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Background: Although altered gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathophysiology of schizophrenia, it is unclear whether the influence of GABA on working memory processes is confounded by nicotine use in this population. It is therefore crucial to evaluate working memory and its underlying mechanisms in non-smokers with schizophrenia to eliminate the confounding effects of nicotine on behavior and neurophysiology., Methods: In this cross-sectional study, working memory was assessed using the verbal N-back task, while GABAergic function was assessed through motor cortical inhibition using single and paired-pulse transcranial magnetic stimulation (TMS) to the left primary motor cortex in 11 non-smokers with schizophrenia and 13 non-smoker healthy subjects., Results: Similar to previously published studies, working memory performance was significantly impaired in the 3-back condition in patients with schizophrenia compared to healthy subjects (p=0.036). In addition, GABAA receptor function was significantly reduced in schizophrenia as assessed by short interval cortical inhibition (SICI) (p=0.005). A positive correlation was found between GABAA inhibition and working memory performance on the 3-back task (r(23)=0.55, p=0.006), suggesting that greater GABAA inhibition is associated with better performance on tasks of working memory., Conclusions: Our findings highlight the role of GABAA receptor dysfunction in working memory and the pathophysiology of schizophrenia, and may represent a selective characteristic of schizophrenia. Moreover, these findings suggest a potential therapeutic role for targeting GABA receptor activity to improve cognition and quality of life in patients with schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Cognition predicts functional competence among individuals with schizophrenia across the lifespan. However, as these individuals age, increasing levels of medical burden may also contribute to functional deficits both directly and indirectly through cognition. Thus, we assessed the relationship among, cognition, medical burden, and functional competence in older individuals with schizophrenia., Methods: We analyzed data obtained from 60 community-dwelling participants with schizophrenia and 30 control participants aged 50 or above. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB), functional competence was assessed using the USCD Performance-Based Skills Assessment (UPSA), and medical burden was assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Group differences were assessed using independent samples t-tests or chi-square tests. Mediation analyses using bootstrapping techniques were used to assess whether cognition mediated the effects of medical burden on functional competence., Results: Participants with schizophrenia had higher levels of medical burden, cognitive deficits, and functional impairments. In participants with schizophrenia, cognition, but not medical burden, predicted functional competence after adjusting for age, education, gender, clinical symptoms, and anticholinergic burden of medications. In control participants, cognition and medical burden both predicted functional competence after adjusting for age, education, and gender. Further, cognition was found to fully mediate the association between medical burden and functional competence in control participants., Conclusion: Cognition is a robust predictor of functional competence among older individuals with schizophrenia, regardless of medical burden. Cognitive deficits associated with schizophrenia may mask any further cognitive impairment associated with medical burden and its impact on function., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Alcohol use disorders (AUDs) are a major health and social problem worldwide. Brain stimulation holds great promise as an investigational tool to help us understand the pathophysiology of alcohol dependence and as a therapeutic tool to treat AUDs. Numerous studies suggest that glutamatergic, gamma-aminobutyric acidergic, and dopaminergic neurotransmission are altered by alcohol consumption and among patients with AUDs. Alcohol's disruption of neurotransmission is likely to play an important role in its detrimental effects on neuroplasticity, which, in turn, may contribute to the pathophysiology of alcohol dependence. Specifically, aberrant neuroplasticity in the brain reward circuitry is a potential mechanism underlying the pathophysiology of alcohol dependence. The dorsolateral prefrontal cortex (DLPFC), a part of the brain's reward circuitry, is directly accessible to noninvasive brain stimulation and may represent a potential target for the treatment of AUDs. While the literature suggests that impairments in neuroplasticity are likely to be present in the DLPFC and brain reward circuitry in alcohol-dependent patients, this is yet to be directly evaluated in humans. Findings from numerous neuromodulatory brain stimulation studies demonstrate that altering neuroplasticity in the DLPFC in alcohol-dependent patients holds promise as a treatment for alcohol dependence, but the optimal neuromodulatory parameters are yet to be identified. Gaining a better understanding of alcohol dependence vis à vis neuroplasticity in the DLPFC and brain reward circuitry can help us optimize the treatment of alcohol dependence using neuromodulatory brain stimulation in the DLPFC., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Binge drinking, resulting in acute alcohol intoxication, is considered an initial step in developing alcohol use disorders (AUDs). It has been suggested that alcohol intoxication may act on mechanisms of neuroplasticity to produce brain changes that contribute to the pathophysiology of AUDs. However, the effect of binge drinking on neuroplasticity has not been evaluated in humans., Objective: The current study was aimed at evaluating the effect of a binge drinking episode on LTP-like neuroplasticity., Methods: In a within-subject randomized, cross-over design, fifteen otherwise healthy binge drinkers were administered paired associative stimulation (PAS) following consumption of alcohol or a placebo beverage. PAS is an experimental paradigm that allows for the induction of associative long-term potentiation (LTP)-like neuroplasticity. Subjects were administered alcohol at a dose of 1.5 g/l of body water, producing a peak blood alcohol concentration (BAC) of 26.1 mM (0.120% BAC). PAS induced neuroplasticity was measured at Post 0 (immediately following PAS), Post 15 (15 minutes following PAS), Post 30 (30 minutes following PAS), Post 60 (60 minutes following PAS) and Post Day 1 (the next day following PAS)., Results: The binge drinking episode inhibited LTP-like neuroplasticity, which was significantly different from placebo at 30 and 60 min following the PAS administration. Examination of longitudinal effects revealed no differences between beverages on LTP-like neuroplasticity the following day., Conclusions: Findings suggest that binge drinking impairs neuroplasticity and while these effects are no longer evident the day after a single binge session, repetitive binging may produce long lasting changes in neuroplasticity that contribute to the development of AUDs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Studies show that deficit syndrome schizophrenia patients, characterized by primary negative symptoms and poor functional outcome, have impairment in specific neural circuits. We assessed whether these same neural circuits are directly linked to functional outcomes across schizophrenia patients., Methods: T1- and diffusion-weighted MR images were obtained for schizophrenia (n=30) and matched healthy control participants (n=30). Negative symptoms and functional outcome were assessed at baseline and 6-month follow-up. Cortical thickness and tract-wise fractional anisotropy (FA) were compared between groups. To assess relationships of neuroimaging measures with functional outcome, principal component analysis (PCA) was performed on tract-wise FA values and components were entered into a multiple regression model for schizophrenia participants., Results: Consistent with the literature, schizophrenia participants showed frontotemporal reductions in cortical thickness and tract-wise FA compared to controls. The top two components from PCA explained 71% of the variance in tract-wise FA values. The second component (associated with inferior longitudinal and arcuate fasciculus FA) was significantly correlated with functional outcome (baseline: β=0.54, p=0.03; follow-up: β=0.74, p=0.047); further analysis revealed this effect was mediated by negative symptoms. Post-hoc network analysis revealed increased cortical coupling between right inferior frontal and supramarginal gyri (connected by the arcuate fasciculus) in schizophrenia participants with poorer functional outcome., Conclusions: Our findings indicate that impairment in the same neural circuitry susceptible in deficit syndrome schizophrenia predicts functional outcome in a continuous manner in schizophrenia participants. This relationship was mediated by negative symptom burden. Our findings provide novel evidence for brain-based biomarkers of longitudinal functional outcome in people with schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Depression is one of the most prevalent mental illnesses worldwide and a leading cause of disability, especially in the setting of treatment resistance. In recent years, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative strategy for treatment-resistant depression and its clinical efficacy has been investigated intensively across the world. However, the underlying neurobiological mechanisms of the antidepressant effect of rTMS are still not fully understood. This review aims to systematically synthesize the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996-2014), Embase (1980-2014) and PsycINFO (1806-2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1647 articles identified, 66 studies met both inclusion and exclusion criteria. rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limits the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggest that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. More research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

