between-subject level. Effects of stressful experiences on OCS four weeks later were partially mediated by depressive and positive symptoms in patients and siblings. Conclusions Findings suggest that severity and variability of co-occurring psychopathology can partly be explained by recent stressful events and the way individuals cope with these experiences. The implementation of coping-oriented interventions could possibly help to prevent development and/or aggravation of co-occurring symptom severity.

  • Delay discounting abnormalities are seen in first-episode schizophrenia but not in bipolar disorder
    Schizophr. Res. (IF 4.569) Pub Date : 2020-01-03
    Huan Wang; Tyler A. Lesh; Richard J. Maddock; Catherine Fassbender; Cameron S. Carter

    Delay discounting (DD) is the phenomenon of individuals discounting future rewards as a function of time. It has been studied extensively in chronic schizophrenia (SZ) and the results of these studies have been variable. Comorbidity in chronic samples could be one reason for the mixed findings and studies in first-episode (FE) samples are surprisingly lacking. Bipolar disorder (BP) which shares some genetic and symptom features with SZ could serve as an interesting comparison group for DD but has been underexplored. Here we present the first study that combines FE SZ, FE BP with psychotic features, as well as healthy controls and study DD with two versions of the task. We found that SZ showed steeper discounting than HC and BP on the well-validated Kirby DD task. SZ showed no difference than HC on a separate DD task with smaller rewards presented with decimal places and shorter delays. As a preliminary finding, DD was found to be positively related to positive symptoms in FE SZ, while no relationship was found between negative symptoms and DD. In addition, we found comparable DD in BP compared to HC. Ultimately, our data may help elucidate the psychopathology in SZ and BP during intertemporal decision making.

  • A meta-analysis of the associations between theory of mind and neurocognition in schizophrenia
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-31
    Élisabeth Thibaudeau; Amélie M. Achim; Carolane Parent; Mélissa Turcotte; Caroline Cellard

    Theory of mind (ToM) refers to the ability to infer the mental states of others. ToM is impaired in schizophrenia and these deficits seem to hinder functional recovery. ToM is thus an important, but complex treatment target, supported by several processes. A large number of studies report significant associations between ToM and neurocognition (e.g. memory, attention), but the neurocognitive domains that are most closely linked to ToM remain to be identified. A meta-analysis was conducted to estimate the magnitude of the associations between ToM and neurocognition in people with schizophrenia. Correlations were extracted from the relevant literature, transformed into effect sizes Zr and pooled as weighted means. Focused-tests were employed to test for differences between neurocognitive domains and for differences linked to the characteristics of ToM tasks. Ninety-one studies (N = 5462) were included. Moderate associations emerged between ToM and each neurocognitive domain (Zrs 0.27–0.43), with no significant difference between domains (χ2(8) = 11.89, p = 0.156). Within the domain of executive functions, abstraction showed a stronger association with ToM (χ2(4) = 18.93, p = 0.001). Several ToM tasks characteristics (e.g. modality of stimuli, type of mental state), were significantly related to the magnitude of the associations between ToM and executive functions, visuospatial/problem solving, attention and episodic memory. These results suggest that ToM is linked to a wide range of neurocognitive abilities in schizophrenia, and that ToM tasks are a significant moderator of these associations. The assessment and treatment of ToM should consider the neurocognitive profile of each patient to understand his difficulties and to tailor interventions.

  • Homeless youth with first-episode psychosis: A 2-year outcome study
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-31
    Isabelle Sarah Lévesque; Amal Abdel-Baki

    Background Psychosis augments the risk of homelessness, the latter is associated with increased morbidity and mortality. Young adults experiencing first-episode psychosis (FEP) are increasingly recognized as being vulnerable to homelessness. However, data on homeless in youth with FEP are sparse. Objectives To compare symptomatic and functional outcomes in homeless v. never homeless FEP, at admission and two years after admission to an Early Psychosis Intervention Service (EIS). Method From October 2005 to April 2011, 167 FEP consecutive admissions (aged 18–30 years old), were recruited in a 2-year prospective longitudinal study in an inner city EIS in Montreal, Canada. Socio-demographic characteristics, symptomatic and functional outcomes, as well as treatments and service use data were collected at admission and annually. Result 26% of FEP were homeless, prior or during the follow-up. Attrition rate was similar among the two groups. At baseline, the homeless group were more likely to have childhood abuse, forensic history, non-affective psychosis, negative symptoms, substance use disorder and cluster B personality. Despite the intensive care of EIS, the similarity of illness severity at baseline and medication adherence rate, homeless FEP had poorer 2-year symptomatic and functional outcomes, although having more long-acting injectable antipsychotics (LAI) (vs oral antipsychotics), community treatment order and hospitalizations. Conclusion Homelessness is a serious and prevalent phenomenon among FEP youth associated with worse symptomatic and functional outcomes. More studies on interventions focusing on potentially modifiable factors (e.g. substance use disorders, social support) are warranted.

