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Background and Hypothesis: The onset of schizophrenia occurs after the age of 40 in up to 20% of cases. We aim to depict risk factors for first-episode psychosis after the age of 40 by comparing late-onset psychosis (LOP) patients to healthy age-matched controls., Study Design: In this case-control study using electronic health records, 142 individuals aged 40-65 years with an encounter for a first episode of psychosis between 2013 and 2021 were included. Four controls (N = 568) were matched to each case on age, sex, race, and year of encounter. Potential risk factors for the primary analysis were captured via structured data and text-mining of medical notes. Conditional logistic regression models were used to assess the odds of LOP with potential risk factors., Study Results: After adjusting for all variables in the main analysis, odds for LOP were increased by immigration (OR 3.30, 95% CI, 1.56-6.98), depression (OR 3.58, 95% CI, 2.01-6.38), anxiety (OR 2.12, 95% CI, 1.20-3.75), cannabis use (OR 3.00, 95% CI, 1.36-6.61), alcohol use disorder (OR 5.46, 95% CI, 2.41-12.36), polysubstance use (OR 4.22, 95% CI, 1.30-13.7), severe trauma (OR 2.29, 95% CI, 1.08-4.48), and caregiver burden (OR 15.26, 95% CI, 3.85-60.48)., Conclusions: Life stressors along with the effects of substance use and other psychiatric conditions may confer some risk to the development of LOP. Replication is required in independent prospective studies. Further research is necessary to truly parse out which of these factors belong on the causal pathway., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome., Methods: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16-35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use., Results: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90-3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54-1.55)., Conclusions: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania., Competing Interests: Dr. Moran is employed by Sage Therapeutics. Dr. Perlis has served as a scientific adviser for Alkermes, Belle Artificial Intelligence, Burrage Capital, Circular Genomics, Genomind, Mila Health, Psy Therapeutics, Swan AI Studios, and Vault Health. Dr. Ongur has received honoraria from Boehringer Ingelheim, Guggenheim LLC, and Neumora for scientific presentations. The other authors report no financial relationships with commercial interests.

Background: Lower socioeconomic status is known to be associated with high mental health burden, there have been few epidemiological studies showing how socioeconomic status has modified the effect of COVID-19 on anxiety and depression., Methods: We analyzed data from the National Health Interview Survey in the United States between 2019 and 2021 and used respondents with a documented income-to-poverty ratio as a measure of income level (n = 79,468). We used frequency of medication use and self-reported frequency of anxious and depressive episodes as the main outcome measures. We performed a multivariable logistic regression with a two-way interaction term between income and survey year., Results: We found a statistically significant worsening of depression and anxiety metrics in respondents with higher income levels from 2019 to 2021. We did not observe a significant change in anxiety and depression metrics for low-income respondents over the same period., Limitations: The data from the NHIS survey is limited primarily by sampling bias (response rate of 50.7 % in 2021), as well as the self-reported nature of the one of the outcome measures., Conclusion: These findings suggest that, within the limits of the National Health Interview Survey, mental health outcomes were worse but stable in a socioeconomically disadvantaged demographic between 2019 and 2021. In a higher socioeconomic bracket, mental health outcomes were less severe than the disadvantaged demographic but were worsening at a greater rate., Competing Interests: Declaration of competing interest QDT reports personal fees from Astellas, Bayer, and Janssen, outside the submitted work. QDT reports research funding from the American Cancer Society, the Defense Health Agency, and Pfizer Global Medical Grants., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: I am funded by the National Institute of Mental Health R01MH122427.

COVID-19 can affect physical and mental health long after acute infection. In this descriptive study, 48 individuals hospitalized for COVID-19 between April and May 2020 were interviewed regarding their experience with COVID-19 after hospitalization. The mean age of participants was 51.1 (±11.91) years (range 25-65 years) and 26 (54.2%) were men. Individuals had a mean of 1.2 (±0.94) comorbidities associated with more severe COVID-19, with hypertension (37.5%) being most common. Nineteen (39.6%) individuals required treatment in the intensive care unit. Participants were interviewed a median time of 553 days (IQR, 405.5-589.0) after discharge from the hospital. Thirty-seven (77.1%) individuals had 5 or more persistent symptoms at time of interview with only 3 (6.3%) experiencing none. The most reported persistent symptoms were fatigue (79.2%), difficulty breathing (68.8%), and muscle weakness (60.4%). Poor quality of life was experienced by 39 (81.3%) participants and 8 (16.7%) had a posttraumatic stress disorder (PTSD) score within the clinical range for diagnosis. For multivariable analyses, persistent fatigue was significantly predicted by number of symptoms during acute COVID-19 (t = 4.4, p < 0.001). Number of symptoms during acute COVID-19 was also significantly associated with persistent dyspnea (t = 3.4, p = 0.002). Higher scores on the Chalder fatigue scale after COVID-19 was significantly associated with poor quality of life (t = 2.6, p = 0.01) and PTSD symptomatology (t = 2.9, p = 0.008). More research is needed to highlight the wide range of resources those suffering from Long COVID require long after discharge., (© 2023 Wiley Periodicals LLC.)