Background: A significant proportion of patients with depression fail to respond to psychotherapy and standard pharmacotherapy, leading to treatment-resistant depression (TRD). Due to the significant prevalence of TRD, alternative therapies for depression have emerged as viable treatments in the armamentarium for this disorder. Repetitive transcranial magnetic stimulation (rTMS) is now being offered in clinical practice in broader numbers. Many studies have investigated various different neurobiological predictors of response of rTMS. However, a synthesis of this literature and an understanding of what biological targets predict response is lacking. This review aims to systematically synthesize the literature on the neurobiological predictors of rTMS in patients with depression., Methods: Medline (1996-2014), Embase (1980-2014), and PsycINFO (1806-2014) were searched under set terms. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually., Results: The search identified 1,673 articles, 41 of which met both inclusion and exclusion criteria. Various biological factors at baseline appear to predict response to rTMS, including levels of certain molecular factors, blood flow in brain regions implicated in depression, electrophysiological findings, and specific genetic polymorphisms., Conclusions: Significant methodological variability in rTMS treatment protocols limits the ability to generalize conclusions. However, response to treatment may be predicted by baseline frontal lobe blood flow, and presence of polymorphisms of the 5-hydroxytryptamine (5-HT) -1a gene, the LL genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) gene, and Val/Val homozygotes of the brain-derived neurotrophic factor (BDNF) gene., (© 2015 Wiley Periodicals, Inc.)

Objective: Cognitive deficits are among the strongest predictors of function in individuals with schizophrenia. This relationship continues to be strong as these individuals grow older into their eight decade. Cognitive remediation (CR) improves cognition in individuals with schizophrenia. This study aims at assessing the feasibility and potential effect of CR in patients with schizophrenia 60 years of age or older., Methods: We adapted a CR protocol involving restorative and strategy-based methods over four cohorts of older outpatients with schizophrenia to target cognitive deficits associated with aging and schizophrenia. CR was provided in eight, 2-h weekly didactic sessions and online at-home exercises. Computerized drill and practice exercises were used with bridging to activities of daily life. Computer exercise selection and difficulty level parameters optimized adherence. Progression individually determined difficulty levels. We modified computer laboratory ergonomics to accommodate mobility needs. Participants were assessed at baseline and end-of-study using clinical and cognitive assessments., Results: Twenty-two participants enrolled: 18 (mean [SD] age: 69.8 [5.3]) completed CR. Mean (SD) global cognition T score from the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery was 27.7 (10) at baseline and 28.8 (9.7) at the completion of the study. These means are over 2 SD below the norms. The change in global cognition was not statistically significant (paired t(17) = -1.18, p = 0.25)., Conclusions: Our pilot study suggests that CR is well tolerated by most older outpatients with schizophrenia. Future studies need to assess whether increasing the frequency or the number of CR sessions leads to significant improvement in cognition., (Copyright © 2015 John Wiley & Sons, Ltd.)

Exciting developments have taken place in the neuroscience research in autism spectrum disorder (ASD), and results from these studies indicate that brain in ASD is associated with aberrant neuroplasticity. Transcranial magnetic stimulation (TMS) has rapidly evolved to become a widely used, safe, and non-invasive neuroscientific tool to investigate a variety of neurophysiological processes, including neuroplasticity. The diagnostic and therapeutic potential of TMS in ASD is beginning to be realized. In this article, we briefly reviewed evidence of aberrant neuroplasticity in ASD, suggested future directions in assessing neuroplasticity using repetitive TMS (rTMS), and discussed the potential of rTMS in rectifying aberrant neuroplasticity in ASD.

Importance: Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS., Objective: To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS., Design, Setting, and Participants: An open-label, single-arm prospective study with a 3- to 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged ≥ 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015., Interventions: Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction., Main Outcomes and Measures: Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels)., Results: Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stability was 50%. Extrapyramidal symptoms (EPSs) were more likely to occur with D2/3R occupancies higher than 60%: 90.5% (19 of 21) of the participants with baseline EPSs and 76.9% (10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancies were lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58% [15%] vs 72% [10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased., Conclusions and Relevance: Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

Newer approaches to characterizing hippocampal morphology can provide novel insights regarding cognitive function across the lifespan. We comprehensively assessed the relationships among age, hippocampal morphology, and hippocampal-dependent cognitive function in 137 healthy individuals across the adult lifespan (18-86 years of age). They underwent MRI, cognitive assessments and genotyping for Apolipoprotein E status. We measured hippocampal subfield volumes using a new multiatlas segmentation tool (MAGeT-Brain) and assessed vertex-wise (inward and outward displacements) and global surface-based descriptions of hippocampus morphology. We examined the effects of age on hippocampal morphology, as well as the relationship among age, hippocampal morphology, and episodic and working memory performance. Age and volume were modestly correlated across hippocampal subfields. Significant patterns of inward and outward displacement in hippocampal head and tail were associated with age. The first principal shape component of the left hippocampus, characterized by a lengthening of the antero-posterior axis was prominently associated with working memory performance across the adult lifespan. In contrast, no significant relationships were found among subfield volumes and cognitive performance. Our findings demonstrate that hippocampal shape plays a unique and important role in hippocampal-dependent cognitive aging across the adult lifespan, meriting consideration as a biomarker in strategies targeting the delay of cognitive aging., (© 2015 Wiley Periodicals, Inc.)

