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Objective: The authors used a large clinical data set to determine which index diagnoses of schizophrenia spectrum disorder were new diagnoses., Methods: Using the Massachusetts All-Payer Claims Database (2012–2016), the authors identified patients with a schizophrenia spectrum disorder diagnosis in 2016 (index diagnosis) and then reviewed patients’ care histories for the previous 12, 24, 36, and 48 months to identify previous diagnoses. Logistic regression was used to examine patient characteristics associated with the index diagnosis being a new diagnosis., Results: Overall, 7,217 individuals ages 15–35 years had a 2016 diagnosis of schizophrenia spectrum disorder; 67.7% had at least 48 months of historical data. Among those with at least 48 months of care history, 23% had no previous diagnoses. Diagnoses from inpatient psychiatric admissions or among female or younger patients were more likely to represent new diagnoses, compared with diagnoses from most other diagnosis locations or among males or older age groups, and outpatient diagnoses were less likely to represent new diagnoses than were most other diagnosis settings. Reviewing 48 instead of 12 months of data reduced estimated rates of new diagnoses from 112 to 66 per 100,000 persons; historical diagnoses were detected for 61% and 77% of patients with 12 or 48 months of care history, respectively., Conclusions: Examining multiple years of patient history spanning all payers and providers is critical to identifying new schizophrenia spectrum disorder diagnoses in large data sets. Review of 48 months of care history resulted in lower rates of new schizophrenia spectrum disorder diagnoses than previously reported.

The high prevalence of nicotine dependence contributes to excess mortality in schizophrenia. Cue reactivity, or the encounter of drug-related cues or contexts, triggers craving, drug-seeking, and relapse. Prior functional magnetic resonance imaging (fMRI) research indicates that individuals with schizophrenia have blunted neural responses to rewarding stimuli in association with more severe negative symptoms. The objectives of this study are to determine if smokers with schizophrenia have altered neural reactivity to smoking cues compared with non-psychiatrically ill smokers and to evaluate the influence of negative symptoms on cue reactivity. Twenty smokers with schizophrenia and 19 control smokers underwent fMRI while viewing smoking-related and neutral cues. The primary analysis was group comparison of Smoking-Neutral contrast using whole-brain analysis (Pcorrected < .05). Smokers with schizophrenia had significantly greater baseline carbon monoxide levels and longer duration of smoking, suggesting more nicotine use. While both groups had greater brain reactivity to smoking vs neutral cues, smokers with schizophrenia had significantly decreased cue reactivity (Smoking-Neutral) compared to controls in bilateral frontal midline regions. There were significant negative correlations between negative symptoms and frontal midline reactivity. Despite greater nicotine use, smokers with schizophrenia exhibited decreased smoking cue-induced neural reactivity in frontal midline regions, suggesting that increased smoking and low cessation rates in schizophrenia are not primarily driven by responses to smoking-related cues. The finding of negative correlations between cue reactivity and negative symptoms is consistent with previous research demonstrating decreased neural responses to rewarding cues, particularly in patients with negative symptoms.

Background: Nicotine improves attention and processing speed in individuals with schizophrenia. Few studies have investigated the effects of nicotine on cognitive control. Prior functional magnetic resonance imaging (fMRI) research demonstrates blunted activation of dorsal anterior cingulate cortex (dACC) and rostral anterior cingulate cortex (rACC) in response to error and decreased post-error slowing in schizophrenia., Methods: Participants with schizophrenia (n = 13) and healthy controls (n = 12) participated in a randomized, placebo-controlled, crossover study of the effects of transdermal nicotine on cognitive control. For each drug condition, participants underwent fMRI while performing the stop signal task where participants attempt to inhibit prepotent responses to "go (motor activation)" signals when an occasional "stop (motor inhibition)" signal appears. Error processing was evaluated by comparing "stop error" trials (failed response inhibition) to "go" trials. Resting-state fMRI data were collected prior to the task., Results: Participants with schizophrenia had increased nicotine-induced activation of right caudate in response to errors compared to controls (DRUG × GROUP effect: p corrected  < 0.05). Both groups had significant nicotine-induced activation of dACC and rACC in response to errors. Using right caudate activation to errors as a seed for resting-state functional connectivity analysis, relative to controls, participants with schizophrenia had significantly decreased connectivity between the right caudate and dACC/bilateral dorsolateral prefrontal cortices., Conclusions: In sum, we replicated prior findings of decreased post-error slowing in schizophrenia and found that nicotine was associated with more adaptive (i.e., increased) post-error reaction time (RT). This proof-of-concept pilot study suggests a role for nicotinic agents in targeting cognitive control deficits in schizophrenia.

