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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: Voice hearing (VH) is a transdiagnostic experience that is common in trauma-related disorders. However, the neural substrates that underlie trauma-related VH remain largely unexplored. While auditory perceptual dysfunction is among the abnormalities implicated in VH in schizophrenia, whether VH in trauma-related disorders also involves auditory perceptual alterations is unknown., Methods: We investigated auditory cortex (AC)-related functional connectivity (FC) in 65 women with trauma-related disorders stemming from childhood abuse with varying severities of VH. Using a novel, computationally driven and individual-specific method of functionally parcellating the brain, we calculated the FC of 2 distinct AC subregions-Heschl's gyrus (corresponding to the primary AC) and lateral superior temporal gyrus (in the nonprimary AC)-with both the cerebrum and cerebellum. Then, we measured the association between VH severity and FC using leave-one-out cross-validation in the cerebrum and voxelwise multiple regression analyses in the cerebellum., Results: We found that VH severity was positively correlated with left lateral superior temporal gyrus-frontoparietal network FC, while it was negatively correlated with FC between the left lateral superior temporal gyrus and both cerebral and cerebellar representations of the default mode network. VH severity was not predicted by FC of the left Heschl's gyrus or right AC subregions., Conclusions: Our findings point to altered interactions between auditory perceptual processing and higher-level processes related to self-reference and executive functioning. This is the first study to show alterations in auditory cortical connectivity in trauma-related VH. While VH in trauma-related disorders appears to be mediated by brain networks that are also implicated in VH in schizophrenia, the results suggest a unique mechanism that could distinguish VH in trauma-related disorders., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Individuals with schizophrenia (SZ) and auditory hallucinations (AHs) display a distorted sense of self and self-other boundaries. Alterations of activity in midline cortical structures such as the prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) during self-reference as well as in the superior temporal gyrus (STG) have been proposed as neuromarkers of SZ and AHs., Methods: In this randomized, participant-blinded, sham-controlled trial, 22 adults (18 males) with SZ spectrum disorders (SZ or schizoaffective disorder) and frequent medication-resistant AHs received one session of real-time fMRI neurofeedback (NFB) either from the STG (n = 11; experimental group) or motor cortex (n = 11; control group). During NFB, participants were instructed to upregulate their STG activity by attending to pre-recorded sentences spoken in their own voice and downregulate it by ignoring unfamiliar voices. Before and after NFB, participants completed a self-reference task where they evaluated if trait adjectives referred to themselves (self condition), Abraham Lincoln (other condition), or whether adjectives had a positive valence (semantic condition). FMRI activation analyses of self-reference task data tested between-group changes after NFB (self>semantic, post>pre-NFB, experimental>control). Analyses were pre-masked within a self-reference network., Results: Activation analyses revealed significantly (p < 0.001) greater activation increase in the experimental, compared to the control group, after NFB within anterior regions of the self-reference network (mPFC, ACC, superior frontal cortex)., Conclusions: STG-NFB was associated with activity increase in the mPFC, ACC, and superior frontal cortex during self-reference. Modulating the STG is associated with activation changes in other, not-directly targeted, regions subserving higher-level cognitive processes associated with self-referential processes and AHs psychopathology in SZ., Clinicaltrials: GOV: Rt-fMRI Neurofeedback and AH in Schizophrenia; https://clinicaltrials.gov/study/NCT03504579., Competing Interests: Declaration of competing interest All authors declare that they have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms., Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive., Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p  = 0.0001, Cohen's d  = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p  < 0.0001, d  = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p  < 0.0001, d  = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons., Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population., Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029., Competing Interests: JC is a member of the scientific advisory board of Hyka and Flow Neuroscience and has been a consultant for Mifu Technologies. 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 © 2023 Shinn, Hurtado-Puerto, Roh, Ho, Hwang, Cohen, Öngür and Camprodon.)

Objective: Medication adherence is an important component of treatment and has the potential to influence illness trajectory in individuals with first-episode psychosis (FEP). We sought to examine time to medication non-adherence as well as factors related to non-adherence in a real-world FEP clinic., Methods: We conducted a survival analysis to examine time to medication non-adherence using data extracted from medical records of patients admitted to a FEP clinic at an academic psychiatric hospital between May 2012 and October 2017 (n = 219). The risk pool included patients who were adherent during the first 6 months in the clinic (n = 122). Data were extracted for the entire length of participants' time in the clinic, up to 66 months. Pre-selected clinical and demographic variables of interest were extracted and entered into a Cox proportional hazards model., Results: Of the risk pool of 122 patients, 37 (30%) had documented non-adherence events. The risk of non-adherence was 0.35 (95% CI, 0.25-0.46) and 0.49 (95% CI, 0.37-0.63) at the 24- and 36-month time points, respectively, and plateaued after 36 months. Non-White race (adjusted HR = 3.69; P  = .003; 95% CI, 1.57-8.70), lack of insight in the prior 6 months (adjusted HR = 3.24; P  = .005; 95% CI, 1.43-7.35), and substance use in the prior 6 months (adjusted HR = 2.58; P  = .022; 95% CI, 1.15-5.81) were significant predictors of non-adherence., Conclusions: Clinicians should consider efforts to strengthen therapeutic alliance with non-White patients, improve insight, and help patients reduce or cease substance use when supporting medication adherence in the FEP population., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Childhood sexual abuse (CSA) is a potentially unique risk factor for auditory hallucinations (AH), but few studies have examined the moderating effects of sex or the association of CSA with limbic gray matter volume (GMV) in transdiagnostic samples of people with psychotic disorders. Here we found that people with psychotic disorders reported higher levels of all surveyed maltreatment types (e.g., physical abuse) than healthy controls, but people with psychotic disorders with AH (n = 41) reported greater CSA compared to both those without AH (n = 37; t = -2.21, p = .03) and controls (n = 37; t = -3.90, p < .001). Among people with psychosis, elevated CSA was most pronounced among females with AH (sex × AH status: F = 4.91, p = .009), held controlling for diagnosis, medications, and other maltreatment (F = 3.88, p = .02), and correlated with the current severity of AH (r = .26, p = .03) but not other symptoms (p's > .16). Greater CSA among patients related to larger GMV of the left amygdala accounting for AH status, diagnosis, medications, and other maltreatment (t = 2.12, p = .04). Among people with psychosis, females with AH may represent a unique subgroup with greater CSA. Prospective high-risk studies integrating multiple measures of maltreatment and brain structure/function may help elucidate the mechanisms linking CSA with amygdala alterations and AH., (© 2022. The Author(s).)