Background: Cortical inhibition (CI) deficits have been demonstrated in schizophrenia using transcranial magnetic stimulation (TMS). These CI deficits may be related to decreased GABA activity which may be involved in schizophrenia pathophysiology. Previous cross-sectional studies have also demonstrated greater CI in patients treated with clozapine than other typical/atypical antipsychotics. However, it is not clear if these differences in CI are a result of treatment-resistant illness which necessitates clozapine or are related to clozapine treatment., Methods: TMS measures of CI (i.e., cortical silent period (CSP) and short-interval cortical inhibition (SICI)) were measured over the motor cortex in 16 patients with schizophrenia before starting clozapine, then 6 weeks and 6 months after starting clozapine., Results: CSP was significantly longer after 6 weeks of treatment with clozapine (p=0.014). From 6 weeks to 6 months, there was no significant difference in CSP (p>0.05). Short-interval cortical inhibition (SICI) was not significantly different at any time after treatment with clozapine (p>0.05)., Conclusions: This prospective-longitudinal study demonstrates that treatment with clozapine is associated with an increase in GABAB mediated inhibitory neurotransmission. Potentiation of GABAB may be a novel neurotransmitter mechanism that is involved in the pathophysiology and treatment of schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia., Method: Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity., Results: The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains., Conclusions: This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Studies of diffusion tensor imaging have focused mainly on the role of deep white matter tract microstructural abnormalities associated with aging and age-related cognitive decline. However, the potential role of superficial white matter (SWM) in aging and, by extension, cognitive-aging, is less clear. Healthy individuals (n = 141; F/M: 66/75 years) across the adult lifespan (18-86 years) underwent diffusion tensor imaging and a battery of cognitive testing. SWM was assessed via a combination of probabilistic tractography and tract-based spatial statistics (TBSS). A widespread inverse relationship of fractional anisotropy (FA) values in SWM with age was observed. SWM-FA adjacent to the precentral gyri was associated with fine-motor-speed, whereas performance in visuomotor-attention/processing speed correlated with SWM-FA in all 4 lobes of the left-hemisphere and in right parieto-occipital SWM-FA (family-wise error corrected p < 0.05). Independent of deep white matter-FA, right frontal and right occipital SWM-FA-mediated age effects on motor-speed and visuomotor-attention/processing speed, respectively. Altogether, our results indicate that SWM-FA contributes uniquely to age-related cognitive performance, and should be considered as a novel biomarker of cognitive-aging., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Magnetic seizure therapy (MST) is a novel brain stimulation modality used to treat refractory depression through the induction of seizures. It is currently being investigated as a potential alternative treatment to electroconvulsive therapy. To our knowledge, there have not been any previous reports of MST-induced mania., Objective: We aim to describe 2 cases of patients with a major depressive episode who developed acute symptoms of mania during a course of MST., Methods: The current report describes 2 cases of mania that occurred in the context of an ongoing open-label study of MST in treatment-resistant depression. The MST was administered 2 or 3 times per week and applied directly over the left and right dorsolateral prefrontal cortex. Treatment is administered until patients achieve remission or a maximum of 24 treatments. A MagVenture Twin coil and MST stimulator were used for treatment. The center of each coil was placed over F3 and F4 according to the 10-20 electroencephalography system., Results: Patient 1 had developed manic symptoms precipitously after the sixth MST treatment, and patient 2 developed manic symptoms after the 23rd MST treatment. In both patients, the MST treatment course was stopped. Their manic symptoms resolved rapidly with pharmacotherapy after cessation of MST treatments., Conclusions: As with electroconvulsive therapy, switches to mania or hypomania should be considered as potential adverse effects of MST.

Objective: Increases in oxidative stress have been consistently reported in younger patients with bipolar disorder (BD) in postmortem brain and blood samples studies. Changes in oxidative stress are also associated with the natural aging process. Thus, the investigation of oxidative stress across the life span of patients with BD is crucial., Methods: We compared the levels of oxidative damage to proteins and lipids in plasma from 110 euthymic older patients with BD I or II (mean±SD age: 63.9±9.7 years) and 75 older healthy individuals (66.0±9.6 years). To assess protein oxidation, we measured the plasma levels of protein carbonyl (PC) and 3-nitrotyrosine (3-NT) using the ELISA technique. To assess lipid peroxidation, we measured plasma levels of lipid hydroperoxide (LPH) and 4-hydroxynonenal (4-HNE) using spectrophotometric assays., Results: LPH levels were higher in patients than in the comparison healthy individuals, whereas there were no significant differences for PC, 3-NT, and 4-HNE between the two groups., Conclusions: The increased levels of an early component of the peroxidation chain (LPH) in euthymic older patients with BD support the hypothesis of a persistent effect of reactive species of oxygen in patients with BD into late life., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Life expectancy in individuals with schizophrenia continues to increase. It is not clear whether cognitive deficits associated with schizophrenia remain as strong predictors of function in older and younger individuals. Thus, we assessed the relationship between cognition and functional competence in individuals with schizophrenia across 7 decades of life., Methods: We analyzed data obtained in 232 community-dwelling participants with schizophrenia (age range: 19-79 years). Cognition was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. Functional competence was assessed using the UCSD Performance-based Skills Assessment, which includes measures of Comprehension and Planning of Recreational Activities Skills, Financial Skills, Communication Skills, Transportation Skills, and Household Management Skills. To assess the effects of Global Cognition on functional competence, we performed hierarchical multivariate linear or logistic regression analyses controlling for age, education, gender, and negative symptoms., Results: Participants' mean age was 49.1 (SD = 13.2, range = 19-79 years), 161 (69%) were male, and 55 (24%) were aged ≥60. Global Cognition was a predictor of Comprehension and Planning Skills (Exp(β) = 1.048), Financial Skills (Exp(β) = 1.104), Communication Skills (ΔR (2) = .31) and Transportation Skills (Exp(β) = 1.066), but not Household Management Skills after adjusting for age, education, gender, and negative symptoms of schizophrenia., Conclusion: Cognition remains a strong predictor of functional competence across the lifespan. These findings suggest that treating cognitive impairment associated with schizophrenia could improve individuals' function independent of their age., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

