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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]

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 &y& Elsevier]

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]

Abstract: 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 μg naltrexone; oxytrex bid and qid treatments provide 2 and 4 μg naltrexone/day, respectively. Following a washout, patients with pain ≥5 on a 0-10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief (≤2) or a tolerable level of side effects. Following titration, the dose was fixed for 12 weeks. Active treatment groups attained comparable analgesia despite significantly lower drug use (P = .03) by oxytrex patients. Patients taking oxytrex bid reported 55% less physical dependence than patients on oxycodone (P = .01) by the Short Opiate Withdrawal Scale 24 h after treatment cessation. Oxytrex bid patients also reported decreased moderate-to-severe constipation (by 44%, P = .01), somnolence (by 33%, P = .03), and pruritus (by 51%, P < .001). This is the first large well controlled study to show strong analgesia with minimal withdrawal symptoms and better safety compared with oxycodone. Perspective: Previous clinical data have shown ultralow-dose naltrexone enhances and prolongs oxycodone analgesia, and preclinical data also show a suppression of opioid tolerance and dependence. A cellular mechanism of action has been demonstrated to be the prevention of aberrant G protein signaling by mu opioid receptors caused by chronic opioid administration. [Copyright &y& Elsevier]