  • Socioeconomic deprivation and blood lipids in first-episode psychosis patients with minimal antipsychotic exposure: Implications for cardiovascular risk
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-30
    Franz Veru-Lesmes; Aldanie Rho; Ridha Joober; Srividya Iyer; Ashok Malla

    Background The influence of socioeconomic deprivation on the cardiovascular health of patients with psychosis-spectrum disorders (PSD) has not been investigated despite the growing recognition of social factors as determinants of health, and the disproportionate rates of cardiovascular mortality observed in PSD. Discordant results have been documented when studying dyslipidemia –a core cardiovascular risk factor– in first-episode psychosis (FEP), before chronic exposure to antipsychotic medications. The objective of the present study is to determine the extent to which socioeconomic deprivation affects blood lipids in patients with FEP, and examine its implications for cardiovascular risk in PSD. Methods Linear regression models, controlling for age, sex, exposure to pharmacotherapy, and physical anergia, were used to test the association between area-based measures of material and social deprivation and blood lipid levels in a sample of FEP patients (n = 208). Results Social, but not material deprivation, was associated with lower levels of total and HDL cholesterol. This effect was statistically significant in patients with affective psychoses, but not in schizophrenia-spectrum disorders. Conclusions Contrary to other reports from the literature, the relationship between socioeconomic disadvantage and blood lipid levels was contingent on the social rather than the material aspects of deprivation. Furthermore, this association also depended on the main diagnostic category of psychosis, suggesting a complex interaction between the environment, psychopathology, and physical health. Future studies exploring health issues in psychosis might benefit from taking these associations into consideration. A better understanding of the biology of blood lipids in this context is necessary.

  • Awareness and rumination moderate the affective pathway to paranoia in daily life
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-28
    Lea Ludwig; Stephanie Mehl; Björn Schlier; Katarina Krkovic; Tania M. Lincoln

    Numerous cross-sectional studies found psychosis to be associated with less awareness of emotions, a decreased use of adaptive (e.g. reappraisal) and an increased use of maladaptive emotion regulation (ER) strategies (e.g. suppression). In this study, we tested whether state levels of emotion awareness and momentary use of specific ER strategies moderate the link between negative affect at one timepoint (t-1) and paranoia at the next timepoint (t) in a six-day experience sampling study. Individuals with psychotic disorders (n = 71) reported on the presence of paranoia, negative affect, emotion awareness and the use of six ER strategies (reappraisal, acceptance, social sharing, distraction, suppression and rumination) ten times per day. Multilevel regression analysis revealed that higher awareness at t-1 reduced the association of negative affect at t-1 and paranoia at t, whereas rumination had an opposite, amplifying moderation effect. Our results provide novel insight into the conditions under which negative affect translates into delusional beliefs. The finding that emotion awareness and rumination have a relevant role corresponds with current psychological conceptualisations of psychosis and with the attempt to treat delusions by focusing on reducing ruminative thoughts. To investigate the causal effect, treatment trials with a focus on enhancing these components of emotion regulation are needed.

  • Basic self-disorders in adolescence predict schizophrenia spectrum disorders in young adulthood: A 7-year follow-up study among non-psychotic help-seeking adolescents
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-27
    Danny Koren; Yair Tzivoni; Liat Schalit; Merav Adres; Noa Reznik; Alan Apter; Josef Parnas

    Background and goals Recent studies indicate that basic self-disorder (SD) is a core clinical phenotype of schizophrenia and its spectrum. The goal of the present study was to test the degree to which SD characterizes the pre-onset phase of schizophrenia-spectrum disorders (SSD). A secondary goal was to replicate previous findings regarding the long-term stability of SD. Method To accomplish these goals, the long-term association of SD in adolescence with SSD seven years later was examined in a sample of 39 non-psychotic, help-seeking adolescents. SD was assessed with the Examination of Anomalous Self-Experience (EASE), and presence of schizophrenia-spectrum and other co-morbid illnesses in young adulthood was assessed with the Operational Criteria+ (OPCRIT+) checklist for psychotic and affective disorders. Results Nine (23.1%) of the 39 participants were diagnosed as suffering from SSD (three Schizophrenia, three non-organic and non-affective psychotic disorder, and three schizotypal disorder) in young adulthood. A diagnosis of SSD in young adulthood was significantly predicted by SD, but not by prodromal symptoms in adolescence. The correlation between the EASE total score at adolescence and young adulthood was moderate and significant (r = 0.64, p < .001). Conclusions These results provide first long-term prospective support, in a sample not enriched for risk for psychosis, for the possibility that SD is a clinical marker of risk for SSD. Also, they provide additional support for the longitudinal persistence of SD over time.

  • Characteristics of youth with reported family history of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-26
    Jerome H. Taylor; Nana Asabere; Monica E. Calkins; Tyler M. Moore; Sunny X. Tang; Rose Mary Xavier; Alison K. Merikangas; Daniel H. Wolf; Laura Almasy; Ruben C. Gur; Raquel E. Gur

    Little is known about the impact of family history of psychosis on youth from community samples. To fill this gap, we compared youth with a first-degree relative with psychosis spectrum symptoms (i.e. family history of psychosis spectrum symptoms, FHPS) to youth without FHPS in a cross-sectional analysis of the Philadelphia Neurodevelopmental Cohort (PNC). The PNC is a racially diverse community sample of 9498 youth ages 8–21 years old, of whom 8928 completed the Family Interview for Genetic Studies to determine FHPS status. Polygenic risk score for schizophrenia (PRSS) was available for a subsample of 4433 European Americans. FHPS youth (n = 489) constituted 5.5% of the analytic sample. After adjusting for environmental risk factors (sociodemographic variables and traumatic stressful events), FHPS youth had lower functioning on the Children's Global Assessment Scale and elevated psychosis spectrum, mood, externalizing, and fear symptoms compared to non-FHPS youth (all p < .001). In the European-American subsample, FHPS status was associated with poorer functioning and greater symptom burden in all four psychopathology domains (all p < .001), even after covarying for PRSS. Thus, ascertaining FHPS is important because it is uniquely associated with symptoms and functional impairment in community youth beyond PRS-S and the environmental risk factors we investigated. Future research identifying environmental causes of FHPS-associated impairment could inform the development of interventions for the broad array of symptoms observed in FHPS youth.