As humans age, a characteristic pattern of widespread neocortical dendritic disruption coupled with compensatory effects in hippocampus and other subcortical structures is shown in postmortem investigations. It is now possible to address age-related effects on gray matter (GM) neuritic organization and density in humans using multishell diffusion-weighted MRI and the neurite-orientation dispersion and density imaging (NODDI) model. In 45 healthy individuals across the adult lifespan (21-84 years), we used a multishell diffusion imaging and the NODDI model to assess the intraneurite volume fraction and neurite orientation-dispersion index (ODI) in GM tissues. We also determined the functional correlates of variations in GM microstructure by obtaining resting-state fMRI and behavioral data. We found a significant age-related deficit in neocortical ODI (most prominently in frontoparietal regions), whereas increased ODI was observed in hippocampus and cerebellum with advancing age. Neocortical ODI outperformed cortical thickness and white matter fractional anisotropy for the prediction of chronological age in the same individuals. Higher GM ODI sampled from resting-state networks with known age-related susceptibility (default mode and visual association networks) was associated with increased functional connectivity of these networks, whereas the task-positive networks tended to show no association or even decreased connectivity. Frontal pole ODI mediated the negative relationship of age with executive function, whereas hippocampal ODI mediated the positive relationship of age with executive function. Our in vivo findings align very closely with the postmortem data and provide evidence for vulnerability and compensatory neural mechanisms of aging in GM microstructure that have functional and cognitive impact in vivo., (Copyright © 2015 the authors 0270-6474/15/351753-10$15.00/0.)

Cognitive deficits are commonly observed in patients with schizophrenia. Converging lines of evidence suggest that these deficits are associated with impaired long-term potentiation (LTP). In our systematic review, this hypothesis is evaluated using neuroimaging literature focused on proton magnetic resonance spectroscopy, positron emission tomography, and single-photon emission computed tomography. The review provides evidence for abnormal dopaminergic, GABAergic, and glutamatergic neurotransmission in antipsychotic-naive/free patients with schizophrenia compared with healthy controls. The review concludes with a model illustrating how these abnormalities could lead to impaired LTP in patients with schizophrenia and consequently cognitive deficits., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The aim of this study was to develop self-report and clinician-rated versions of an insight scale that would be easy to administer, sensitive to small changes, and inclusive of the core dimensions of clinical insight into psychosis. Ten-item self-report (VAGUS-SR) and five-item clinician-rated (VAGUS-CR) scales were designed to measure the dimensions of insight into psychosis and evaluated in 215 and 140 participants, respectively (www.vagusonline.com). Tests of reliability and validity were performed. Both the VAGUS-SR and VAGUS-CR showed good internal consistency and reliability. They demonstrated good convergent and discriminant validity. Both versions were strongly correlated with one another and with the Schedule for the Assessment of Insight and Birchwood Insight Scale. Exploratory factor analyses identified three possible latent components of insight. The VAGUS-CR and VAGUS-SR are valid, reliable and easy to administer. They are build on previous insight scales with separate clinician-rated and self-report versions. The VAGUS-SR exhibited a multidimensional factor structure. Using a 10-point Likert scale for each item, the VAGUS has the capacity to detect small, temporally sensitive changes in insight, which is essential for intervention studies with neurostimulation or rapidly acting medications., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Impaired insight into illness is a prevalent feature of schizophrenia, which negatively influences treatment adherence and clinical outcomes. Little is known about the effects of aging on insight impairment. We aimed to review the available research literature on the effects of aging on insight into illness in schizophrenia, in relation to positive, negative, and cognitive symptoms. Ultimately, we propose a trajectory of insight in schizophrenia across the lifespan., Method: A systematic Medline® literature search was conducted, searching for English language studies describing the relationship of insight into illness in schizophrenia with aging., Results: We identified 62 studies. Insight impairment is associated with illness severity, premorbid intellectual function (i.e. IQ), executive function, and memory. Insight impairment improves modestly during midlife, worsening again in late life. It tends to fluctuate with each episode of psychosis, likely in relation to worsening positive symptoms that improve with antipsychotic treatment. The relationship between insight impairment and cognitive dysfunction appears to attenuate with age, while the relationship with lower premorbid intellectual function is preserved. The association between impaired insight and negative symptoms is unclear., Conclusions: The available literature suggests that the course of insight impairment follows a U-shaped curve, where insight impairment is severe during the first episode of psychosis, modestly improves over midlife, and declines again in late life. Future studies are required to investigate the trajectory of insight into illness and its core domains across the lifespan from prodromal phase to late life., (Copyright © 2014 John Wiley & Sons, Ltd.)