Schizophrenia is associated with a high prevalence of smoking. Functional connectivity between the dorsal anterior cingulate (dACC) and limbic regions including the ventral striatum, extended amygdala and parahippocampal areas has been previously implicated in the genetics and clinical severity of smoking. In this study, we test the hypothesis that dACC functional circuits are key paths for the high risk of smoking comorbidity in schizophrenia. Resting state functional magnetic resonance imaging (fMRI) was performed using the dACC as a seed region in smoking and nonsmoking patients with schizophrenia (n = 54), matched controls (n = 65), and nonpsychotic first-degree relatives (n = 24). Multiple regions had decreased connectivity with the dACC in schizophrenia patients when compared with matched controls (n = 65). Several of these functional circuits were also associated with nicotine addiction severity; the largest cluster included limbic areas such as the parahippocampal, extended amygdala, ventral striatal, and posterior insula regions, indicating an overlap of schizophrenia and nicotine addiction on to this circuit. These same functional connectivity-defined circuits were also significantly impaired in schizophrenia nonsmokers compared with control nonsmokers and in nonpsychotic first-degree relatives. Functional connectivity between the dACC and limbic regions is inherently abnormal in schizophrenia, related to its genetic liability regardless of smoking, and overlaps with a nicotine addiction-related circuit. Our findings establish a biologically defined brain circuit mechanism that contributes to the high prevalence of smoking.

Background: Systems level modeling of functional magnetic resonance imaging data has demonstrated dysfunction of several large-scale brain networks in schizophrenia. Anomalies across multiple functional networks associated with schizophrenia could be due to diffuse pathology across multiple networks or, alternatively, dysfunction at converging control(s) common to these networks. The right anterior insula has been shown to modulate activity in the central executive and default mode networks in healthy individuals. We tested the hypothesis that right anterior insula modulation of central executive and default mode networks is disrupted in schizophrenia and associated with cognitive deficits., Methods: In 44 patients with schizophrenia and 44 healthy control subjects, we used seed-based resting state functional connectivity functional magnetic resonance imaging analysis to examine connectivity between right insular subregions and central executive/default mode network regions. We also performed two directed connectivity analyses of resting state data: Granger analysis and confirmatory structural equation modeling. Between-group differences in path coefficients were used to evaluate anterior insula modulation of central executive and default mode networks. Cognitive performance was assessed with the rapid visual information processing task, a test of sustained attention., Results: With multiple connectivity techniques, we found compelling, corroborative evidence of disruption of right anterior insula modulation of central executive and default mode networks in patients with schizophrenia. The strength of right anterior insula modulation of these networks predicted cognitive performance., Conclusions: Individuals with schizophrenia have impaired right anterior insula modulation of large-scale brain networks. The right anterior insula might be an emergent pathophysiological gateway in schizophrenia., (Copyright © 2013 Society of Biological Psychiatry. All rights reserved.)

Schizophrenia (SZ) is associated with high rates of smoking. We previously found that resting state functional connectivity (rsFC) between the dorsal anterior cingulate (dACC) and striatum is independently associated with nicotine addiction and psychiatric illness. Since the insula is implicated in nicotine dependence, we hypothesized that SZ smokers will have greater dysfunction in smoking-related insular and dACC circuits than normal control smokers (NC) independent of smoking severity, consistent with an inherent disease-related weakening of smoking-related circuits. Nicotine challenge was used to demonstrate that decreased rsFC in identified circuits reflects addiction trait and is not affected by pharmacological state. Twenty-four NC smokers and 20 smokers with SZ matched on nicotine addiction severity participated in a resting state fMRI study and were scanned during two separate sessions while receiving a placebo or nicotine patch, in a randomized, cross-over design. Using individualized, anatomically defined anterior and posterior insula and dACC as regions of interest (ROI), whole brain rsFC was performed using each ROI as a seed. Significant negative correlations between smoking severity and rsFC between insula, dACC and striatum were found for both groups. Furthermore, smokers with SZ demonstrated additive reductions in circuit strength between the dACC and insula compared to NC smokers independent of smoking severity. Nicotine challenge did not significantly alter rsFC in insula-dACC-striatal circuits. Reduced rsFC strength between the insula, dACC and striatum is associated with nicotine addiction severity in both non-psychiatrically ill and in SZ smokers. Decreased insula-dACC rsFC may index overlapping circuitry associated with smoking and SZ., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Theta-alpha range oscillations have been associated with MMN in healthy controls. Our previous studies showed that theta-alpha activities are highly heritable in schizophrenia patients' families. We aimed to test the hypothesis that theta-alpha activities may contribute to MMN in schizophrenia patients and their family members., Methods: We compared MMN and single trial oscillations during MMN in 95 patients, 75 first-degree relatives, 87 controls, and 34 community subjects with schizophrenia spectrum personality (SSP) traits., Results: We found that (1) MMN was reduced in patients (p<0.001) and SSP subjects (p=0.047) but not in relatives (p=0.42); (2) there were augmented 1-20 Hz oscillations in patients (p=0.02 to <0.001) during standard and deviant stimuli; (3) theta-alpha (5-12 Hz) oscillations had the strongest correlation to MMN in controls and relatives (ΔR(2)=21.4-23.9%, all p<0.001), while delta (<5 Hz) showed the strongest correlation to MMN in schizophrenia and SSP trait subjects; and, (4) MMN (h(2)=0.56, p=0.002) and theta-alpha (h(2)=0.55, p=0.004) were heritable traits., Conclusions: Low frequency oscillations have a robust relationship with MMN and the relationship appears altered by schizophrenia; and schizophrenia patients showed augmented low frequency activities during the MMN paradigm., Significance: The results encourage investigation of low frequency oscillations to elucidate the neurophysiological pathology underlying MMN abnormalities in schizophrenia., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

There is growing recognition that neural oscillations are important in a wide range of perceptual and cognitive functions. One of the key issues in electrophysiological studies of schizophrenia is whether high or low frequency oscillations, or both, are related to schizophrenia because many brain functions are modulated with frequency specificities. Many recent electrophysiological studies of schizophrenia have focused on high frequency oscillations at gamma band and in general support gamma band dysfunction in schizophrenia. We discuss the concept that gamma oscillation abnormalities in schizophrenia often occur in the background of oscillation abnormalities of lower frequencies. The review discusses the basic neurobiology for the emergence of oscillations of all frequency bands in association with networks of inhibitory interneurons and the convergence and divergence of such mechanisms in generating high vs low frequency oscillations. We then review the literature of oscillatory frequency abnormalities identified in each frequency band in schizophrenia. By describing some of the key functional roles exerted by gamma, low frequencies, and their cross-frequency coupling, we conceptualize that even isolated alterations in gamma or low frequency oscillations may impact the interactions of high and low frequency bands that are involved in key cognitive functions. The review concludes that studying the full spectrum and the interaction of gamma and low frequency oscillations may be critical for deciphering the complex electrophysiological abnormalities observed in schizophrenia patients.

Tobacco use is the top preventable cause of early mortality in schizophrenia. Over 60% of people with schizophrenia smoke, three times the general prevalence. The biological basis of this increased risk is not understood, and existing interventions do not target schizophrenia-specific pathology. We therefore used a connectome-wide analysis to identify schizophrenia-specific circuits of nicotine addiction. We reanalyzed data from two studies: In Cohort 1, 35 smokers (18 schizophrenia, 17 control) underwent resting-state fMRI and clinical characterization. A multivariate pattern analysis of whole-connectome data was used to identify the strongest links between cigarette use and functional connectivity. In Cohort 2, 12 schizophrenia participants and 12 controls were enrolled in a randomized, controlled crossover study of nicotine patch with resting-state fMRI. We correlated change in network functional connectivity with nicotine dose. In Cohort 1, the strongest (p < 0.001) correlate between connectivity and cigarette use was driven by individual variation in default mode network (DMN) topography. In individuals with greater daily cigarette consumption, we observed a pathological expansion of the DMN territory into the identified parieto-occipital region, while in individuals with lower daily cigarette consumption, this region was external to the DMN. This effect was entirely driven by schizophrenia participants. Given the relationship between DMN topography and nicotine use we observed in Cohort 1, we sought to directly test the impact of nicotine on this network using an independent second cohort. In Cohort 2, nicotine reduced DMN connectivity in a dose-dependent manner (R = −0.50; 95% CI −0.75 to −0.12, p < 0.05). In the placebo condition, schizophrenia subjects had hyperconnectivity compared to controls (p < 0.05). Nicotine administration normalized DMN hyperconnectivity in schizophrenia. We here provide direct evidence that the biological basis of nicotine dependence is different in schizophrenia and in non-schizophrenia populations. Our results suggest the high prevalence of nicotine use in schizophrenia may be an attempt to correct a network deficit known to interfere with cognition. [ABSTRACT FROM AUTHOR]