  • Linguistic dual tasking reduces emotionality, vividness and credibility of voice memories in voice-hearing individuals: Results from a controlled trial
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-26
    Alyssa Jongeneel; Suzanne C. van Veen; Dorien Scheffers; Heleen Riper; Marcel A. van den Hout; Mark van der Gaag; David van den Berg

    Dual taxation of the working memory during recall is an effective strategy to reduce the emotionality and vividness of visual intrusive memories and potentially changes dysfunctional beliefs associated with the memories. This study tested the hypothesis that dual tasking decreases emotionality, vividness and credibility of auditory intrusive images (i.e., memories of auditory hallucinations) with a two-level (time: pre and post; condition: dual tasking and recall only) within-subjects design. Thirty-seven voice-hearing participants selected two negative voice-hearing experiences. They recalled one of these experiences while performing a lingual dual task (i.e., language game on smartphone app) and recalled one memory without a dual task (in counterbalanced order). During the pre-test and post-test, emotionality and vividness of the voice-hearing memories were rated, as well as the credibility of the voice statements. There was a significantly greater decrease in emotionality, vividness and credibility during dual tasking than during recall only. This study provides proof of principle that the salience and credibility of the content of auditory hallucinations can be reduced by dual tasking; the clinical implications are also discussed.

  • Prediction of individual responses to electroconvulsive therapy in patients with schizophrenia: Machine learning analysis of resting-state electroencephalography
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-26
    Beomjun Min; Minah Kim; Junhee Lee; Jung-Ick Byun; Kon Chu; Ki-Young Jung; Sang Kun Lee; Jun Soo Kwon

    Background Electroconvulsive therapy (ECT) has strong efficacy in patients with treatment refractory schizophrenia. However, access to ECT has been limited by high costs, professional labor, treatment duration, and significant adverse effects. To provide support for the decision to perform ECT, we aimed to predict individual responses to ECT among patients with schizophrenia using machine learning analysis of resting-state electroencephalography (EEG). Methods Forty-seven patients diagnosed with schizophrenia or schizoaffective disorder with EEG recordings before the course of ECT were treated at Seoul National University Hospital. Among these patients, 29 were responders who showed scores of 3 or less on the Clinical Global Impression Severity scale after the course of ECT. Transfer entropy (TE), which represents information flow, was extracted from baseline EEG data and used as a feature. Feature selection was performed with four methods, including Random Subset Feature Selection (RSFS). The random forest classifier was used to predict individual ECT responses. Results The averaged TE, especially in frontal regions, was higher in ECT responders than in nonresponders. A predictive model using the RSFS method classified ECT responders and nonresponders with 85.3% balanced accuracy, 85.2% accuracy, 88.7% sensitivity, and 81.8% specificity. The positive predictive value was 82.6%, and the negative predictive value was 88.2%. Conclusions The results of the current study suggest that higher effective connectivity in frontal areas may be associated with a favorable ECT response. Furthermore, personalized decisions to perform ECT in clinical practice could be augmented by resting-state EEG biomarkers of the ECT response in schizophrenia patients.

  • Relationship between resting-state theta phase-gamma amplitude coupling and neurocognitive functioning in patients with first-episode psychosis
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-26
    Tak Hyung Lee; Minah Kim; Wu Jeong Hwang; Taekwan Kim; Yoo Bin Kwak; Jun Soo Kwon

    Background Although cognitive dysfunction is a core element of schizophrenia, the neurobiological underpinnings of the pathophysiology are not yet sufficiently understood. Because the resting state is crucial for cognitive functioning and electroencephalography (EEG) can reflect instantaneous neural activity, we investigated theta phase-gamma amplitude coupling (TGC) of resting-state EEG and its relationship with cognitive function in patients with first-episode psychosis (FEP) to reveal the neural correlates of cognitive dysfunction. Methods A total of 59 FEP patients and 50 healthy controls (HCs) underwent resting-state, eyes-closed EEG recordings and performed the Trail Making Test Part A (TMT-A) and Part B (TMT-B) and California Verbal Learning Test (CVLT). TGC from the source signal of the resting-state EEG in default mode network (DMN)-related brain regions was compared between groups. Correlation analyses were performed between TGC and cognitive function test performance in FEP patients. Results Mean resting-state TGC was larger for the FEP patients than for the HCs. Patients with FEP showed increased TGC in the left posterior cingulate cortex, which was correlated with better performance on the TMT-A and TMT-B and on immediate and delayed recall in the CVLT. Conclusions These results suggest that patients with FEP show compensatory hyperactivation of resting-state TGC in DMN-related brain regions, which may be related to the reallocation of cognitive resources to prepare for successful cognitive execution. This study not only highlights the neural underpinnings of cognitive dysfunction in FEP patients but also provides useful background to support the development of treatments for cognitive dysfunction in schizophrenia.

