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Adherence to antipsychotic medication is critical for the treatment of patients with schizophrenia. Impaired insight into illness is one of the principal drivers of medication nonadherence, which contributes to negative clinical outcomes. The aims of this study were to examine the relationships between impaired insight and (1) rates of antipsychotic medication nonadherence, and (2) time to medication nonadherence using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Insight was assessed using the Positive and Negative Syndrome Scale (PANSS) item G12 (lack of judgment and insight). Patients were divided into 3 groups based on their degree of insight impairment, i.e. no impairment (PANSS G12 = 1), minimal impairment (PANSS G12 = 2-3), and moderate-to-severe insight impairment (PANSS G12 ≥ 4). Medication nonadherence was defined as taking less than 80% of monthly pill counts. Kaplan-Meier survival and Cox regression analyses were performed to examine differences in time to medication nonadherence between insight groups. There were significant differences between insight groups in the percentage of nonadherent patients at 6 months (χ 2 (2) = 8.80, p = 0.012) and 18 months (χ 2 (2) = 10.04, p = 0.007) after study initiation. Moderate-to-severe insight impairment was associated with earlier nonadherence compared to minimal (χ 2  = 4.70, p = 0.030) or no impairment (χ 2  = 11.92, p = 0.001). The association remained significant after adjustment for illness severity, substance use, attitudes toward medication, cognition, level of hostility, and depression. The results of this study indicate a strong link between impaired insight and antipsychotic medication nonadherence. Interventions to enhance insight early during treatment may help improve medication adherence, and in turn, long-term clinical and functional outcomes in patients with schizophrenia. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Widespread structrual abnormalities in subcortical brain regions have been identified in patients with schizophrenia. However, only a few studies have examined the neuroanatomical profiles of patients with treatment-resistant schizophrenia. The aim of this study was to compare differences in subcortical and hippocampal volumes between: (i) treatment-resistant patients who are non-responders to both first-line antipsychotics and clozapine (URS), (ii) treatment-resistant patients who are non-responders to first-line antipsychotics but are responders to clozapine (CLZ-Resp), (iii) responders to first-line antipsychotics (FL-Resp), and (iv) healthy controls. T1-weighted images of 103 participants (27 URS, 29 CLZ-Resp, 21 FL-Resp, and 26 healthy controls) were obtained. Group differences in striatal, thalamic, globus pallidus, amygdala, and hippocampus volumes were examined. Multiple regression analyses were performed to examine the associations between subcortical and hippocampal volumes and participant characteristics. The FL-Resp group showed larger striatal and globus pallidus volumes compared to the URS group and larger post-commissural putamen and globus pallidus volumes compared to healthy controls. The URS group showed smaller thalamic volume compared to healthy controls. There were no subcortical or hippocampal volume differences between the URS and CLZ-Resp groups. Differences in subcortical and hippocampal structural volumes were not related to symptom severity or chlorpromazine antipsychotic dose equivalents. Our findings suggest different structural volume alterations in subcortical brain regions between treatment-resistant schizophrenia and responders to first-line antipsychotics. Whether subcortical structure compromise is a distinct pathophysiological marker of treatment-resistant schizophrenia, or a result of antipsychotic exposure, remains to be explored., Competing Interests: Declaration of Competing Interest J.K. has received funding from the CAMH Foundation and the Ontario Graduate Scholarship (OGS). E.P. has received funding from the Healthy Brains for Healthy Lives Postdoctoral Fellowship, the Vanier Canada Graduate Scholarship, the OGS, and the Canada Graduate Scholarship – Master's. Y.I. has received fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. S.N. has received fellowship grants from the Canadian Institutes of Health Research (CIHR), research support from Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past 3 years. He has also received research support, manuscript fees, or speaker's honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past 3 years. J.K.C. has received funding from the CIHR Doctoral Award and the Canada Graduate Scholarship – Master's. F.C. has received funding from CIHR, the Ontario Mental Health Post-Doctoral Fellowship Award, CAMH Foundation, the Brain & Behavior Research Foundation (Formerly NARSAD), and the Vancouver Coastal Health Research Institute. G.R. has received consultant fees from Neurocrine Biosciences and Synchroneuron, as well as research support from Novartis. P.G. reports receiving research support from CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and CAMH. A.G.-G. has received support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen. All other authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cognitive biases may contribute to the formation and maintenance of positive symptoms in patients with schizophrenia. However, cognitive reflection (i.e., the ability to use analytical thinking to override intuitive responses) has not been explicitly examined in schizophrenia patients using the cognitive reflection test (CRT). Using the CRT, we examined the degree of analytical and intuitive reasoning employed during problem solving in patients with schizophrenia versus healthy controls. Fifty-eight outpatients with schizophrenia and fifty-eight age- and sex-matched healthy controls (18-35 years of age) participated in this study. In addition to CRT performance, neurocognition, apathy, impulsivity, depression, insight, and clinical symptoms were evaluated. Patients with schizophrenia produced significantly fewer analytical responses (U = 1167.00, p<0.05) and more intuitive responses (U = 1273.50, p<0.05) compared to healthy controls. Patients without significant cognitive impairment also produced fewer analytical responses compared to controls (U = 894.50, p<0.05). Among patients, analytical thinking was positively correlated with working memory (r = 0.27, p<0.05), and affective symptoms (r = 0.31, p<0.05). Analytical reasoning was not significantly correlated with positive symptoms, avolition, or impulsivity. Patients with schizophrenia demonstrate less analytical and more intuitive reasoning while problem solving compared to healthy controls. This reduction in cognitive reflection is not significantly explained by global cognitive impairment or motivational deficits., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in relation to the current investigation., (Copyright © 2019. Published by Elsevier B.V.)

Background: The relationship between dopamine D 2 receptor (D 2 R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses., Aim and Methods: We investigated the influence of estimated D 2 R (Est.D 2 R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18-62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D 2 R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D 2 R., Results: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D 2 R did not predict IIA, and Est.D 2 R did not serve either a moderating or mediating role in both regression and path analyses., Conclusions: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D 2 R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity., (Copyright © 2018. Published by Elsevier Inc.)

Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine-the only antipsychotic with an indication for TR-SCZ-is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline ® database to identify English language publications exploring the impact of delay in clozapine initiation on treatment outcomes in patients with TR-SCZ. Additionally, clinico-demographic factors associated with clozapine delay were examined. Our search identified four retrospective studies that showed an association between longer delay in clozapine initiation and poorer treatment outcomes, even after including covariates, such as age, sex, and duration of illness. In addition, we found six studies that showed an association between age and clozapine delay, but results with regard to other clinico-demographic variables were inconsistent. Overall, the available literature reveals a possible link between delay in clozapine use and poorer treatment outcomes in patients with TR-SCZ. However, given the relatively small number of studies on this clinically important topic, future research is warranted to draw more definitive conclusions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D 2/3 receptor (D 2/3 R) blockade by antipsychotics., Methods: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D 2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate., Results: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: β = -.38, t = -2.48, P = .01; left: β = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (β = -.43, t = -0.26, P = .03)., Conclusion: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D 2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Patients with schizophrenia (SCZ) tend to sample less information when making a decision, jumping to conclusions (JTC) without sufficient evidence. This "JTC bias" may be a trait marker of the disease and may not improve with antipsychotic treatment. We conducted a double-blind, placebo-controlled trial to test whether intranasal oxytocin could reduce JTC in stable, medicated patients with SCZ and healthy controls (HCs). We also explored whether striatal volume, clinical symptoms, and baseline social functioning (SF) was related to JTC performance., Methods: Forty-three male, medicated SCZ patients (Mean Age: 40.81±11.44) and sixteen HCs (Mean Age: 30.38±9.85) participated in a double-blind, placebo-controlled, cross-over study. Participants completed the Beads Task on two separate visits (minimum 20days apart). Participants were randomized to receive either intranasal oxytocin (50IU in solution) or intranasal placebo (saline). Twenty of the SCZ patients and all sixteen HCs also provided T1 MRIs (3-T)., Results: Patients with SCZ took fewer draws to decision (DTD) than HCs (t(57)=2.78, p=0.007). Oxytocin did not significantly change DTD in patients (t(42)=-1.11, p=0.27), nor in HCs (t(15)=-0.62, p=0.55). Exploratory analyses found ventral caudate volumes were negatively correlated with DTD (r(18)=-0.50, p=0.03) in patients. Moreover, oxytocin was more likely to improve JTC in patients with lower baseline SF. However, these exploratory findings did not survive correction for multiple comparisons., Conclusions: We replicate increased JTC in SCZ. However, acute intranasal oxytocin did not modify JTC. Future studies with larger samples should explore how brain morphology and SF are related to JTC performance in patients with SCZ., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rationale: Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial., Objective: The objective of this study was to examine the relationship between antipsychotic-related dopamine D 2/3 receptor occupancy and negative symptoms in patients with schizophrenia., Methods: Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [ 11 C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose., Results: No significant relationship was found between antipsychotic-related dopamine D 2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship., Conclusions: Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

Current literature suggests that the pathology of schizophrenia (SCZ) has developmental origins. However, the neurodevelopmental theory of SCZ cannot solely explain progressive neurodegenerative processes in the illness. There is evidence of accelerated cognitive decline and increased risk of dementia in elderly patients with SCZ. Investigating β-amyloid (Aβ), we conducted a systematic review focusing on Aβ in patients with SCZ. An OVID literature search using PsychINFO, Medline, and Embase databases was conducted, looking for studies that compared Aβ levels between patients with SCZ and either elderly control subjects, patients with Alzheimer disease (AD), or patients with other psychiatric illnesses. Among 14 identified studies, 11 compared Aβ between SCZ and elderly control subjects, 7 between SCZ and AD, and 3 between SCZ and other psychiatric illnesses. As a result, no evidence was found suggesting that Aβ levels differ in patients with SCZ from elderly control subjects or patients with other psychiatric illnesses. All seven studies reported lower cortical Aβ in patients with SCZ than patients with AD. Furthermore, three of the four studies, which investigated the relationship between Aβ and cognitive impairment in SCZ, observed no association between two factors. The limitations of the included studies are small sample sizes, the inclusion of cerebrospinal fluid Aβ or postmortem plaques rather than cortical Aβ assessment in vivo, and the investigation of different brain regions. In conclusion, Aβ deposition is not associated with cognitive decline in late-life SCZ. Future studies should investigate other neurodegenerative indicators in SCZ to better understand the pathophysiologic mechanisms underlying this illness., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to develop self-report and clinician-rated versions of an insight scale that would be easy to administer, sensitive to small changes, and inclusive of the core dimensions of clinical insight into psychosis. Ten-item self-report (VAGUS-SR) and five-item clinician-rated (VAGUS-CR) scales were designed to measure the dimensions of insight into psychosis and evaluated in 215 and 140 participants, respectively (www.vagusonline.com). Tests of reliability and validity were performed. Both the VAGUS-SR and VAGUS-CR showed good internal consistency and reliability. They demonstrated good convergent and discriminant validity. Both versions were strongly correlated with one another and with the Schedule for the Assessment of Insight and Birchwood Insight Scale. Exploratory factor analyses identified three possible latent components of insight. The VAGUS-CR and VAGUS-SR are valid, reliable and easy to administer. They are build on previous insight scales with separate clinician-rated and self-report versions. The VAGUS-SR exhibited a multidimensional factor structure. Using a 10-point Likert scale for each item, the VAGUS has the capacity to detect small, temporally sensitive changes in insight, which is essential for intervention studies with neurostimulation or rapidly acting medications., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)