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 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: AJ is a consultant for Axial Biotherapeutics for activities unrelated to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ward, Beermann, Nawaz, Halko, Janes, Moran and Brady.)

Background: Nicotine-dependent individuals have altered activity in neurocognitive networks such as the default mode (DMN), salience (SN) and central executive networks (CEN). One theory suggests that, among chronic tobacco smokers, nicotine abstinence drives more DMN-related internal processing while nicotine replacement suppresses DMN and enhances SN and CEN. Whether acute nicotine impacts network dynamics in non-smokers is, however, unknown., Methods: In a randomized double-blind crossover study, 17 healthy non-smokers (8 females) were administered placebo and nicotine (2-mg lozenge) on two different days prior to collecting resting-state functional magnetic resonance imaging (fMRI). Previously defined brain states in 462 individuals that spatially overlap with well-characterized resting-state networks including the DMN, SN, and CEN were applied to compute state-specific dynamics at rest: total time spent in state, persistence in each state after entry, and frequency of state transitions. We examined whether nicotine acutely alters these resting-state dynamics., Results: A significant drug-by-state interaction emerged; post-hoc analyses clarified that, relative to placebo, nicotine suppressed time spent in a frontoinsular-DMN state (posterior cingulate cortex, medial prefrontal cortex, anterior insula, striatum and orbitofrontal cortex) and enhanced time spent in a SN state (anterior cingulate cortex and insula). No significant findings were observed for persistence and frequency., Conclusions: In non-smokers, nicotine biases resting-state brain function away from the frontoinsular-DMN and toward the SN, which may reduce internally focused cognition and enhance salience processing. While past work suggests nicotine impacts DMN activity, the current work shows nicotinic influences on a specific DMN-like network that has been linked with rumination and depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nicotine enhances the reinforcement of non-drug rewards by increasing nucleus accumbens (NAcc) reactivity to anticipatory cues. This anticipatory effect is selective as no clear evidence has emerged showing that nicotine acutely changes reward receipt reactivity. However, repeated rewarding experiences shift peak brain reactivity from hedonic reward outcome to the motivational anticipatory cue yielding more habitual cue-induced behavior. Given nicotine's influence on NAcc reactivity and connectivity, it is plausible that nicotine acutely induces this shift and alters NAcc functional connectivity during reward processing. To evaluate this currently untested hypothesis, a randomized crossover design was used in which healthy non-smokers were administered placebo and nicotine (2-mg lozenge). Brain activation to monetary reward anticipation and outcome was evaluated with functional magnetic resonance imaging. Relative to placebo, nicotine induced more NAcc reactivity to reward anticipation. Greater NAcc activation during anticipation was significantly associated with lower NAcc activation to outcome. During outcome, nicotine reduced NAcc functional connectivity with cortical regions including the anterior cingulate cortex, orbitofrontal cortex, and insula. These regions showed the same negative relationship between reward anticipation and outcome as noted in the NAcc. The current findings significantly improve our understanding of how nicotine changes corticostriatal circuit function and communication during distinct phases of reward processing and critically show that these alterations happen acutely following a single dose. The implications of this work explain nicotinic modulation of general reward function, which offer insights into the initial drive to smoke and the subsequent difficulty in cessation.