  • Revisiting anticipatory hedonic processing in patients with schizophrenia: An examination between representation activation and maintenance
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-24
    Ling-ling Wang; Chao Yan; Yu-xin Shao; Qin-yu Lv; David Neumann; Ulrich Ettinger; Eric F.C. Cheung; Zheng-hui Yi; Raymond C.K. Chan

    Background Anticipatory anhedonia is one of the key deficits found in patients with schizophrenia (SCZ). However, the underlying mechanism of this deficit remains unclear. The present study examined whether representation activation and maintenance capacity influenced anticipatory experiences in SCZ patients. Methods We recruited 46 SCZ patients (26 males) and 45 matched healthy controls (24 males). The Reward Representation Activation and Maintenance (RRAM) Task was administrated to assess anticipatory experience and representation activation and maintenance capacity. Results SCZ patients exhibited lower subjective arousal than controls in anticipation of rewards with high probability when representation activation and maintenance were difficult to accomplish. SCZ patients also tended to reduce their button presses more than HC when they were required to maintain reward representation. Conclusions Our findings suggest that representation activation and maintenance may partially account for anticipatory anhedonia observed in SCZ patients.

  • Independent support for corticopallidal contributions to schizophrenia-related functional impairment
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-24
    Goda Tarcijonas; William Foran; Annie Blazer; Shaun M. Eack; Beatriz Luna; Deepak K. Sarpal

    Background Abnormalities between the prefrontal cortex and basal ganglia have been described by numerous studies of schizophrenia (SZ). We recently reported that individuals with first episode SZ who develop greater vocational and social impairments show lower baseline functional connectivity between the globus pallidus (GP) and regions of the intrinsic salience network. Here we extend these findings to probe the integrity of this system in individuals with chronic illness. Methods All data were obtained from a publicly available Center of Biomedical Research Excellence dataset (http://fcon_1000.projects.nitric.org/indi/retro/cobre.html) that included resting-state fMRI and structural scans, and an array of clinical and neuropsychological measures. Participants with SZ were divided into high- or low-functioning groups based on scores across measures of psychopathology and cognitive functioning. Corticopallidal functional connectivity was examined between low- and high-functioning individuals with SZ and matched healthy control participants. We focused on connectivity between GP structures and a priori regions of the salience network that were significant in our previous study. Exploratory voxel-wise analyses were also conducted. Results Lower functioning individuals with SZ demonstrated less connectivity between bilateral GP externa and nodes within the salience network, relative to healthy controls. No connectivity differences were observed between low- and high-functioning individuals with SZ. Exploratory voxel-wise analyses highlighted additional large-scale corticopallidal abnormalities in lower-functioning participants with SZ. Conclusions These results confirm our previous work in a more chronic cohort of individuals with SZ. Our findings further advance corticopallidal connectivity as a biomarker of functional impairments in SZ and lay the groundwork for treatment-based studies.

  • Dynamic Causal Modelling suggests impaired effective connectivity in patients with schizophrenia spectrum disorders during gesture-speech integration
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-24
    Adrian Wroblewski; Yifei He; Benjamin Straube

    Integrating visual and auditory information during gesture-speech integration (GSI) is important for successful social communication, which is often impaired in schizophrenia. Several studies suggested the posterior superior temporal sulcus (pSTS) to be a relevant multisensory integration site. However, intact STS activation patterns were often reported in patients. Thus, here we used Dynamic Causal Modelling (DCM) to analyze whether information processing in schizophrenia spectrum disorders (SSD) is impaired during GSI on network level. We investigated GSI in three different samples. First, we replicated a recently published connectivity model for GSI in a healthy subject group (n = 19). Second, we investigated differences between patients with SSD and a matched healthy control group (n = 17 each). Participants were presented videos of an actor performing intrinsically meaningful gestures accompanied by spoken sentences in German or Russian, or just telling a German sentence without gestures. Across all groups, fMRI analyses revealed similar activation patterns, and DCM analyses resulted in the same winning model for GSI. This finding directly replicates previous results. However, patients revealed significantly reduced connectivity in the verbal pathway (from left middle temporal gyrus (MTG) to left STS). The clinical significance of this connection is supported by its correlations with the severity of concretism and a subscale of negative symptoms (SANS). Our model confirms the importance of the pSTS as integration site during audio-visual integration. Patients showed generally intact connectivity during GSI, but revealed impaired information transfer via the verbal pathway. This might be the basis of interpersonal communication problems in patients with SSD.

  • Developmental and symptom profiles in early-onset psychosis
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-23
    Marianna Giannitelli; Douglas F. Levinson; David Cohen; Jean Xavier; Claudine Laurent-Levinson

    Psychotic disorders in children are more heterogeneous than is captured by categorical diagnoses. In a new cohort of children and adolescents, we evaluated the relationships among age at onset (AAO), clinical symptoms and developmental impairments. Patients with schizophrenia and other “spectrum” psychotic diagnoses (N = 88; AAO 6–17, mean 12.6) were evaluated with diagnostic interviews, a new clinical scale (Lifetime Dimensions of Psychosis Scale-Child and Adolescent), and neuropsychological and medical evaluations. Key findings were replicated in an adult cohort of 2420 cases, including 127 with retrospective AAO<13. Factor and cluster analyses were carried out to identify clinical profiles. Five clinical factors were identified in each cohort: Positive, Bizarre Positive, Negative/Formal Thought Disorder, Depression and Mania. Earlier AAO predicted severity of bizarre positive symptoms in children and of bizarre and other symptoms in adults. Four clinical clusters in the child cohort were characterized by: more severe bizarre positive symptoms (N = 31); negative symptoms (N = 15); premorbid autism spectrum features and developmental delay (N = 12); and depressive symptoms with heterogeneous diagnoses and mild positive/negative symptoms (N = 25). Previous factor-analytic studies of childhood psychosis did not specifically consider bizarre positive symptoms. Here, bizarre positive symptoms emerged as clinical markers of severe, childhood-onset psychosis similar to adult schizophrenia. The four clusters are clinically meaningful and useful for treatment planning and potentially for biological research. Childhood-onset cases are rare and thus difficult to study, but additional, larger cohorts may be useful in dissecting the biological and developmental heterogeneity of psychotic disorders.