A childhood history of attention deficit hyperactivity disorder (ADHD) is common in psychotic disorders, yet prescription stimulants may interact adversely with the physiology of these disorders. Specifically, exposure to stimulants leads to long-term increases in dopamine release. We therefore hypothesized that individuals with psychotic disorders previously exposed to prescription stimulants will have an earlier onset of psychosis. Age of onset of psychosis (AOP) was compared in individuals with and without prior exposure to prescription stimulants while controlling for potential confounding factors. In a sample of 205 patients recruited from an inpatient psychiatric unit, 40% (n = 82) reported use of stimulants prior to the onset of psychosis. Most participants were prescribed stimulants during childhood or adolescence for a diagnosis of ADHD. AOP was significantly earlier in those exposed to stimulants (20.5 vs. 24.6 years stimulants vs. no stimulants, p < 0.001). After controlling for gender, IQ, educational attainment, lifetime history of a cannabis use disorder or other drugs of abuse, and family history of a first-degree relative with psychosis, the association between stimulant exposure and earlier AOP remained significant. There was a significant gender × stimulant interaction with a greater reduction in AOP for females, whereas the smaller effect of stimulant use on AOP in males did not reach statistical significance. In conclusion, individuals with psychotic disorders exposed to prescription stimulants had an earlier onset of psychosis, and this relationship did not appear to be mediated by IQ or cannabis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Theta-alpha range oscillations have been associated with MMN in healthy controls. Our previous studies showed that theta-alpha activities are highly heritable in schizophrenia patients’ families. We aimed to test the hypothesis that theta-alpha activities may contribute to MMN in schizophrenia patients and their family members. Methods: We compared MMN and single trial oscillations during MMN in 95 patients, 75 first-degree relatives, 87 controls, and 34 community subjects with schizophrenia spectrum personality (SSP) traits. Results: We found that (1) MMN was reduced in patients (p <0.001) and SSP subjects (p =0.047) but not in relatives (p =0.42); (2) there were augmented 1–20Hz oscillations in patients (p =0.02 to <0.001) during standard and deviant stimuli; (3) theta-alpha (5–12Hz) oscillations had the strongest correlation to MMN in controls and relatives (ΔR 2 =21.4–23.9%, all p <0.001), while delta (<5Hz) showed the strongest correlation to MMN in schizophrenia and SSP trait subjects; and, (4) MMN (h 2 =0.56, p =0.002) and theta-alpha (h 2 =0.55, p =0.004) were heritable traits. Conclusions: Low frequency oscillations have a robust relationship with MMN and the relationship appears altered by schizophrenia; and schizophrenia patients showed augmented low frequency activities during the MMN paradigm. Significance: The results encourage investigation of low frequency oscillations to elucidate the neurophysiological pathology underlying MMN abnormalities in schizophrenia. [Copyright &y& Elsevier]

• Hospitalizations for psychosis/cannabis use more likely in areas where cannabis legalized. • Recreational cannabis legalization associated with greater rate of hospitalization for psychosis associated with cannabis use. • Findings warrant future longitudinal studies to evaluate psychosis in U.S. states. The 2017 National Inpatient Sample database was utilized to investigate the association between cannabis legalization in the United States and hospitalizations for psychosis associated with cannabis use. We compared the odds of hospital discharges for psychosis associated with cannabis use in adults between the Pacific census division (where most states legalized recreational cannabis use) and other divisions using multivariable logistic regression, adjusting for confounders. We calculated a score for each census division representing cannabis legality as the population-weighted sum of state scores: 1=illegal or cannabidiol/low potency cannabis; 2= medical marijuana; and 3=recreational and medical marijuana legalized. Pearson's correlation coefficients (r) quantified the relationship between scores and the proportion of hospitalizations with psychosis associated with cannabis. In 2017, there were an estimated 129,070 hospital discharges for psychosis associated with cannabis use. The Pacific census division had significantly higher odds of discharges than other divisions (adjusted odds ratio 1.55; 95% confidence interval 1.25 – 1.93). There was a significant correlation between the cannabis legality score and proportion of hospital discharges for psychosis associated with cannabis use (r = 0.67, p <0.05). In conclusion, we observed a higher proportion of hospital discharges for psychosis associated with cannabis use in areas with more liberal cannabis legalization laws. [ABSTRACT FROM AUTHOR]