Background: Childhood trauma is common and associated with worse psychiatric outcomes. Yet, clinicians may not inquire about childhood trauma due to a misconception that patients cannot provide reliable reports. The goal of this study was to examine the reliability of self-reports of childhood trauma in psychotic disorders., Methods: We examined the test-retest reliability of the Childhood Trauma Questionnaire (CTQ) in schizophrenia (SZ, n = 19), psychotic bipolar disorder (BD, n = 17), and healthy control (HC, n = 28) participants who completed the CTQ on ≥2 occasions over variable time periods (mean 19.6 months). We calculated the intraclass correlation (ICC) for the total CTQ score, each of the five CTQ domains, and the minimization/denial subscale for the three groups. For any CTQ domains showing low test-retest reliability (ICC < 0.61), we also explored whether positive, negative, depressive, and manic symptom severity were associated with CTQ variability., Results: We found high ICC values for the total CTQ score in all three groups (SZ 0.82, BD 0.85, HC 0.88). The ICC values for CTQ subdomains were also high with the exceptions of scores for sexual abuse in BD (0.40), emotional neglect in SZ (0.60), and physical neglect in BD (0.51) and HC (0.43). In exploratory analyses, self-reports of sexual abuse in BD were associated with greater severity of depressive symptoms (β = 0.108, p = 0.004)., Conclusions: Patients with SZ and BD can provide reliable self-reports of childhood trauma, especially related to physical and emotional abuse. The presence of psychosis should not deter clinicians from asking patients about childhood trauma., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Childhood maltreatment represents a form of trauma capable of altering fundamental neurobiological properties and negatively impacting neurodevelopmental processes. An outcome of childhood maltreatment is the emergence of psychopathology, which might become evident during childhood or adolescence, but might also project into adulthood. In this Review, we propose a biobehavioural framework in which childhood maltreatment and the associated aberrant neurobiological mechanisms and behavioural processes additionally lead to the onset of altered pain processing and, ultimately, the existence of pain syndromes. Considering that subpopulations of maltreated children show preserved function and minimal psychiatric or pain symptoms, compensatory mechanisms-perhaps instilled by robust psychosocial support systems-are also discussed. We present validated tools and experimental methods that could facilitate better comprehension of the interactions between childhood maltreatment, psychopathology, and pain. Such tools and approaches can in parallel be implemented to monitor abnormal pain-related processes and potentially guide early intervention strategies in cases of childhood maltreatment., Competing Interests: Declaration of interests JG-H has received consulting fees from Alkermes Biopharmaceuticals and Sunovion Pharmaceuticals, and serves on the scientific advisory board for Mightier by Neuromotion Labs. JU has received consulting fees from Orion Corporation. MC, MHT, HvdH, DO, and AKS declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: A central objective of early psychosis therapy is to restore social functioning (e.g., through employment and education). Employment and educational outcomes during the COVID-19 pandemic were examined in a well-defined cohort of patients receiving care in an early psychosis clinic., Methods: Data were extracted from the electronic health records of 128 patients receiving care at McLean Hospital's first-episode psychosis (FEP) clinic between January 1 and September 21 in 2019 and 2020. Using a generalized linear model with a Gaussian distribution and robust standard errors, the authors compared the average changes in the weekly employment and education proportions before and after COVID-19 lockdowns with the same changes in 2019., Results: Employment losses among patients with FEP were greater than among the general population and persisted through the end of follow-up. In 2020, average employment after a stay-at-home order was instituted was 33% lower than before the order compared with the change in employment during the same period in 2019. The effect was stronger among men and those who identified as non-White, were age <21 years, or did not have a college education. Although educational engagement recovered in the fall of 2020, it still remained below the 2019 levels., Conclusions: Employment disruptions were major and persistent among the FEP population, which might affect short- and long-term outcomes. Innovative approaches are needed to help patients transition to remote employment, file unemployment claims, and use online hiring platforms to ameliorate the indirect effects of the COVID-19 pandemic.

Background: Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simplest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning., Methods: To measure generalization in schizophrenia, 37 individuals with a nonaffective psychotic disorder and 32 demographically matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging. Skin conductance and neural responses to conditioned (CS+), neutral (CS-), and generalization stimuli were measured. Explicit memory ratings reflecting successful generalization were also collected after the scanning, as well as measures of symptom severity., Results: Compared with healthy control subjects, individuals with nonaffective psychotic disorders showed significant deficits in fear generalization across multiple measurements, with impairments in memory ratings and reductions in activation and deactivation of the salience and default networks, respectively, during fear generalization. Moreover, in the psychotic disorder group, greater behavioral and neural abnormalities in generalization were associated with higher levels of negative symptoms., Conclusions: Fear generalization is impaired in psychotic illness. Given that successful generalization relies on a dynamic balance between excitatory and inhibitory neurotransmission, these results reveal a potentially quantifiable mechanism linked to negative symptoms that can be investigated further in future human and experimental animal studies., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: People with psychotic disorders may be disproportionately affected by the traumatic effects of the COVID-19 pandemic. Childhood trauma, which also increases vulnerability to subsequent stressors, is common in individuals with psychosis. In this study, we investigated the intersection of the pandemic, childhood trauma, and psychotic and trauma-related symptoms in individuals with psychotic disorders., Methods: We administered a cross-sectional survey to 151 participants [47 schizophrenia (SZ), 53 psychotic bipolar disorder (BP)], 51 healthy control (HC)] during the COVID-19 pandemic. Participants were asked about exposure to the pandemic's impacts, childhood trauma, and post-traumatic stress, dissociative, and psychotic symptoms., Results: BP reported greater negative impacts to emotional health than SZ and HC and to non-COVID physical health than HC. SZ reported less impact on work and employment during the pandemic. There were no other group differences in pandemic-related adversities. We also found that cumulative exposure to the pandemic's negative impacts was significantly associated with PTSD symptoms but not psychotic or dissociative symptoms. Moreover, the number of adversities an individual experienced during the pandemic was strongly associated with the cumulative number of traumatic experiences they had in childhood., Discussion: Our results suggest that having a psychotic disorder does not, in and of itself, increase susceptibility to the pandemic's negative impacts. Instead, we provide evidence of a graded relationship between cumulative exposure to the pandemic's negative impacts and PTSD symptom severity, as well as a graded relationship between cumulative childhood traumatic experiences and the number pandemic adversities, across diagnoses., (© The Author(s) 2021. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Psychiatric diagnosis is often treated as a stable construct both clinically and in research; however, some evidence suggests that diagnostic change may be common, which may impact research validity and clinical care. In the present study we examined diagnostic stability in individuals with psychosis over time. Participants with a diagnosis of any psychotic disorder ( n = 142) were assessed at two timepoints using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. We found a 25.4% diagnostic change rate across the total sample. People with an initial diagnosis of psychosis not otherwise specified and schizophreniform disorder had the highest rates of change, followed by those with schizophrenia and schizoaffective disorder; people with bipolar disorder had the lowest change rate. Most participants with an unstable initial diagnosis of schizophrenia, schizophreniform disorder, bipolar disorder, or psychosis not otherwise specified converted to a final diagnosis of schizoaffective disorder. Participants with an unstable initial diagnosis of schizoaffective disorder most frequently converted to a diagnosis of schizophrenia. Our findings suggest that diagnostic change is relatively common, occurring in approximately a quarter of patients. People with an initial diagnosis of schizophrenia-spectrum disorder were more likely to have a diagnostic change, suggesting a natural stability of some diagnoses more so than others., Competing Interests: The 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 © 2021 Wood, Carroll, Shinn, Ongur and Lewandowski.)

The cerebellum, a structure historically associated with motor control, has more recently been implicated in several higher-order auditory-cognitive functions. However, the exact functional pathways that mediate cerebellar influences on auditory cortex (AC) remain unclear. Here, we sought to identify auditory cortico-cerebellar pathways based on intrinsic functional connectivity magnetic resonance imaging. In contrast to previous connectivity studies that principally consider the AC as a single functionally homogenous unit, we mapped the cerebellar connectivity across different parts of the AC. Our results reveal that auditory subareas demonstrating different levels of interindividual functional variability are functionally coupled with distinct cerebellar regions. Moreover, auditory and sensorimotor areas show divergent cortico-cerebellar connectivity patterns, although sensorimotor areas proximal to the AC are often functionally grouped with the AC in previous connectivity-based network analyses. Lastly, we found that the AC can be functionally segmented into highly similar subareas based on either cortico-cerebellar or cortico-cortical functional connectivity, suggesting the existence of multiple parallel auditory cortico-cerebellar circuits that involve different subareas of the AC. Overall, the present study revealed multiple auditory cortico-cerebellar pathways and provided a fine-grained map of AC subareas, indicative of the critical role of the cerebellum in auditory processing and multisensory integration., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Auditory hallucinations (AH) are typically associated with schizophrenia (SZ), but they are also prevalent in bipolar disorder (BD). Despite the large body of research on the neural correlates of AH in SZ, the pathophysiology underlying AH remains unclear. Few studies have examined the neural substrates associated with propensity for AH in BD. Investigating AH across the psychosis spectrum has the potential to inform about the neural signature associated with the trait of AH, irrespective of psychiatric diagnosis., Methods: We compared resting state functional magnetic resonance imaging data in psychosis patients with (n = 90 AH; 68 SZ, 22 BD) and without (n = 55 NAH; 16 SZ, 39 BD) lifetime AH. We performed region of interest (ROI)-to-ROI functional connectivity (FC) analysis using 91 cortical, 15 subcortical, and 26 cerebellar atlas-defined regions. The primary aim was to identify FC differences between patients with and without lifetime AH. We secondarily examined differences between AH and NAH within each diagnosis., Results: Compared to the NAH group, patients with AH showed higher FC between cerebellum and frontal (left precentral gyrus), temporal [right middle temporal gyrus (MTG), left inferior temporal gyrus (ITG), left temporal fusiform gyrus)], parietal (bilateral superior parietal lobules), and subcortical (left accumbens, left palldium) brain areas. AH also showed lower FC between temporal lobe regions (between right ITG and right MTG and bilateral superior temporal gyri) relative to NAH., Conclusions: Our findings suggest that dysconnectivity involving the cerebellum and temporal lobe regions may be common neurofunctional elements associated with AH propensity across the psychosis spectrum. We also found dysconnectivity patterns that were unique to lifetime AH within SZ or bipolar psychosis, suggesting both common and distinct mechanisms underlying AH pathophysiology in these disorders., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: Diagnostic shifts in first episode psychosis (FEP) are not uncommon. Many studies examining diagnostic stability use structured diagnostic interviews. Less is known about the stability of FEP diagnoses made clinically., Methods: We conducted a retrospective chart review of patients enrolled in a transdiagnostic FEP clinic. For the 96 patients followed clinically at least 2 years, we compared diagnoses at intake and 24 months., Results: Diagnostic stability was high for bipolar disorder (89%), schizoaffective disorder (89%), and schizophrenia (82%). Psychosis not otherwise specified (13%) was more unstable, with limited baseline differences that would enable clinicians to predict who would convert to a primary psychotic vs affective psychotic disorder., Conclusions: Our real-world clinical sample shows that FEP diagnoses, with the exception of unspecified psychosis, are diagnostically stable, even without structured diagnostic interviews., (© 2020 John Wiley & Sons Australia, Ltd.)

Voice hearing (VH) can occur in trauma spectrum disorders (TSD) such as posttraumatic stress disorder (PTSD) and dissociative disorders. However, previous estimates of VH among individuals with TSD vary widely. In this study, we sought to better characterize the rate and phenomenology of VH in a sample of 70 women with TSD related to childhood abuse who were receiving care in a specialized trauma program. We compared the rate of VH within our sample using two different measures: 1) the auditory hallucination (AH) item in the Structured Clinical Interview for DSM-IV-TR (SCID), and 2) the thirteen questions involving VH in the Multidimensional Inventory of Dissociation (MID), a self-report questionnaire that comprehensively assesses pathological dissociation. We found that 45.7% of our sample met threshold for SCID AH, while 91.4% met criteria for MID VH. Receiver operating characteristics (ROC) analyses showed that while SCID AH and MID VH items have greater than chance agreement, the strength of agreement is only moderate, suggesting that SCID and MID VH items measure related but not identical constructs. Thirty-two patients met criteria for both SCID AH and at least one MID VH item ("unequivocal VH"), 32 for at least one MID VH item but not SCID AH ("ambiguous VH"), and 6 met criteria for neither ("unequivocal non-VH"). Relative to the ambiguous VH group, the unequivocal VH group had higher dissociation scores for child voices, and higher mean frequencies for child voices and Schneiderian voices. Our findings suggest that VH in women with TSD related to childhood abuse is common, but that the rate of VH depends on how the question is asked. We review prior studies examining AH and/or VH in TSD, focusing on the measures used to ascertain these experiences, and conclude that our two estimates are consistent with previous studies that used comparable instruments and patient samples. Our results add to growing evidence that VH-an experience typically considered psychotic or psychotic-like-is not equivalent to having a psychotic disorder. Instruments that assess VH apart from psychotic disorders and that capture their multidimensional nature may improve identification of VH, especially among patients with non-psychotic disorders., (Copyright © 2020 Shinn, Wolff, Hwang, Lebois, Robinson, Winternitz, Öngür, Ressler and Kaufman.)

A first episode of psychosis (FEP) can derail a patient's educational goals, including attainment of a college education, and this can have lasting ramifications for socioeconomic and health outcomes. Despite this, few studies have examined return to college, which is an important index of real-world educational success after a FEP. In this study, we conducted a longitudinal medical record review of patients in a transdiagnostic outpatient FEP program and performed survival analysis, setting return to college as the endpoint, among the subset of patients whose college education was interrupted. We found that 82% (93/114) of college-enrolled FEP individuals experienced disruptions to their education after FEP, but that return to college also occurred in a substantial proportion (49/88, 56%) among those on leave who had follow-up data. In this sample, the median time to college return was 18 months. When separated by baseline diagnostic category, FEP patients with affective psychotic disorders (FEAP, n = 45) showed faster time to college return than those with primary psychotic disorders (FEPP, n = 43) (median 12 vs 24 mo; P = .024, unadjusted). When adjusted for having no more than 1 psychiatric hospitalization at intake and absence of cannabis use in the 6 months prior to intake (which were also significant predictors), differences by diagnostic category were more significant (hazard ratio 2.66, 95% CI 1.43-4.94, P = .002). Participation in education is an important outcome for stakeholders, and students with FEP can be successful in accomplishing this goal., (© The Author(s) 2020. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background: Visual hallucinations (VH) are a common, but understudied symptom of psychosis, experienced by individuals across diagnostic categories of psychotic and neuropsychiatric conditions. There are limited data on VH and associated clinical phenotypes in adult idiopathic psychotic disorders, which are needed to elucidate their relevance to psychotic illness paradigms., Method: In this cross-sectional study, we examined clinical risk factors for VH in a well-characterized sample of 766 patients with adult psychotic disorders across diagnostic categories of schizophrenia (n = 227), schizoaffective disorder (n = 210), and bipolar I disorder (n = 329). The Structured Clinical Interview for DSM-IV-TR was used for diagnosis and symptom measurements., Results: The prevalence of VH was 26.1% (200/766). Multivariate logistic regression showed that VH were independently associated with the presence of hallucinations in other modalities, including auditory, tactile, olfactory, and gustatory hallucinations. History of a suicide attempt and catatonic behavior were also associated with VH. In addition, specific delusions were associated with VH, in particular, delusions of control, and religious, erotomanic and jealousy delusions. Diagnosis, negative symptoms, and family history of psychosis were not independent predictors of VH., Conclusions: Results showed the clinical and disease relevance of VH as they were associated with severe morbidity of illness, including suicide attempts and catatonic behavior. Findings also suggest a phenotype associated with hallucinations in other modalities and specific types of delusions. Based on our findings, VH may be a significant factor in assessing for suicidality and illness severity, warranting clinical attention and further study of underlying mechanisms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hallucinations in children and adolescents are now known to occur on a continuum from healthy to psychopathology-related phenomena. Although hallucinations in young populations are mostly transient, they can cause substantial distress. Despite hallucinations being widely investigated, research so far has had limited implications for clinical practice. The present article has 3 main aims: (1) to review research findings since 2014 (when the last major review of the area was published); (2) to present assessment tools validated to measure hallucinations in children and adolescents; and (3) to discuss therapeutic strategies and clinical issues. We conclude by presenting a tailored care model for clinicians and outline future challenges for research.

Increased non-right-handedness (NRH) probably reflects neurodevelopmental abnormalities in psychiatric disorders. Past studies of NRH have focused more on schizophrenia (SZ) than bipolar disorder (BPD). We report results on NRH in two large studies. In (1), NRH was compared among BPD patients with psychosis, SZ patients, and healthy controls (HC). NRH was elevated in BPD with psychosis and SZ patients relative to HC, but not SZ relative to BPD. In (2), NRH was compared between BPD patients with and without psychosis. NRH was similarly elevated in both. The findings suggest that NRH may reflect shared brain anomalies in SZ and BPD., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: The cerebellum, which modulates affect and cognition in addition to motor functions, may contribute substantially to the pathophysiology of mood and psychotic disorders, such as bipolar disorder. A growing literature points to cerebellar abnormalities in bipolar disorder. However, no studies have investigated the topographic representations of resting state cerebellar networks in bipolar disorder, specifically their functional connectivity to cerebral cortical networks., Methods: Using a well-defined cerebral cortical parcellation scheme as functional connectivity seeds, we compared ten cerebellar resting state networks in 49 patients with bipolar disorder and a lifetime history of psychotic features and 55 healthy control participants matched for age, sex, and image signal-to-noise ratio., Results: Patients with psychotic bipolar disorder showed reduced cerebro-cerebellar functional connectivity in somatomotor A, ventral attention, salience, and frontoparietal control A and B networks relative to healthy control participants. These findings were not significantly correlated with current symptoms., Conclusions: Patients with psychotic bipolar disorder showed evidence of cerebro-cerebellar dysconnectivity in selective networks. These disease-related changes were substantial and not explained by medication exposure or substance use. Therefore, they may be mechanistically relevant to the underlying susceptibility to mood dysregulation and psychosis. Cerebellar mechanisms deserve further exploration in psychiatric conditions, and this study's findings may have value in guiding future studies on pathophysiology and treatment of mood and psychotic disorders, in particular., Competing Interests: Financial Disclosures Dr. Öngür reports having received research support from Roche Genentech in 2014. All other authors report no biomedical financial interests or potential conflicts of interest.

Aims: Most programs specializing in the treatment of first-episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first-episode psychosis., Methods: We assessed baseline characteristics of patients in the 2.5 years since program initiation. We examined how initial referral diagnoses compare with current diagnoses, calculating the proportion of diagnostic changes., Results: At 2.5 years, patients in McLean OnTrack consist of 30 (33.0%) individuals with primary psychotic disorder, 40 (44.0%) with affective psychosis, 19 (20.9%) with psychotic disorder not otherwise specified (NOS) who do not meet full criteria for either category and two (2.2%) individuals with no psychosis. Although patients with affective psychosis had higher pre-morbid functioning, all three categories of psychosis had similar rates of prior hospitalizations and substance use. The retention rate in the psychotic disorder NOS group was lower than that in affective and primary psychotic disorders. Finally, diagnoses changed over the course of treatment in 50.5% of patients., Conclusions: Diagnostic heterogeneity appears to be the norm among patients with first-episode psychosis, and diagnoses commonly evolve over the illness course. Baseline indices of illness severity were similar across categories and suggest the need for early intervention, irrespective of specific diagnosis. We discuss the benefits and challenges of a transdiagnostic approach to early intervention in first-episode psychosis, treating patients who share many but not all characteristics., (© 2015 Wiley Publishing Asia Pty Ltd.)

Objectives: A variety of treatment options exist for schizophrenia, but the effects of these treatments on brain function are not clearly understood. To facilitate the development of more effective treatment strategies, it is important to identify how brain function in schizophrenia patients is affected by the diverse therapeutic approaches that are currently available. The aim of the present article is to systematically review the evidence for functional brain changes associated with different treatment modalities for schizophrenia., Methods: We searched PubMed for longitudinal functional MRI (fMRI) studies reporting on the effects of antipsychotic medications (APM), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), cognitive remediation therapy (CRT) and cognitive behavioral therapy for psychosis (CBTp) on brain function in schizophrenia., Results: Thirty six studies fulfilled the inclusion criteria. Functional alterations were observed in diverse brain regions. Across intervention modalities, changes in fMRI parameters were reported most commonly in frontal brain regions including prefrontal cortex, anterior cingulate and inferior frontal cortex., Conclusions: We conclude that current treatments for schizophrenia commonly induce functional brain alterations in frontal brain regions. However, interpretability is limited by inconsistency in task and region of interest selection, and failures to replicate. Further task independent fMRI studies examining treatment effects with whole brain analysis are needed to deepen our insights., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Balance between the redox pair of nicotinamide adenine dinucleotides (oxidized NAD+ and reduced NADH), reflects the oxidative state of cells and the ability of biological systems to carry out energy production. A growing body of evidence suggests that an "immuno-oxidative" pathway including oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell-mediated immune response may contribute to disruptions in brain activity in schizophrenia (SZ). The aim of this study is to assess possible redox imbalance in SZ patients by using a novel in vivo 31 P MRS technique. The participants included 40 healthy controls, 21 chronic SZ, 13 first-episode (FE) SZ, and 18 FE bipolar disorder (BD) patients (as a psychiatric control group). All participants initially underwent structural imaging at a 3 Tesla (3 T) and 31 P MRS measurements were performed on a 4 T MR scanner. NAD+ and NADH components were determined by nonlinear least-square fitting of the model simulated spectra; these incorporated prior chemical shift and coupling constant information to in vivo resonances obtained from 31 P MRS experiments. We found a significant reduction in the NAD+/NADH ratio in chronically ill SZ patients compared to a matched healthy control group, and in FE SZ patients compared to both a matched FE BD patient group and a matched healthy control group. These findings provide evidence for redox imbalance in the brain in all phases of SZ, potentially reflecting oxidative stress., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Auditory hallucinations (AH) are a symptom that is most often associated with schizophrenia, but patients with other neuropsychiatric conditions, and even a small percentage of healthy individuals, may also experience AH. Elucidating the neural mechanisms underlying AH in schizophrenia may offer insight into the pathophysiology associated with AH more broadly across multiple neuropsychiatric disease conditions. In this paper, we address the problem of classifying schizophrenia patients with and without a history of AH, and healthy control (HC) subjects. To this end, we performed feature extraction from resting state functional magnetic resonance imaging (rsfMRI) data and applied machine learning classifiers, testing two kinds of neuroimaging features: (a) functional connectivity (FC) measures computed by lattice auto-associative memories (LAAM), and (b) local activity (LA) measures, including regional homogeneity (ReHo) and fractional amplitude of low frequency fluctuations (fALFF). We show that it is possible to perform classification within each pair of subject groups with high accuracy. Discrimination between patients with and without lifetime AH was highest, while discrimination between schizophrenia patients and HC participants was worst, suggesting that classification according to the symptom dimension of AH may be more valid than discrimination on the basis of traditional diagnostic categories. FC measures seeded in right Heschl's gyrus (RHG) consistently showed stronger discriminative power than those seeded in left Heschl's gyrus (LHG), a finding that appears to support AH models focusing on right hemisphere abnormalities. The cortical brain localizations derived from the features with strong classification performance are consistent with proposed AH models, and include left inferior frontal gyrus (IFG), parahippocampal gyri, the cingulate cortex, as well as several temporal and prefrontal cortical brain regions. Overall, the observed findings suggest that computational intelligence approaches can provide robust tools for uncovering subtleties in complex neuroimaging data, and have the potential to advance the search for more neuroscience-based criteria for classifying mental illness in psychiatry research.

Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the "cognitive dysmetria" and "dysmetria of thought" models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral cortex are reciprocally connected via a modular, closed-loop network architecture, but few schizophrenia neuroimaging studies have taken into account the topographical and functional heterogeneity of the cerebellum. In this study, using a previously defined 17-network cerebral cortical parcellation system as the basis for our functional connectivity seeds, we systematically investigated connectivity abnormalities within the cerebellum of 44 schizophrenia patients and 28 healthy control participants. We found selective alterations in cerebro-cerebellar functional connectivity. Specifically, schizophrenia patients showed decreased cerebro-cerebellar functional connectivity in higher level association networks (ventral attention, salience, control, and default mode networks) relative to healthy control participants. Schizophrenia patients also showed increased cerebro-cerebellar connectivity in somatomotor and default mode networks, with the latter showing no overlap with the regions found to be hypoconnected within the same default mode network. Finally, we found evidence to suggest that somatomotor and default mode networks may be inappropriately linked in schizophrenia. The relationship of these dysconnectivities to schizophrenia symptoms, such as neurological soft signs and altered sense of agency, is discussed. We conclude that the cerebellum ought to be considered for analysis in all future studies of network abnormalities in SZ, and further suggest the cerebellum as a potential target for further elucidation, and possibly treatment, of the underlying mechanisms and network abnormalities producing symptoms of schizophrenia.

Background: In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities., Methods: In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1 × 3 × 3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants., Results: The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group., Conclusions: The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Study Objectives: In schizophrenia there is a dramatic reduction of sleep spindles that predicts deficient sleep-dependent memory consolidation. Eszopiclone (Lunesta), a non-benzodiazepine hypnotic, acts on γ-aminobutyric acid (GABA) neurons in the thalamic reticular nucleus where spindles are generated. We investigated whether eszopiclone could increase spindles and thereby improve memory consolidation in schizophrenia., Design: In a double-blind design, patients were randomly assigned to receive either placebo or 3 mg of eszopiclone. Patients completed Baseline and Treatment visits, each consisting of two consecutive nights of polysomnography. On the second night of each visit, patients were trained on the motor sequence task (MST) at bedtime and tested the following morning., Setting: Academic research center., Participants: Twenty-one chronic, medicated schizophrenia outpatients., Measurements and Results: We compared the effects of two nights of eszopiclone vs. placebo on stage 2 sleep spindles and overnight changes in MST performance. Eszopiclone increased the number and density of spindles over baseline levels significantly more than placebo, but did not significantly enhance overnight MST improvement. In the combined eszopiclone and placebo groups, spindle number and density predicted overnight MST improvement., Conclusion: Eszopiclone significantly increased sleep spindles, which correlated with overnight motor sequence task improvement. These findings provide partial support for the hypothesis that the spindle deficit in schizophrenia impairs sleep-dependent memory consolidation and may be ameliorated by eszopiclone. Larger samples may be needed to detect a significant effect on memory. Given the general role of sleep spindles in cognition, they offer a promising novel potential target for treating cognitive deficits in schizophrenia.

The presence of a single first-rank auditory hallucination (FRAH) or bizarre delusion (BD) is sufficient to satisfy the symptom criterion for a DSM-IV-TR diagnosis of schizophrenia. We queried two independent databases to investigate how prevalent FRAH and BD are in schizophrenia spectrum disorders and whether the diagnosis depends on them. FRAH was common in both datasets (42.2% and 55.2%) and BD was present in the majority of patients (62.5% and 69.7%). However, FRAH and BD rarely determined the diagnosis. In the first database, we found only seven cases among 325 patients (2.1%) and in the second database we found only one case among 201 patients (0.5%) who were diagnosed based on FRAH or BD alone. Among patients with FRAH, 96% had delusions, 14-42% had negative symptoms, 15-21% had disorganized or catatonic behavior, and 20-23% had disorganized speech. Among patients with BD, 88-99% had hallucinations, 17-49% had negative symptoms, 20-27% had disorganized or catatonic behavior, and 21-25% had disorganized speech. We conclude that FRAH and BD are common features of schizophrenia spectrum disorders, typically occur in the context of other psychotic symptoms, and very rarely constitute the sole symptom criterion for a DSM-IV-TR diagnosis of schizophrenia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Schizophrenia is a heterogeneous disorder that may consist of multiple etiologies and disease processes. Auditory hallucinations (AH), which are common and often disabling, represent a narrower and more basic dimension of psychosis than schizophrenia. Previous studies suggest that abnormal primary auditory cortex activity is associated with AH pathogenesis. We thus investigated functional connectivity, using a seed in primary auditory cortex, in schizophrenia patients with and without AH and healthy controls, to examine neural circuit abnormalities associated more specifically with AH than the myriad other symptoms that comprise schizophrenia., Methods: Using resting-state fMRI (rsfMRI), we investigated functional connectivity of the primary auditory cortex, located on Heschl's gyrus, in schizophrenia spectrum patients with AH. Participants were patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder with lifetime AH (n=27); patients with the same diagnoses but no lifetime AH (n=14); and healthy controls (n=28)., Results: Patients with AH vulnerability showed increased left Heschl's gyrus functional connectivity with left frontoparietal regions and decreased functional connectivity with right hippocampal formation and mediodorsal thalamus compared to patients without lifetime AH. Furthermore, among AH patients, left Heschl's gyrus functional connectivity covaried positively with AH severity in left inferior frontal gyrus (Broca's area), left lateral STG, right pre- and postcentral gyri, cingulate cortex, and orbitofrontal cortex. There were no differences between patients with and without lifetime AH in right Heschl's gyrus seeded functional connectivity., Conclusions: Abnormal interactions between left Heschl's gyrus and regions involved in speech/language, memory, and the monitoring of self-generated events may contribute to AH vulnerability., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Auditory hallucinations (AH) are a cardinal feature of schizophrenia spectrum disorders. They are not disease specific, however, and can occur in other conditions, including affective psychoses., Methods: In this descriptive, cross-sectional study, we examined AH in relation to other psychotic symptoms, mood symptoms, illness severity, and functional status in 569 patients with psychosis (n = 172 schizophrenia, n = 153 schizoaffective disorder, n = 244 bipolar disorder with psychotic features)., Results: A total of 323 (56.7%) patients reported a lifetime history of AH (75.6% of patients with schizophrenia, 71.9% schizoaffective disorder, and 34.0% bipolar disorder). The mean score for the hallucinations item (P3) of the Positive and Negative Syndrome Scale in the AH group was 3.66 ± 1.79, indicating mild to moderate state hallucinations severity. Auditory hallucinations were strongly associated with hallucinations in other sensory modalities and with the first-rank symptoms of delusions of control, thought insertion, and thought broadcasting. Multivariate analysis showed that AH were associated with lower education even after controlling for diagnosis, age, and sex. There was no association between AH and functional status as measured by the Multnomah Community Ability Scale., Conclusions: Auditory hallucinations are associated with specific clinical features across the continuum of both schizophrenic and affective psychoses independent of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Sleep spindles are thought to induce synaptic changes and thereby contribute to memory consolidation during sleep. Patients with schizophrenia show dramatic reductions of both spindles and sleep-dependent memory consolidation, which may be causally related., Methods: To examine the relations of sleep spindle activity to sleep-dependent consolidation of motor procedural memory, 21 chronic, medicated schizophrenia outpatients and 17 healthy volunteers underwent polysomnography on two consecutive nights. On the second night, participants were trained on the finger-tapping motor sequence task (MST) at bedtime and tested the following morning. The number, density, frequency, duration, amplitude, spectral content, and coherence of stage 2 sleep spindles were compared between groups and examined in relation to overnight changes in MST performance., Results: Patients failed to show overnight improvement on the MST and differed significantly from control participants who did improve. Patients also exhibited marked reductions in the density (reduced 38% relative to control participants), number (reduced 36%), and coherence (reduced 19%) of sleep spindles but showed no abnormalities in the morphology of individual spindles or of sleep architecture. In patients, reduced spindle number and density predicted less overnight improvement on the MST. In addition, reduced amplitude and sigma power of individual spindles correlated with greater severity of positive symptoms., Conclusions: The observed sleep spindle abnormalities implicate thalamocortical network dysfunction in schizophrenia. In addition, the findings suggest that abnormal spindle generation impairs sleep-dependent memory consolidation in schizophrenia, contributes to positive symptoms, and is a promising novel target for the treatment of cognitive deficits in schizophrenia., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Bipolar disorder and schizophrenia overlap in symptoms and may share some underlying neural substrates. The medial prefrontal cortex (MPFC) may have a crucial role in the psychophysiology of both these disorders. In this study, we examined the functional connectivity between MPFC and other brain regions in bipolar disorder and schizophrenia using resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI data were collected from 14 patients with bipolar disorder, 16 patients with schizophrenia, and 15 healthy control subjects. Functional connectivity maps from the MPFC were computed for each subject and compared across the three groups. The three groups showed distinctive patterns of functional connectivity between MPFC and anterior insula, and between MPFC and ventral lateral prefrontal cortex (VLPFC). The bipolar disorder group exhibited positive correlations between MPFC and insula, and between MPFC and VLPFC, whereas the control group exhibited anticorrelations between these regions. The schizophrenia group did not exhibit any resting-state correlation or anticorrelation between the MPFC and the VLPFC or insula. In contrast, neither patient group exhibited the significant anticorrelation between dorsal lateral prefrontal cortex (DLPFC) and MPFC that was exhibited by the control group. The decoupling of DLPFC with MPFC in bipolar disorder and schizophrenia is consistent with the impaired executive functioning seen in these disorders. Functional connectivity between MPFC and insula/VLPFC distinguished bipolar disorder from schizophrenia, and may reflect differences in the affective disturbances typical of each illness.

The default-mode network (DMN) consists of a set of brain areas preferentially activated during internally focused tasks. We used functional magnetic resonance imaging (fMRI) to study the DMN in bipolar mania and acute schizophrenia. Participants comprised 17 patients with bipolar disorder (BD), 14 patients with schizophrenia (SZ) and 15 normal controls (NC), who underwent 10-min resting fMRI scans. The DMN was extracted using independent component analysis and template-matching; spatial extent and timecourse were examined. Both patient groups showed reduced DMN connectivity in the medial prefrontal cortex (mPFC) (BD: x=-2, y=54, z=-12; SZ: x=-2, y=22, z=18). BD subjects showed abnormal recruitment of parietal cortex (correlated with mania severity) while SZ subjects showed greater recruitment of the frontopolar cortex/basal ganglia. Both groups had significantly higher frequency fluctuations than controls. We found ventral mPFC abnormalities in BD and dorsal mPFC abnormalities in SZ. The higher frequency of BOLD signal oscillations observed in patients suggests abnormal functional organization of circuits in both disorders. Further studies are needed to determine how these abnormalities are related to specific symptoms of each condition., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To critically review the literature on topiramate in the treatment of substance-related disorders., Data Sources: A PubMed search of human studies published in English through January 2009 was conducted using the following search terms: topiramate and substance abuse, topiramate and substance dependence, topiramate and withdrawal, topiramate and alcohol, topiramate and nicotine, topiramate and cocaine, topiramate and opiates, and topiramate and benzodiazepines., Study Selection: 26 articles were identified and reviewed; these studies examined topiramate in disorders related to alcohol, nicotine, cocaine, methamphetamine, opioids, Ecstasy, and benzodiazepines., Data Extraction: Study design, sample size, topiramate dose and duration, and study outcomes were reviewed., Data Synthesis: There is compelling evidence for the efficacy of topiramate in the treatment of alcohol dependence. Two trials show trends for topiramate's superiority over oral naltrexone in alcohol dependence, while 1 trial suggests topiramate is inferior to disulfiram. Despite suggestive animal models, evidence for topiramate in treating alcohol withdrawal in humans is slim. Studies of topiramate in nicotine dependence show mixed results. Human laboratory studies that used acute topiramate dosing show that topiramate actually enhances the pleasurable effects of both nicotine and methamphetamine. Evidence for topiramate in the treatment of cocaine dependence is promising, but limited by small sample size. The data on opioids, benzodiazepines, and Ecstasy are sparse., Conclusions: Topiramate is efficacious for the treatment of alcohol dependence, but side effects may limit widespread use. While topiramate's unique pharmacodynamic profile offers a promising theoretical rationale for use across multiple substance-related disorders, heterogeneity both across and within these disorders limits topiramate's broad applicability in treating substance-related disorders. Recommendations for future research include exploration of genetic variants for more targeted pharmacotherapies., (©Copyright 2010 Physicians Postgraduate Press, Inc.)

Background: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood., Objective: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers., Design: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task., Setting: Participants were recruited from the general community to a research center., Participants: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women)., Main Outcome Measures: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum., Results: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity., Conclusions: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.