In people with schizophrenia, cognitive abilities - including memory - are strongly associated with functional outcome. Long-term potentiation (LTP) is a form of neuroplasticity that is believed to be the physiological basis for memory. It has been postulated that antipsychotic medication can impair long-term potentiation and cognition by altering dopaminergic transmission. Thus, a systematic review was performed in order to assess the relationship between antipsychotics and D2 antagonists on long-term potentiation. The majority of studies on LTP and antipsychotics have found that acute administration of antipsychotics was associated with impairments in LTP in wild-type animals. In contrast, chronic administration and acute antipsychotics in animal models of schizophrenia were not. Typical and atypical antipsychotics and other D2 antagonists behaved similarly, with the exception of clozapine and olanzapine. Clozapine caused potentiation independent of tetanization, while olanzapine facilitated tetanus-induced potentiation. These studies are limited in their ability to model the effects of antipsychotics in patients with schizophrenia as they were largely performed in wild-type animals as opposed to humans with schizophrenia, and assessed after acute rather than chronic treatment. Further studies using patients with schizophrenia receiving chronic antipsychotic treatment are needed to better understand the effects of these medications in this population., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D(2/3) receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D(2/3) relative receptor occupancy (RRO) on clinical outcomes in this population., Design: Open-label intervention., Setting: Centre for Addiction and Mental Health, Toronto., Participants: Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for D(2/3) RRO in dorsal putamen was assessed, using the region of interest analysis of [¹¹C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale., Results: Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D(2/3) RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D(2/3) RRO., Conclusion: EPS diminished less than 70% D(2/3) RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Working memory is associated with gamma oscillations (30-50 Hz). Previous studies have demonstrated altered gamma oscillations in the elderly population that may be related to general cognitive decline. However, it is unknown how gamma oscillations change with age or if there is an age when gamma oscillations optimally mediate working memory performance. That is, gamma oscillations may be maximal in middle-aged adults compared to younger and elderly adults. The objective of this study was to evaluate working memory evoked gamma oscillations in adults aged 19-29 years (mean 23.32 ± 2.85 1 SD) compared to adults aged 30-60 years (mean 39.10 ± 8.11 1 SD)., Methods: Subjects completed the verbal N-back task administered at four working loads (0, 1, 2, 3), while electroencephalography (EEG) was collected. Gamma power was measured during correct responses., Results: Reduced gamma oscillations were observed in the adults aged 19-29 compared to those aged 30-60 years. Age was found to be positively related to the power of gamma oscillations. No differences were found on N-Back accuracy., Conclusions: Increased working memory evoked gamma oscillatory activity may provide a neurophysiological marker in the healthy aging brain., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Prominent regional cortical thickness reductions have been shown in schizophrenia. In contrast, little is known regarding alterations of structural coupling between regions in schizophrenia and how these alterations may be related to cognitive impairments in this disorder., Methods: T1-weighted magnetic resonance images were acquired in 54 patients with schizophrenia and 68 healthy control subjects aged 18-55 years. Cortical thickness was compared between groups using a vertex-wise approach. To assess structural coupling, seeds were selected within regions of reduced thickness, and brain-wide cortical thickness correlations were compared between groups. The relationships between identified patterns of circuit structure disruption and cognitive task performance were then explored., Results: Prominent cortical thickness reductions were found in patients compared with controls at a 5% false discovery rate in a predominantly frontal and temporal pattern. Correlations of the left dorsolateral prefrontal cortex (DLPFC) with right prefrontal regions were significantly different in patients and controls. The difference remained significant in a subset of 20 first-episode patients. Participants with stronger frontal interhemispheric thickness correlations had poorer working memory performance., Conclusions: We identified structural impairment in a left-right DLPFC circuit in patients with schizophrenia independent of illness stage or medication exposure. The relationship between left-right DLPFC thickness correlations and working memory performance implicates prefrontal interhemispheric circuit impairment as a vulnerability pathway for poor working memory performance. Our findings could guide the development of novel therapeutic interventions aimed at improving working memory performance in patients with schizophrenia., (© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Late-life mental illness is a growing concern. Current medications have limited efficacy and are associated with safety concerns. A variety of brain stimulation approaches offers alternative treatments. We performed a systematic literature search on the efficacy and safety of brain stimulation in late-life mental illnesses, excluding unipolar nonpsychotic depression. Studies on deep brain stimulation, electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and vagal nerve stimulation that enrolled exclusively older adults (≥65 years) or analyzed older adults as a separate group were included. The search identified 1,181 publications, of which 43 met the above inclusion criteria: 24 were related to the treatment of non-unipolar depression (ECT: 21; rTMS: 2; ECT and rTMS: 1), 14 related to dementia (ECT: 7[2 of these studies were also related to depression]; vagal nerve stimulation: 2; rTMS: 4; deep brain stimulation: 1), and 7 to schizophrenia (ECT: 7). These studies reported a high degree of variability in efficacy and safety with promising results in general, particularly in the treatment of dementia and schizophrenia. Most publications were limited by small sample sizes, lack of control conditions, and lack of randomization. Large studies with a randomized controlled design or other designs such as crossover or off-on-off-on are needed. In contrast to the empiric and nonspecific use of ECT, future studies using modalities other than ECT could focus on novel biologically based interventions that target specific circuitry. These interventions could also be combined with other non-brain stimulation treatments for possible synergistic effects., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

This paper aims to review longitudinal studies assessing the impact of cognition on function in patients with schizophrenia. PubMed and Scholars Portal were searched using search terms related to schizophrenia, cognition, function, and longitudinal studies. Some functional abilities have been studied more than others. Some studies suggest that the impact of cognition on function depends on the severity of baseline cognitive deficits. Other studies suggest that the impact of cognition on function depend on what phase of the illness the patient is in or what stage in that particular function the patient is involved in. Finally, few studies assessed interactions between cognition and other aspects of schizophrenia in predicting function, such as functional capacity, insight, motivation, and negative symptoms. More longitudinal and comprehensive studies are needed. A focus on community living is of high public significance as patients with schizophrenia continue to grow old. Future studies should also focus on the longitudinal interactions between cognition and other dimensions of schizophrenia as well as on the biological factors that underlie these interactions.

Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical-evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of θ- and γ-activity and θ-phase-γ-amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied.

Impaired insight into illness is a common but poorly understood phenomenon in schizophrenia. Several studies in midlife adults with schizophrenia have reported an association between impaired insight and illness severity, executive dysfunction, premorbid intellectual function, and to a lesser degree attention. Aging is associated with a decline in attention and executive function. Thus, the relationship between cognition and insight is expected to differ between younger and older adults with schizophrenia. This study assessed this relationship among 50 patients with schizophrenia 60 years and older. Insight was explained by illness severity (16.2% of the variance) and premorbid intellectual function (23.9% of the variance), but not by attention or executive function. Our findings suggest that the predictors of insight in schizophrenia differ early and later in life. In particular, insight's association with attention and executive function observed in younger patients is attenuated by age-related changes in cognition. In contrast, premorbid intellectual function continues to be a strong predictor of insight in late life, which highlights the need to better understand and enhance cognitive function early in the course of schizophrenia., (© 2013.)