Background: The prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit-hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied., Methods: We used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. The outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases., Results: We assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09)., Conclusions: Among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. (Funded by the National Institute of Mental Health and others.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Women experience greater difficulty quitting smoking than men, which may be explained by sex differences in brain circuitry underlying cognitive control. Prior work has linked reduced interhemispheric executive control network (ECN) coupling with poor executive function, shorter time to relapse, and greater substance use. Lower structural connectivity between a key ECN hub, the dorsolateral prefrontal cortex (DLPFC), and the dorsal striatum (DS) also contributes to less efficient cognitive control recruitment, and reduced intrahemispheric connectivity between these regions has been associated with smoking relapse. Therefore, sex differences were probed by evaluating interhemispheric ECN and intrahemispheric DLPFC-DS connectivity. To assess the potential sex by nicotine interaction, a pilot sample of non-smokers was evaluated following acute nicotine and placebo administration., Methods: Thirty-five smokers (19 women) completed one resting state functional magnetic resonance imaging scan. Seventeen non-smokers (8 women) were scanned twice using a repeated measures design where they received 2 and 0 mg nicotine., Results: In smokers, women had less interhemispheric ECN and DLPFC-DS coupling than men. In non-smokers, there was a drug x sex interaction where women, relative to men, had weaker ECN coupling following nicotine but not placebo administration., Conclusions: The current work indicates that nicotine-dependent women, versus men, have weaker connectivity in brain networks critically implicated in cognitive control. How these connectivity differences contribute to the behavioral aspects of smoking requires more testing. However, building on the literature, it is likely these deficits in functional connectivity contribute to the lower abstinence rates noted in women relative to men., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Smoking is associated with significant morbidity and mortality. Understanding the neurobiology of the rewarding effects of nicotine promises to aid treatment development for nicotine dependence. Through its actions on mesolimbic dopaminergic systems, nicotine engenders enhanced responses to drug-related cues signaling rewards, a mechanism hypothesized to underlie the development and maintenance of nicotine addiction., Methods: We evaluated the effects of acute nicotine on neural responses to anticipatory cues signaling (nondrug) monetary reward or loss among 11 nonsmokers who had no prior history of tobacco smoking. In a double-blind, crossover design, participants completed study procedures while wearing nicotine or placebo patches at least 1 week apart. In each drug condition, participants underwent functional magnetic resonance imaging while performing the monetary incentive delay task and performed a probabilistic monetary reward task, probing reward responsiveness as measured by response bias toward a more frequently rewarded stimulus., Results: Nicotine administration was associated with enhanced activation, compared with placebo, of right fronto-anterior insular cortex and striatal regions in response to cues predicting possible rewards or losses and to dorsal anterior cingulate for rewards. Response bias toward rewarded stimuli correlated positively with insular activation to anticipatory cues., Conclusion: Nicotinic enhancement of monetary reward-related brain activation in the insula and striatum in nonsmokers dissociated acute effects of nicotine from effects on reward processing due to chronic smoking. Reward responsiveness predicted a greater nicotinic effect on insular activation to salient stimuli., Implications: Previous research demonstrates that nicotine enhances anticipatory responses to rewards in regions targeted by midbrain dopaminergic systems. The current study provides evidence that nicotine also enhances responses to rewards and losses in the anterior insula. A previous study found enhanced insular activation to rewards and losses in smokers and ex-smokers, a finding that could be due to nicotine sensitization or factors related to current or past smoking. Our finding of enhanced anterior insula response after acute administration of nicotine in nonsmokers provides support for nicotine-induced sensitization of insular response to rewards and losses.

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.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

Introduction: Nicotinic acetylcholine receptors are present in the cerebral white matter (WM). We hypothesized that WM response to nicotine can be detected by diffusion tensor imaging (DTI); and that such responses may be associated with nicotine-led cognitive enhancement in sustained attention., Methods: A randomized, nicotine-placebo patch, crossover, double-blind clinical trial in two non-overlapping cohorts of smokers was used to test the hypothesis. The discovery cohort consisted of 39 subjects (N = 20/19 controls/schizophrenic patients, age = 36.8 ± 10.1 years) and the replication cohorts consisted of 38 healthy smokers (31.7 ± 10.5 years). WM integrity was measured by fractional anisotropy (FA) values for the whole brain and nine preselected WM tracts using tract-based-spatial-statistics., Results: Nicotine significantly enhanced FA values for the genu of corpus callosum compared with placebo (ΔFAgenu) (p = 0.01) in smokers with low recent smoking exposure as measured by low average cotinine level. This finding was replicated in the second cohort (p = 0.02). ΔFAgenu values explained 22% of variance in performance of a sustained attention task during the nicotine session (p = 0.006). However, this effect was limited to schizophrenia patients (r = 0.62 and 0.09; p = 0.003 and 0.7 for patients and controls, respectively)., Conclusion: Acute pharmacological influence of nicotine patch on WM integrity appeared present, but was dependent on nicotine intake from recent smoking. Change in the WM integrity in the genu of corpus callosum was associated with a significant proportion of variability of nicotine-led changes in sustained attention/working memory of the smokers. Further studies will be necessary to understand biophysical underpinning of the nicotine-related changes in FA.

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.

Unlabelled: Physical dependence or withdrawal is an expected effect of prolonged opioid therapy. Oxytrex (oxycodone + ultralow-dose naltrexone) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing. In this 719-patient, double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid. Each oxytrex tablet contains 1 microg naltrexone; oxytrex bid and qid treatments provide 2 and 4 microg naltrexone/day, respectively. Following a washout, patients with pain >or=5 on a 0-10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief (