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Background Treatment-resistant schizophrenia (TRS) and treatment-responsive schizophrenia may exhibit distinct pathophysiology. Several functional magnetic resonance imaging (fMRI) studies have used resting-state functional connectivity analyses (rs-FC) in TRS patients to identify markers of treatment resistance. However, to date, existing findings have not been systematically evaluated. Methods A systematic literature search using Embase, MEDLINE, PsycINFO, ProQuest, PUBMED, and Scopus was performed. The query sought fMRI articles investigating rs-FC in treatment response or resistance in patients with schizophrenia. Only studies that examined treatment response, operationalized as the explicit categorization of patients by their response to antipsychotic medication, were considered eligible. Pairwise comparisons between patient groups and controls were extracted from each study. Results The search query identified 159 records. Ten studies met inclusion criteria. Five studies examined not TRS (NTRS), and 8 studies examined TRS. Differences in rs-FC analysis methodology precluded direct comparisons between studies. However, disruptions in areas involved in visual and auditory information processing were implicated in both patients with TRS and NTRS. Changes in connectivity with sensorimotor network areas tended to appear in the context of TRS but not NTRS. Moreover, there was some indication that this connectivity could be affected by clozapine. Conclusions Functional connectivity may provide clinically meaningful biomarkers of treatment response and resistance in schizophrenia. Studies generally identified similar areas of disruption, though methodological differences largely precluded direct comparison between disruption effects. Implementing data sharing as standard practice will allow future reviews and meta-analyses to identify rs-FC correlates of TRS.

Background Obesity is up to 4 times higher in patients with schizophrenia than in the general population. However, the link between obesity and schizophrenia in the absence of antipsychotic use is unclear. Therefore, we aimed to examine differences in obesity measures (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) in antipsychotic-naive and minimally treated (up to 2 weeks of lifetime antipsychotic exposure) patients with psychosis compared to healthy controls (HCs). Methods A systematic search was conducted using Ovid Medline®, PsycINFO, and Embase. Standardized mean differences (SMDs) in obesity measures between groups were calculated. Separate sensitivity analyses were performed to examine the effects of age, sex, and ethnicity; antipsychotic exposure; and schizophrenia-related psychosis on SMDs. Results A total of 23 studies were included in the meta-analysis (BMI = 23, WC = 9, WHR = 5). BMI was lower (SMD = −0.19, 95% CI = −0.34 to −0.05, P = 0.009) and WHR was elevated (SMD = 0.34, 95% CI = 0.14 to 0.55, P = 0.001) in patients. These differences remained after analyses were restricted to patients matched with HCs for age, sex, and ethnicity; to antipsychotic-naive patients; and to patients with schizophrenia-related diagnoses. Conclusions Differences in BMI and WHR were observed in never and minimally treated patients with psychosis compared to HCs. Future research is warranted to understand these alterations in the context of body fat biomarkers and neuropathology of psychiatric disorders, independent of the effects of antipsychotics.

Childhood trauma in schizophrenia (SCZ) is associated with aberrant neurobiological downstream effects and cognitive deficits that markedly hinder patient outcome and functioning. However, the relationship between specific forms of childhood abuse and the tendency for certain personality traits in patients with SCZ has not been comprehensively studied yet. We recruited 374 SCZ patients and screened for history of physical abuse (PA), emotional abuse (EA), sexual abuse (SA), physical neglect (PN) and emotional neglect (EN) using the Childhood Trauma Questionnaire and measured personality traits using the NEO Five-Factor inventory. Using CTQ cut-off scores, the prevalence of EA, PA, SA, EN and PN was 60.7%, 42.0%, 37.7%, 64.2% and 54.3% respectively. Exposure to any form of childhood abuse was associated with increased neuroticism. Exposure to EA, SA, PN and EN was correlated with decreased agreeableness and conscientiousness scores. PN, EN and PA exposure was associated with decreased openness while EA, PN and EN exposure was associated with decreased extraversion. Furthermore, a positive correlation was found between all forms of childhood abuse and trait neuroticism whereas negative correlations were found between certain forms of childhood abuse and all other personality traits. Exposure to specific forms of childhood abuse was associated with specific personality traits in patients with SCZ.

Background No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia.

Background Recent developments in neuroimaging have advanced the understanding of biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear. Methods Systematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapine's efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT). Results 25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest that hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus. Conclusion Existing literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapine's efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging.

Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions.Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight-Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses.As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC).Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample.

Impaired insight into illness is a common but poorly understood phenomenon in schizophrenia. Several studies in midlife adults with schizophrenia have reported an association between impaired insight and illness severity, executive dysfunction, premorbid intellectual function, and to a lesser degree attention. Aging is associated with a decline in attention and executive function. Thus, the relationship between cognition and insight is expected to differ between younger and older adults with schizophrenia. This study assessed this relationship among 50 patients with schizophrenia 60 years and older. Insight was explained by illness severity (16.2% of the variance) and premorbid intellectual function (23.9% of the variance), but not by attention or executive function. Our findings suggest that the predictors of insight in schizophrenia differ early and later in life. In particular, insight's association with attention and executive function observed in younger patients is attenuated by age-related changes in cognition. In contrast, premorbid intellectual function continues to be a strong predictor of insight in late life, which highlights the need to better understand and enhance cognitive function early in the course of schizophrenia.

Emotionally driven violence is facilitated by increased arousal. It may be a consequence of an information-processing deficit and the cognitive attributions for the stimuli given by the subject. The aim of this study was to compare the P50 evoked potential responses of violent patients with schizophrenia with non-violent patients with schizophrenia and healthy controls.Patients were classified into violent and non-violent in accordance to the Overt Aggression Scale. P50 auditory evoked potentials of 32 unmedicated patients with schizophrenia (violent=14, non-violent=18) and 17 healthy controls were recorded during five runs of 30 click pairs.Healthy controls exhibited a lower S2/S1 ratio when compared to violent (p0.001) and non-violent (p=0.04) patients. Using a cutoff point of 0.50 for S2/S1 ratio to define abnormal gating a significant proportion of violent patients did not show P50 suppression (71.4%) in comparison to non-violent patients (38.9%) and healthy controls (23.5%) (p=0.02).Violent behavior in patients with schizophrenia could be associated with a disturbed information sensory gating. Violence in patients with schizophrenia may be facilitated by an increased arousal which may in turn be the result of an information-processing deficit.

No study has examined dopamine D₂/₃ receptor (D₂/₃R) availability in antipsychotic-free older patients with schizophrenia.We included patients with schizophrenia 50 years or older who were antipsychotic-free for at least 3 months. We compared non-displaceable binding potential (BPND) of [(11)C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls.Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=.42, p=.52).The preliminary results suggest no differences in D₂/₃R availability between antipsychotic-free older patients with schizophrenia and controls.

Background Movement disorders are common in individuals with schizophrenia, even in those who are not exposed to antipsychotic medications. Extrapyramidal symptoms (EPS) are among the most common abnormal movements in schizophrenia, but their relationship with other features of the illness such as cognition is not well characterized. Methods Three hundred and twenty-five individuals with schizophrenia who were not receiving any antipsychotic or anticholinergic medication and participated in the baseline visit of the Clinical Antipsychotic Treatment of Intervention Effectiveness study were included in the present study. EPSs were assessed using the Simpson-Angus Scale, while cognition was measured with a comprehensive neuropsychological test battery. The relationship between EPS and cognitive test performance was evaluated both dimensionally and categorically. Results Greater severity of EPS was significantly associated with worse cognitive test performance evaluated using a composite score. Eighty-six patients were identified as having parkinsonism and these patients performed worse on cognitive tests than non-parkinsonian patients. These findings remained significant even after accounting for other variables such as severity of psychopathology, sedation, akathisia and dyskinesia. Conclusions The present results demonstrate that severity of EPS is reliably linked with poorer scores on tests of cognition. While this may reflect a common pathophysiology underlying neuromotor and neurocognitive deficits, it may also be the case that parkinsonian symptoms such as rigidity and bradykinesia impede test taking ability. Regardless of mechanism, inferences regarding cognitive impairment should take into account the presence of EPS, as well as other variables that may mediate cognitive test findings.

Diffusion tensor imaging (DTI) studies in patients with schizophrenia have shown abnormalities in the microstructure of white matter tracts. Specifically, reduced fractional anisotropy (FA) has been described across multiple white matter tracts, in studies that have mainly included patients treated with antipsychotic medications.To compare FA in antipsychotic-naïve patients experiencing a first episode of psychosis (FEP) to FA in healthy controls to demonstrate that the variance of FA can be grouped, in a coincidental manner, in four predetermined factors in accordance with a theoretical partition of the white matter tracts, using a principal components analysis (PCA).Thirty-five antipsychotic-naïve FEP patients and 35 age- and gender-matched healthy controls underwent DTI at 3T. Analysis was performed using a tract-based spatial statistics (TBSS) method and exploratory PCA.DTI analysis showed extensive FA reduction in white matter tracts in FEP patients compared with the control group. The PCA grouped the white matter tracts into four factors explaining 66% of the total variance. Comparison of the FA values within each factor highlighted the differences between FEP patients and controls.Our study confirms extensive white matter tracts anomalies in patients with schizophrenia, more specifically, in drug-naïve FEP patients. The results also indicate that a small number of white matter tracts share common FA anomalies that relate to deficit symptoms in FEP patients. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in FEP patients.

Background There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. Method A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. Results Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000 mg/day for ≥ 6 weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. Conclusion Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response.

Background While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D 2 receptor density over 6–24 months, no study has examined the long-term stability of D 2 receptor measures in medicated patients. Methods Four schizophrenia patients receiving a stable dose of risperidone underwent [ 11 C]raclopride positron emission tomography scans on two occasions 5–14 months apart. Results Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D 2 binding potential and D 2 occupancy were good. Conclusions The finding supports the validity of quantification of D 2 receptor binding in longitudinal PET studies of medicated patients with schizophrenia.