Oligodendrocyte genes and white matter tracts have been implicated in the pathophysiology of schizophrenia and may play an important etiopathogenic role in cognitive dysfunction in schizophrenia. The objective of the present study in 60 chronic schizophrenia patients individually matched to 60 healthy controls was to determine whether 1) white matter tract integrity influences cognitive performance, 2) oligodendrocyte gene variants influence white matter tract integrity and cognitive performance, and 3) effects of oligodendrocyte gene variants on cognitive performance are mediated via white matter tract integrity. We used the partial least-squares multivariate approach to ascertain relationships among oligodendrocyte gene variants, integrity of cortico-cortical and subcortico-cortical white matter tracts, and cognitive performance. Robust relationships among oligodendrocyte gene variants, white matter tract integrity, and cognitive performance were found in both patients and controls. We also showed that effects of gene variants on cognitive performance were mediated by the integrity of white matter tracts. Our results were strengthened by bioinformatic analyses of gene variant function. To our knowledge, this is the first study that has brought together these lines of investigation in the same population and highlights the importance of the oligodendrocyte/white matter pathway in schizophrenia, particularly as it pertains to cognitive function.

Post-mortem studies have demonstrated alterations in superficial white matter (SWM) in schizophrenia patients. Diffusion tensor imaging (DTI) can be used to assess SWM in vivo, and compare SWM fractional anisotropy (FA) in schizophrenia patients vs healthy controls. The assessment of SWM in vivo also provides an opportunity to identify novel neural correlates of cognitive performance, and potential cognitive impairment in schizophrenia patients. Forty-four patients with schizophrenia and 44 matched healthy controls underwent neuroimaging and cognitive protocols. Using an SWM mask and tract-based spatial statistics, differences in SWM-FA were examined between groups. SWM-FA clusters different between groups were then used to predict cognitive performance with multiple linear regression. The relative contribution of SWM fiber subtypes (deep white matter extensions vs U-fibers and intraregional fibers) from significantly different clusters was examined. Compared to controls, patients with schizophrenia had reduced FA in five SWM clusters: the largest a left posterior parieto-occipital cluster, followed by four clusters in the left frontal lobe. SWM-FA in the frontal lobe clusters predicted attention, working memory, and processing speed performance in healthy controls, but not in patients with schizophrenia. The majority of streamlines tracked from these clusters were restricted to U-fibers and intraregional fibers, rather than deep white matter extensions. Our analyses revealed prominent SWM disruption in patients with schizophrenia compared to controls. SWM-cognition relationships shown in healthy individuals were disrupted in patients with schizophrenia. SWM may be an important neurobiological substrate of cognitive performance and a novel cortical treatment target for cognitive deficits in schizophrenia patients.

Importance: A major obstacle to the identification of the neurobiological correlates of schizophrenia is the substantial clinical heterogeneity present in this disorder. Dividing schizophrenia into "deficit" and "nondeficit" subtypes may reduce heterogeneity and facilitate identification of neurobiological markers of disease., Objective: To determine whether patients with deficit schizophrenia differ from patients with nondeficit schizophrenia and healthy controls in neuroimaging-based measures of white matter tracts and gray matter morphology., Design: A cross-sectional neuroimaging study of patients with the deficit or nondeficit subtype of schizophrenia and healthy controls., Setting: University hospital., Participants: Seventy-seven patients with schizophrenia and 79 healthy controls., Interventions: All participants were administered the Structured Clinical Interview for DSM-IV-TR Axis I Disorders and the Positive and Negative Syndrome Scale; IQ was measured using the Wechsler Test for Adult Reading; global cognitive impairment was grossly assessed using the Mini-Mental State Examination; comorbid physical illness burden was measured by administration of the Clinical Information Rating Scale-Geriatrics; high-resolution magnetic resonance imaging was performed as part of a multimodal imaging protocol; and deficit status was determined using the proxy scale for the deficit syndrome., Main Outcome Measures: Diffusion-based measures of white matter tracts, cortical thickness, cortical surface area, and volumes of subcortical structures., Results: In both an individually matched approach (18 patients with deficit schizophrenia, 18 patients with nondeficit schizophrenia, and 18 healthy controls) and an unmatched population-based approach (18 patients with deficit schizophrenia, 59 patients with nondeficit schizophrenia, and 79 health controls), the patients with deficit schizophrenia demonstrated disruption of white matter tracts compared with patients with nondeficit schizophrenia and healthy controls at the right inferior longitudinal fasciculus, the right arcuate fasciculus, and the left uncinate fasciculus. These findings were supported in patients with first-episode schizophrenia (n = 20) who had a deficit score that was strongly correlated with disruption at these same tracts. In contrast, patients with schizophrenia of either subtype exhibited cortical thickness reductions compared with healthy controls, in near-identical neuroanatomic patterns. Surface areas and subcortical volumes did not differ significantly among the 3 groups., Conclusions and Relevance: The convergence of findings in our individually matched sample, our unmatched overall sample, and our first-episode schizophrenia sample demonstrate (1) white matter tract disruption as a neurobiological feature of the deficit syndrome and (2) reductions in cortical thickness as a common feature of patients with a diagnosis of schizophrenia. When taken with previous results in gray matter, our findings in white matter tracts point to neural circuitry important for socioemotional function as a core neurobiological feature of the deficit subtype of schizophrenia.

Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial., Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions., Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%., Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.

Introduction: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia., Methods: Both voxel-based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation-based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates., Results: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation-based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01)., Conclusion: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume-based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations., (Copyright © 2012 Wiley Periodicals, Inc.)

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 (MIR137) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia (n=510; F1,506=17.7, P=3.1 × 10(-5)). In an imaging-genetics subsample that included additional matched controls (n=213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity (F3,209=13.6, P=3.88 × 10(-8)) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls.