  • Ecological momentary assessment of everyday social experiences of people with schizophrenia: A systematic review
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-23
    Jasmine Mote; Daniel Fulford

    Introduction Our goal in the current review was to summarize the existing literature on the utility of ecological momentary assessment (EMA) in assessing the social experiences of people with schizophrenia (SZ). We were further interested in examining the associations between EMA-reported social outcomes and traditional assessments of social functioning. Methods We conducted a systematic review of EMA studies published between January 1, 1990 and October 31, 2018 from PubMed and PsycINFO electronic databases. We included EMA studies that assessed social experiences (proportion of time spent alone/with others, affective experiences when with others, social stress, factors related to social experiences) in people with SZ. We included studies that examined associations between laboratory-based, self-report, or clinical assessments of functioning with EMA-reported social experiences. Results We identified 22 EMA studies for inclusion in this review. Though heterogeneous in aspects of social experiences assessed, the current literature suggests that people with SZ report more social stress and a preference to be alone when they are with others (nine out of 10 studies). People with SZ report more positive affect when they are with others compared to being alone, and equivalent amounts of positive affect during social experiences as healthy controls (all four studies assessed). Five studies assessed the coherence between functioning assessments and momentary social experiences, with mixed results. Conclusion We discuss limitations of the literature and future directions. EMA shows promise in assessing more granular aspects of social experience (including social stress and social pleasure) in people with SZ compared to other methods.

  • Predictive validity of conversion from the clinical high risk syndrome to frank psychosis
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-19
    Laura A. Yoviene Sykes; Maria Ferrara; Jean Addington; Carrie E. Bearden; Kristin S. Cadenhead; Tyrone D. Cannon; Barbara A. Cornblatt; Diana O. Perkins; Daniel H. Mathalon; Larry J. Seidman; Ming T. Tsuang; Elaine F. Walker; Thomas H. McGlashan; Kristen A. Woodberry; Albert R. Powers; Allison N. Ponce; John D. Cahill; Jessica M. Pollard; Scott W. Woods

    Although the clinical high risk for psychosis (CHR) paradigm has become well-established over the past two decades, one key component has received surprisingly little investigative attention: the predictive validity of the criteria for conversion or transition to frank psychosis. The current study evaluates the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. Participants included 33 SIPS converters and 399 CHR non-converters both from the North American Prodromal Longitudinal Study (NAPLS-2), as well as a sample of 67 separately ascertained first-episode psychosis (FEP) patients from the STEP program. Comparisons were made at baseline and one-year follow-up on demographic, diagnostic stability (SCID), and available measurement domains relating to severity of illness (psychotropic medication, psychosocial treatment, and resource utilization). Principal findings are: 1) a large majority of cases in both SIPS converters (n = 27/33, 81.8%) and FEP (n = 57/67, 85.1%) samples met criteria for continued psychosis at one-year follow-up; 2) follow-up prescription rates for current antipsychotic medication were higher in SIPS converters (n = 17/32, 53.1%) compared to SIPS non-converters (n = 81/397, 20.4%), and similar as compared to FEP cases (n = 39/65, 60%); and 3) at follow-up, SIPS converters had higher rates of resource utilization (psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS non-converters and were similar to FEP in most categories. The results suggest that the SIPS definition of psychosis onset carries substantial predictive validity. Limitations and future directions are discussed.

  • Basic symptoms in young people at ultra-high risk of psychosis: Association with clinical characteristics and outcomes
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-19
    S. Youn; L.J. Phillips; G.P. Amminger; G. Berger; E.Y.H. Chen; L. de Haan; J.A. Hartmann; I.B. Hickie; S. Lavoie; C. Markulev; P.D. McGorry; N. Mossaheb; D.H. Nieman; M. Nordentoft; A. Riecher-Rössler; M.R. Schäfer; M. Schlögelhofer; S. Smesny; B. Nelson

    There has been limited research into the predictive value of basic symptoms and their relationship with other psychopathology in patients identified using the ‘ultra high risk’ (UHR) for psychosis approach. The current study investigated whether basic symptoms, specifically cognitive disturbances (COGDIS), were associated with a greater risk of transition to psychotic disorder and persistent attenuated psychotic symptoms (APS) at medium term follow-up (mean = 3.4 years) in UHR patients, as well as with general psychopathology at baseline. The sample included 304 UHR participants (mean age = 19.12 years) involved in an international multicenter trial of omega-3 fatty acids. UHR individuals who also met the COGDIS criteria (basic symptoms risk criteria) did not have a greater risk of transition than those who met the UHR criteria alone. However, meeting COGDIS risk criteria was associated with a greater likelihood of meeting the UHR attenuated psychotic symptoms risk group (i.e., having persistent attenuated psychotic symptoms) at 12-month follow-up (odds ratio = 1.85; 95% CI = 1.03, 3.32). Greater severity of cognitive basic symptoms was also independently associated with more severe general psychopathology at study entry. The findings do not support the notion that combined risk identification approaches (UHR and basic symptoms) aid in the identification of individuals at greatest risk of psychosis, although this interpretation is limited by the modest transition to psychosis rate (13%) and the time of follow up. However, the findings indicate that basic symptoms may be a clinically useful marker of more severe general psychopathology in UHR groups and risk for persistent attenuated psychotic symptoms.