Background: Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels., Methods: In a 4-week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n = 13) or sham (n = 12) rTMS treatment course., Results: The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohen's d = .92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects., Conclusions: These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

We reviewed novel brain stimulation approaches that modify neuroplasticity and are used in the treatment and study of schizophrenia. We searched PubMed and Scholars Portal using search terms related to schizophrenia, brain stimulation, and neuroplasticity. Various brain stimulation approaches simulating a range of experimental protocols that induce synaptic long-term potentiation or depression have been developed. By far, repetitive transcranial magnetic stimulation (rTMS) has been the most widely used in the field of schizophrenia. Its application has been associated with mixed results in treating treatment-resistant symptoms and cognitive deficits associated with schizophrenia. Compared to the other approaches, rTMS is probably the least similar to plasticity-inducing cellular paradigms. Other approaches, such as paired associative stimulation, theta-burst stimulation, and transcranial direct current stimulation, are in their incipient stages in the study and treatment of schizophrenia, with promising early results. Numerous brain stimulation approaches have been developed to treat resistant dimensions of schizophrenia. Notwithstanding some promising reports, optimization of the methods and large randomized controlled trials are still needed.

The adaptations resulting from neural plasticity lead to changes in cognition and behaviour, which are strengthened through repeated exposure to the novel environment or stimulus. Learning and memory have been hypothesized to occur through modifications of the strength of neural circuits, particularly in the hippocampus and cortex. Cognitive deficits, specifically in executive functioning and negative symptoms, may be a corollary to deficits in neural plasticity. Moreover, the main excitatory and inhibitory neurotransmitters associated with neural plasticity have also been extensively investigated for their role in the cognitive deficits associated with schizophrenia. Transcranial magnetic stimulation (TMS) represents some of the most promising approaches to directly explore the physiological manifestations of neural plasticity in the human brain. Three TMS paradigms (use-dependent plasticity, paired associative stimulation, and repetitive TMS) have been used to evaluate neurophysiological measures of neural plasticity in the healthy brain and in patients with schizophrenia, and to examine the brain's responses to such stimulation. In schizophrenia, deficits in neural plasticity have been consistently shown which parallel the molecular evidence appearing to be entwined with this debilitating disorder. Such pathophysiology may underlie the learning and memory deficits that are key symptoms of this disorder and may even be a key mechanism involved in treatment with antipsychotics.

Objectives: The objectives of this study were to determine the effect of aging, schizophrenia, and their interaction on cognitive function., Design: Cross-sectional controlled study., Setting: Community living., Participants: A total of 235 subjects with schizophrenia age 19-79 and 333 comparison subjects age 20-81., Measurements: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB)., Results: Older age was associated with poorer performance on 9 of 10 MCCB tests in both subjects with schizophrenia and comparison subjects. Subjects with schizophrenia were impaired relative to comparison subjects on each of the 10 tests. However, there was no interaction between aging and schizophrenia on any test. Essentially the same results were observed when analyzing performance on the seven MCCB cognitive domains and MCCB global composite score., Conclusions: Consistent with other reports, schizophrenia appears to be a disorder marked by generalized cognitive dysfunction. However, the rate of cognitive decline appears to be similar to that observed in healthy comparison subjects. They do not experience acceleration in cognitive aging, which supports the hypothesis that schizophrenia is a syndrome of premature aging. Longitudinal studies including very old patients are needed to confirm and extend these findings., (Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study is to compare the Empirical Behavioral Rating Scale (E-BEHAVE-AD), Neurobehavioral Rating Scale (NBRS), and Neuropsychiatric Interview (NPI) in detecting behavioral disturbance and psychotic symptoms in dementia and characterizing changes in response to treatment., Design: Eighty-seven subjects in the randomized controlled trial "Continuation Pharmacotherapy for Agitation of Dementia" were included in this analysis. We compared the detection in, and changes of, both agitation and psychosis, using these three instruments. A receiver operating characteristic analysis was performed to compare the performance of the three instruments in detecting global improvement., Results: The instruments were equally likely to detect agitation. The NBRS was most likely to detect psychosis. Although the NPI best detected improvement in agitation, the instruments were equal for detecting improvement in psychosis. In the receiver operating characteristic analysis for overall clinical improvement in response to treatment, there were no differences in the areas under the correlated curves for the three instruments, but they demonstrated different sensitivity and specificity at different cutoff points for target symptom reduction. The E-BEHAVE-AD performed best at a cut point of 30% target symptom reduction and the NBRS and NPI both performed best at 50%., Conclusion: The E-BEHAVE-AD, NBRS, and NPI were more similar than different in characterizing symptoms but differed in detecting response to treatment. Differences in sensitivity and specificity may lead clinicians to prefer a specific instrument, depending on their goal and the expected magnitude of response to any specific intervention., (Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE:: In younger patients with schizophrenia, positron emission tomography (PET) studies have identified a therapeutic window of striatal dopamine D2/3 receptor occupancy of 65%-80%. This type of empirical information is not available in late life. Our primary aim was to assess the effect of changes in D2/3 relative receptor occupancy (RRO) on clinical outcomes in this population. DESIGN:: Open-label intervention. SETTING:: Centre for Addiction and Mental Health, Toronto. PARTICIPANTS:: Subjects with schizophrenia age 50 years or more who were clinically stable and previously maintained on oral risperidone for more than 6 months. INTERVENTION:: A dose reduction of risperidone of up to 40%, followed by a 3-month follow-up. MEASUREMENTS:: Dopamine D2/3 RRO in dorsal putamen was assessed, using the region of interest analysis of [C]raclopride PET scans, before and after the dose reduction. Clinical assessments included the Positive and Negative Syndrome Scale and the Simpson-Angus Scale. RESULTS:: Nine subjects (mean ± SD age: 58 ± 7 years; mean ± SD baseline risperidone dose: 3.4 ± 1.6 mg/day) participated in the study. Extrapyramidal symptoms (EPS) were present in six subjects and were associated with 70% or more D2/3 RRO in the putamen (range: 70%-87%). Following the dose reduction, EPS resolved in five subjects. Two subjects experienced a clinical worsening at 52% and at less than 50% D2/3 RRO. CONCLUSION:: EPS diminished less than 70% D2/3 RRO, which suggests a lower therapeutic window for older patients with schizophrenia than that for younger patients. Although these findings have to be replicated in a larger sample, they have important implications for future drug development and clinical guidelines in late-life schizophrenia.

Objectives: High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). There are few published reports on the efficacy of sequential bilateral rTMS compared to HFL and sham rTMS. Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD., Methods: Subjects between the ages of 18 and 85 were recruited from a tertiary care university hospital. Seventy-four subjects with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. The rates of remission were compared among the three treatment groups., Results: The remission rates differed significantly among the three treatment groups using a modified intention to treat analysis that excluded subjects who did not respond to electroconvulsive therapy (ECT) during the current episode. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the unilateral group did not differ from either group., Conclusion: These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.

Background: Cognitive deficits are core features in schizophrenia. Disruption in cholinergic neurotransmission has been associated with executive dysfunction in animals and humans. The objective of this study was to evaluate the impact of compromised cholinergic pathways on executive versus non-executive cognitive functions of patients with schizophrenia., Methods: 62 patients with schizophrenia and 62 age- and sex-matched non-psychiatric control subjects ("controls") were assessed and compared using: clinical measures, cognitive measures of global cognition, executive function, and memory; and an MRI-based visual rating scale that assesses damage strategically localized within the cholinergic pathways., Results: 11 of the 62 patients with schizophrenia (17.7%) and 6 of the 62 controls (9.7%) had compromised cholinergic pathways. These proportions were not statistically significant. Patients and controls with compromised cholinergic pathways were more impaired on measures related to executive function than patients or controls without compromised pathways., Conclusions: Patients with schizophrenia have worse executive function than controls. Compromised cholinergic pathways appear to worsen the executive dysfunction observed in schizophrenia. If these preliminary findings are replicated, they could lead to the identification of a subgroup of patients with schizophrenia who could specifically benefit from interventions enhancing cholinergic neurotransmission., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Myelin and oligodendrocyte disruption may be a core feature of schizophrenia pathophysiology. The purpose of the present study was to localize the effects of previously identified risk variants in the myelin-associated glycoprotein (MAG) gene on brain morphometry in schizophrenia patients and healthy controls. Forty-five schizophrenia patients and 47 matched healthy controls underwent clinical, structural magnetic resonance imaging, and genetics procedures. Gray and white matter cortical lobe volumes along with hippocampal volumes were calculated from T1-weighted MRI scans. Each subject was also genotyped for the two disease-associated MAG single nucleotide polymorphisms (rs720308 and rs720309). Repeated measures general linear model (GLM) analysis found significant region by genotype and region by genotype by diagnosis interactions for the effects of MAG risk variants on lobar gray matter volumes. No significant associations were found with lobar white matter volumes or hippocampal volumes. Follow-up univariate GLMs found the AA genotype of rs720308 predisposed schizophrenia patients to left temporal and parietal gray matter volume deficits. These results suggest that the effects of the MAG gene on cortical gray matter volume in schizophrenia patients can be localized to temporal and parietal cortices. Our results support a role for MAG gene variation in brain morphometry in schizophrenia, align with other lines of evidence implicating MAG in schizophrenia, and provide genetically based insight into the heterogeneity of brain imaging findings in this disorder.

Background: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting., Design: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates., Setting: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007., Participants: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril)., Measurements: A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder., Results: A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years., Conclusions: Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.

Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Lithium is the oldest and still one of the most frequently prescribed mood stabilizers in the treatment of bipolar disorder. Nonetheless, the evidence for lithium efficacy in older patients with bipolar disorder is almost entirely extrapolated from younger adult patients. Here we review the literature on lithium in older patients with bipolar disorder, concentrating on the past 3 years. A definitive study demonstrating the efficacy and safety of lithium in older patients with bipolar disorder is still missing. However, several lines of indirect evidence suggest that it is beneficial and advantageous over other mood stabilizers in the acute and maintenance treatment of late-life bipolar disorder. In addition, lithium may have unique properties as a regenerative therapeutic with specific benefits in reducing the cognitive impairment and suicide rates associated with bipolar disorder across the adult lifespan. Aging-associated pharmacokinetic and pharmacodynamic changes as well as increased rates of medical comorbidities and polypharmacy predispose older patients to a higher risk of lithium toxicity. Careful monitoring and adjustment of lithium dosage is especially important in older adults to minimize the risk of toxicity.

Although patients with schizophrenia are reported to have excess mortality compared with the general population, many affected patients will nonetheless survive and continue to have the disorder in later life. Consequently, geriatric schizophrenia will be a significant public health concern in the years to come, and evidence-based treatment of schizophrenia in older patients is becoming an urgent issue. However, there has been a paucity of comparative data to guide selection of antipsychotics for schizophrenia in late life. The primary aim of this review was to synthesize the available evidence on management of late-life schizophrenia with antipsychotic medications; a secondary aim was to evaluate treatment resistance in this population. Accordingly, PubMed and EMBASE were searched using the keywords 'antipsychotics', 'age' and 'schizophrenia' to identify psychopharmacological studies of antipsychotics in late-life schizophrenia (last search 30 April 2011). The literature search identified 23 prospective studies of use of antipsychotics for schizophrenia in older patients (generally age ≥65 years), including eight double-blind trials. The sample size was smaller than 40 patients for 52% of the studies. Two of the double-blind studies were post hoc analyses and one was a placebo-controlled trial. In the largest double-blind study, olanzapine (n = 88, median dose 10 mg/day) and risperidone (n = 87, median dose 2 mg/day) were compared in patients not resistant to these therapies, with similar effects. There have also been several open-label trials of these two agents that have shown efficacy and tolerability in non-resistant patients. Evidence on other antipsychotics has been scarce and less robust. The gold standard for treatment-resistant schizophrenia is clozapine. However, almost all of the studies of clozapine to date have effectively excluded older patients with schizophrenia. Only one small study has evaluated clozapine (n = 24, mean dose 300 mg/day) in comparison with chlorpromazine (n = 18, mean dose 600 mg/day) in a difficult-to-treat older population; the investigators reported that both treatments were similarly efficacious. Furthermore, there has been little compelling evidence in favour of or against augmentation of antipsychotics with other psychotropic medications in the older age group. Treatment of non-resistant, late-life schizophrenia with olanzapine and risperidone appears to be supported by the available evidence. However, data on geriatric patients with schizophrenia are generally scarce, particularly for treatment-resistant subpopulations, underscoring the need for more research in this important area.