  • Negative symptoms predict high relapse rates and both predict less favorable functional outcome in first episode psychosis, independent of treatment strategy
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-19
    Lex Wunderink; Jan van Bebber; Sjoerd Sytema; Nynke Boonstra; Rob R. Meijer; Johanna T.W. Wigman

    Background In first episode psychosis (FEP) baseline negative symptoms (BNS) and relapse both predict less favorable functional outcome. Relapse-prevention is one of the most important goals of treatment. Apart from discontinuation of antipsychotics, natural causes of relapse are unexplained. We hypothesized that BNS, apart from predicting worse functional outcome, might also increase relapse risk. Methods We performed a post-hoc analysis of 7-year follow-up data of a FEP cohort (n = 103) involved in a dose-reduction/discontinuation (DR) vs. maintenance treatment (MT) trial. We examined: 1) what predicted relapse, 2) what predicted functional outcome, and 3) if BNS predicted relapse, whether MT reduced relapse rates compared to DR. After remission patients were randomly assigned to DR or MT for 18 months. Thereafter, treatment was uncontrolled. Outcomes BNS and duration of untreated psychosis (DUP) predicted relapse. Number of relapses, BNS, and treatment strategy predicted functional outcome. BNS was the strongest predictor of relapse, while number of relapses was the strongest predictor of functional outcome above BNS and treatment strategy. Overall and within MT, but not within DR, more severe BNS predicted significantly higher relapse rates. Treatment strategies did not make a difference in relapse rates, regardless of BNS severity. Interpretation BNS not only predicted worse functional outcome, but also relapses during follow-up. Since current low dose maintenance treatment strategies did not prevent relapse proneness in patients with more severe BNS, resources should be deployed to find optimal treatment strategies for this particular group of patients.

  • Using the Kano model to display the most cited authors and affiliated countries in schizophrenia research
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-18
    Chien-Ho Lin; Po-Hsin Chou; Willy Chou; Tsair-Wei Chien

    In order to improve individual research achievements (IRA), this study investigates which affiliated countries and authors earn the most cited IRAs and whether those types of articles are associated with the number of cited papers on schizophrenia from a leading journal in the field. The Kano model was used for displaying the IRAs. Clusters of medical subject headings (MeSH) were applied to explore the core concepts of a given journal. This study aimed to apply social network analysis (SNA) and an authorship-weighted scheme (AWS) to inspect the association between MeSH terms and IRA. About 2,008 abstracts published between 2012 and 2016 in the journal Schizophrenia Research were downloaded from Pubmed Central using the keyword (Schizophr Res)[Journal] on September 20, 2018. The MeSH terms were clustered by using SNA to separate the core concepts and compare the differences in bibliometric indices (i.e., h, Ag, x and author impact factor or AIF). Visual dashboards were shown on Google Maps. Results indicate that (1) the US, the UK, and Canada earn the highest x-index; (2) the top one author from the US has the highest x-index (= 5.73 with x-core at cited = 16.44 and citable = 2); (3) the article type of schizophrenic psychology shows distinctly higher frequencies than others; and (4) article types are associated with the number of cited papers. Four approaches of the Kano model, SNA, MeSH terms, and AWS can be accommodated to display IRAs, classify article types, and quantify coauthor contributions in the article byline, respectively, and applied to other scientific disciplines in the future, not just in this specific journal.

  • Can we accurately classify schizophrenia patients from healthy controls using magnetic resonance imaging and machine learning? A multi-method and multi-dataset study
    Schizophr. Res. (IF 4.569) Pub Date : 2017-12-21
    Julie L. Winterburn; Aristotle N. Voineskos; Gabriel A. Devenyi; Eric Plitman; Camilo de la Fuente-Sandoval; Nikhil Bhagwat; Ariel Graff-Guerrero; Jo Knight; M. Mallar Chakravarty

    Machine learning is a powerful tool that has previously been used to classify schizophrenia (SZ) patients from healthy controls (HC) using magnetic resonance images. Each study, however, uses different datasets, classification algorithms, and validation techniques. Here, we perform a critical appraisal of the accuracy of machine learning methodologies used in SZ/HC classifications studies by comparing three machine learning algorithms (logistic regression [LR], support vector machines [SVMs], and linear discriminant analysis [LDA]) on three independent datasets (435 subjects total) using two tissue density estimates and cortical thickness (CT). Performance is assessed using 10-fold cross-validation, as well as a held-out validation set. Classification using CT outperformed tissue densities, but there was no clear effect of dataset. LR, SVMs, and LDA each yielded the highest accuracies for a different feature set and validation paradigm, but most accuracies were between 55 and 70%, well below previously reported values. The highest accuracy achieved was 73.5% using CT data and an SVM. Taken together, these results illustrate some of the obstacles to constructing effective disease classifiers, and suggest that tissue densities and CT may not be sufficiently sensitive for SZ/HC classification given current available methodologies and sample sizes.

  • Support vector machine-based classification of first episode drug-naïve schizophrenia patients and healthy controls using structural MRI
    Schizophr. Res. (IF 4.569) Pub Date : 2017-12-06
    Yuan Xiao; Zhihan Yan; Youjin Zhao; Bo Tao; Huaiqiang Sun; Fei Li; Li Yao; Wenjing Zhang; Shah Chandan; Jieke Liu; Qiyong Gong; John A. Sweeney; Su Lui

    Although regional brain deficits have been demonstrated in schizophrenia patients by structural MRI studies, one important question that remains largely unanswered is whether the complex and subtle deficits revealed by MRI could be used as objective biomarkers to discriminate patients from healthy controls individually. To address this question, a total of 326 right-handed participants were recruited, including 163 drug-naïve first-episode schizophrenia (FES) patients and 163 demographically matched healthy controls. High-resolution anatomic data were acquired from all subjects and processed via Freesurfer software to obtain cortical thickness and surface area measurements. Subsequently, the Support Vector Machine (SVM) was used to explore the potential utility for cortical thickness and surface area measurements in the differentiation of individual patients and healthy controls. The accuracy of correct classification of patients and controls was 85.0% (specificity 87.0%, sensitivity 83.0%) for surface area and 81.8% (specificity 85.0%, sensitivity 76.9%) for cortical thickness (p < 0.001 after permutation testing). Regions contributing to classification accuracy mainly included the gray matter in default mode, central executive, salience, and visual networks. Current findings, in a sample of never-treated FES patients, suggest that the patterns of illness-related gray matter changes has potential as a biomarker for identifying structural brain alterations in individuals with schizophrenia. Future prospective studies are needed to evaluate the utility of imaging biomarkers for research and potentially for clinical purpose.

  • Individualized prediction of psychosis in subjects with an at-risk mental state
    Schizophr. Res. (IF 4.569) Pub Date : 2017-09-19
    Eleni Zarogianni; Amos J. Storkey; Stefan Borgwardt; Renata Smieskova; Erich Studerus; Anita Riecher-Rössler; Stephen M. Lawrie

    Early intervention strategies in psychosis would significantly benefit from the identification of reliable prognostic biomarkers. Pattern classification methods have shown the feasibility of an early diagnosis of psychosis onset both in clinical and familial high-risk populations. Here we were interested in replicating our previous classification findings using an independent cohort at clinical high risk for psychosis, drawn from the prospective FePsy (Fruherkennung von Psychosen) study. The same neuroanatomical-based pattern classification pipeline, consisting of a linear Support Vector Machine (SVM) and a Recursive Feature Selection (RFE) achieved 74% accuracy in predicting later onset of psychosis. The discriminative neuroanatomical pattern underlying this finding consisted of many brain areas across all four lobes and the cerebellum. These results provide proof-of-concept that the early diagnosis of psychosis is feasible using neuroanatomical-based pattern recognition.

  • Effective connectivity within a triple network brain system discriminates schizophrenia spectrum disorders from psychotic bipolar disorder at the single-subject level
    Schizophr. Res. (IF 4.569) Pub Date : 2018-02-03
    Lena Palaniyappan; Gopikrishna Deshpande; Pradyumna Lanka; D. Rangaprakash; Sarina Iwabuchi; Susan Francis; Peter F. Liddle

    Objective Schizophrenia spectrum disorders (SSD) and psychotic bipolar disorder share a number of genetic and neurobiological features, despite a divergence in clinical course and outcome trajectories. We studied the diagnostic classification potential that can be achieved on the basis of the structure and connectivity within a triple network system (the default mode, salience and central executive network) in patients with SSD and psychotic bipolar disorder. Methods Directed static connectivity and its dynamic variance was estimated among 8 nodes of the three large-scale networks. Multivariate autoregressive models of deconvolved resting state functional magnetic resonance imaging time series were obtained from 57 patients (38 with SSD and 19 with bipolar disorder and psychosis). We used 2/3 of the patients for training and validation of the classifier and the remaining 1/3 as an independent hold-out test data for performance estimation. Results A high level of discrimination between bipolar disorder with psychosis and SSD (combined balanced accuracy = 96.2%; class accuracies 100% for bipolar and 92.3% for SSD) was achieved when effective connectivity and morphometry of the triple network nodes was combined with symptom scores. Patients with SSD were discriminated from patients with bipolar disorder and psychosis as showing higher clinical severity of disorganization and higher variability in the effective connectivity between salience and executive networks. Conclusions Our results support the view that the study of network-level connectivity patterns can not only clarify the pathophysiology of SSD but also provide a measure of excellent clinical utility to identify discrete diagnostic/prognostic groups among individuals with psychosis.

  • Improving individual predictions: Machine learning approaches for detecting and attacking heterogeneity in schizophrenia (and other psychiatric diseases)
    Schizophr. Res. (IF 4.569) Pub Date : 2017-11-01
    Hugo G. Schnack

    Psychiatric diseases are very heterogeneous both in clinical manifestation and etiology. With the recent rise of using machine learning techniques to attempt to diagnose and prognose these disorders, the issue of heterogeneity becomes increasingly important. With the growing interest in personalized medicine, it becomes even more important to not only classify someone as a patient with a certain disorder, its treatment needs a more precise definition of the underlying neurobiology, since different biological origins of the same disease may require (very) different treatments. We review the possible contributions that machine learning techniques could make to explore the heterogeneous nature of psychiatric disorders with a focus on schizophrenia. First we will review how heterogeneity shows up and how machine learning, or multivariate pattern recognition methods in general, can be used to discover it. Secondly, we will discuss the possible uses of these techniques to attack heterogeneity, leading to improved predictions and understanding of the neurobiological background of the disorder.

  • Neuroanatomical heterogeneity of schizophrenia revealed by semi-supervised machine learning methods
    Schizophr. Res. (IF 4.569) Pub Date : 2017-12-21
    Nicolas Honnorat; Aoyan Dong; Eva Meisenzahl-Lechner; Nikolaos Koutsouleris; Christos Davatzikos

    Schizophrenia is associated with heterogeneous clinical symptoms and neuroanatomical alterations. In this work, we aim to disentangle the patterns of neuroanatomical alterations underlying a heterogeneous population of patients using a semi-supervised clustering method. We apply this strategy to a cohort of patients with schizophrenia of varying extends of disease duration, and we describe the neuroanatomical, demographic and clinical characteristics of the subtypes discovered. Methods We analyze the neuroanatomical heterogeneity of 157 patients diagnosed with Schizophrenia, relative to a control population of 169 subjects, using a machine learning method called CHIMERA. CHIMERA clusters the differences between patients and a demographically-matched population of healthy subjects, rather than clustering patients themselves, thereby specifically assessing disease-related neuroanatomical alterations. Voxel-Based Morphometry was conducted to visualize the neuroanatomical patterns associated with each group. The clinical presentation and the demographics of the groups were then investigated. Results Three subgroups were identified. The first two differed substantially, in that one involved predominantly temporal-thalamic-peri-Sylvian regions, whereas the other involved predominantly frontal regions and the thalamus. Both subtypes included primarily male patients. The third pattern was a mix of these two and presented milder neuroanatomic alterations and comprised a comparable number of men and women. VBM and statistical analyses suggest that these groups could correspond to different neuroanatomical dimensions of schizophrenia. Conclusion Our analysis suggests that schizophrenia presents distinct neuroanatomical variants. This variability points to the need for a dimensional neuroanatomical approach using data-driven, mathematically principled multivariate pattern analysis methods, and should be taken into account in clinical studies.

  • Infections, antibiotic treatment and the mircrobiome in relation to schizophrenia
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-16
    Amalie W. Klein-Petersen; Ole Köhler-Forsberg; Michael E. Benros

    Schizophrenia is a heterogeneous disorder with several potential pathophysiological mechanisms, including immune activation. Infections have been identified as a significant contributing risk factor for schizophrenia; this association is reviewed together with the potential impact of antibiotic treatment and alterations of the intestinal microbiota. Both infections and the treatment with antibiotics may alter the composition of the gut microbiota, causing dysbiosis, which in animal studies has been associated with alterations of behavior. Of the few studies that have been conducted on humans, some have suggested alterations in the microbial composition of individuals with schizophrenia compared to healthy controls, albeit with conflicting results. Recently, increased attention has emerged regarding potential adverse effects from antibiotics, as a number of these have been associated with an increased risk of psychotic episodes. Particularly, the fluoroquinolones have been associated with neurotoxic adverse events. The association between schizophrenia and infections, antibiotic treatment and dysbiosis, may be an epiphenomenon, which could be explained by other confounding factors. However, these associations could be causal and could therefore be important risk factors in a subgroup of patients. Large-scale well-matched longitudinal studies are needed with measurements of immune markers from multiple biological samples, ranging from material close to the brain, as cerebrospinal fluid and brain-scans targeting neuroinflammation, to analysis of blood and intestinal microbiota. This would help to obtain more definite results on the association between infections, immune components and microbiota alterations in relation to schizophrenia.

  • Characterization of a schizophrenia patient with a rare RELN deletion by combining genomic and patient-derived cell analyses
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-14
    Yuko Arioka; Akihiro Hirata; Itaru Kushima; Branko Aleksic; Daisuke Mori; Norio Ozaki

    Genetic studies have identified rare RELN variants as risk factors for psychiatric disorders. However, additional genetic factors appear to be necessary for disease onset. Detailed genetic information and the use of patient-derived neuronal cells may thus enable to discover these disease-related additional factors. Here, we performed whole-genome sequencing of a schizophrenia patient with a rare RELN deletion and his healthy mother, and examined the phenotypes of 3D-cultured neuronal cells derived from induced pluripotent stem cells of this patient. Our results revealed that, along with the RELN deletion, neuronal death was promoted in this patient; thus, neuronal death may be a vulnerable factor for schizophrenia.

  • Voice patterns in schizophrenia: A systematic review and Bayesian meta-analysis
    Schizophr. Res. (IF 4.569) Pub Date : 2019-12-13
    Alberto Parola; Arndis Simonsen; Vibeke Bliksted; Riccardo Fusaroli

    Voice atypicalities have been a characteristic feature of schizophrenia since its first definitions. They are often associated with core negative symptoms such as flat affect and alogia, and with the social impairments seen in the disorder. This suggests that voice atypicalities may represent a marker of clinical features and social functioning in schizophrenia. We systematically reviewed and meta-analyzed the evidence for distinctive acoustic patterns in schizophrenia, as well as their relation to clinical features. We identified 46 articles, including 55 studies with a total of 1254 patients with schizophrenia and 699 healthy controls. Summary effect sizes (Hedges'g and Pearson's r) estimates were calculated using multilevel Bayesian modeling. We identified weak atypicalities in pitch variability (g = −0.55) related to flat affect, and stronger atypicalities in proportion of spoken time, speech rate, and pauses (g's between −0.75 and −1.89) related to alogia and flat affect. However, the effects were mostly modest (with the important exception of pause duration) compared to perceptual and clinical judgments, and characterized by large heterogeneity between studies. Moderator analyses revealed that tasks with a more demanding cognitive and social component showed larger effects both in contrasting patients and controls and in assessing symptomatology. In conclusion, studies of acoustic patterns are a promising but, yet unsystematic avenue for establishing markers of schizophrenia. We outline recommendations towards more cumulative, open, and theory-driven research.

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上海纽约大学William Glover