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Little is known about factors that contribute to attrition in clinical trials of the pharmacotherapy of psychotic depression. The purpose of this study was to identify factors associated with attrition during acute pharmacotherapy in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II) clinical trial. Sociodemographic and clinical variables were assessed at baseline in 269 men and women, aged 18-85 years, who were treated with up to 12 weeks of open-label sertraline plus olanzapine. Univariate analyses examined the association of baseline variables with overall non-completion, as well as reasons for non-completion. Logistic regression was used to model the relationship of the significant univariate predictors with non-completion and its reasons. Seventy-four (27.5 %) participants did not complete the acute treatment phase of STOP-PD II. Male gender, younger age, inpatient status, higher Clinical Global Impression (CGI) severity of illness, and higher severity of psychomotor disturbance were associated with non-completion in univariate analyses. In regression models, higher CGI severity of illness score was the only significant independent predictor of non-completion, explained by withdrawal of consent. Our findings have implications for the retention of persons with psychotic depression in clinical trials., Competing Interests: Declaration of competing interest R. A. Ihaddadene has no competing interests; G.S. Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, Sunovion; P. Marino received research support from the NIMH at the time this work was done; B.S. Meyers received research support from the NIMH at the time this work was done; B.H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received research support during the past three years from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past three years, he has also been an unpaid consultant to Myriad Neuroscience; N.H Neufeld has served on an advisory board for Boehringer Ingelheim; he has received grant support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, Labatt Family Network for Research on the Biology of Depression and the University of Toronto (including an Academic Scholars Award); A.J. Rothschild has received, in the past three years, grant or research support from Compass Pathways, Janssen, Otsuka, and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry. In the past three years, he has been a consultant to Daiichi Sankyo, Inc., Sage Therapeutics, Xenon Pharmaceuticals, Neumora Therapeutics, Zydus Pharmaceuticals (USA), Inc., Sandoz, Inc., and Lupin Pharmaceuticals, Inc. He has received royalties in the past three years for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®, Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009, The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010, The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012, and from UpToDate®; A.N. Voineskos has received funding from the NIMH, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto; E.M. Whyte has received grant support from the NIMH and HRSA; A.J. Flint has received grant support from the U.S. National Institutes of Health, Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, Brain Canada, Ontario Brain Institute, Alzheimer's Association, AGE-WELL, the Canadian Foundation for Healthcare Improvement, and the University of Toronto; K.S. Bingham has received grant support from the University of Toronto., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Some data suggest that antipsychotics may adversely affect brain structure. We examined the relationship among olanzapine exposure, relapse, and changes in brain structure in patients with major depressive disorder with psychotic features. We analyzed data from the Study of the Pharmacotherapy of Psychotic Depression II trial (STOP-PD II), a randomized, placebo-controlled trial in patients with psychotic depression who attained remission on sertraline and olanzapine and were randomized to continue sertraline plus olanzapine or placebo for 36 weeks. Olanzapine steady state concentration (SSC) were calculated based on sparsely-sampled levels. Rates of relapse and changes in brain structure were assessed as outcomes. There were significant associations between dosage and relapse rates (N = 118; HR = 0.94, 95% CI [0.897, 0.977], p = 0.002) or changes in left cortical thickness (N = 44; B = -2.0 × 10 -3 , 95% CI [-3.1 × 10 -3 , -9.6 × 10 -4 ], p < 0.001) and between SSC and changes in left cortical thickness (N = 44; B = -8.7 × 10 -4 , 95% CI [-1.4 × 10 -3 , -3.6 × 10 -4 ], p = 0.001). Similar results were found for the right cortex. These associations were no longer significant when the analysis was restricted to participants treated with olanzapine. Our findings suggest that, within its therapeutic range, the effect of olanzapine on relapse or cortical thickness does not depend on its dosage or SSC. Further research is needed on the effect of olanzapine and other antipsychotics on mood symptoms and brain structure., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Remitted psychotic depression (MDDPsy) has heterogeneity of outcome. The study's aims were to identify subgroups of persons with remitted MDDPsy with distinct trajectories of depression severity during continuation treatment and to detect predictors of membership to the worsening trajectory., Method: One hundred and twenty-six persons aged 18-85 years participated in a 36-week randomized placebo-controlled trial (RCT) that examined the clinical effects of continuing olanzapine once an episode of MDDPsy had remitted with sertraline plus olanzapine. Latent class mixed modeling was used to identify subgroups of participants with distinct trajectories of depression severity during the RCT. Machine learning was used to predict membership to the trajectories based on participant pre-trajectory characteristics., Results: Seventy-one (56.3%) participants belonged to a subgroup with a stable trajectory of depression scores and 55 (43.7%) belonged to a subgroup with a worsening trajectory. A random forest model with high prediction accuracy (AUC of 0.812) found that the strongest predictors of membership to the worsening subgroup were residual depression symptoms at onset of remission, followed by anxiety score at RCT baseline and age of onset of the first lifetime depressive episode. In a logistic regression model that examined depression score at onset of remission as the only predictor variable, the AUC (0.778) was close to that of the machine learning model., Conclusions: Residual depression at onset of remission has high accuracy in predicting membership to worsening outcome of remitted MDDPsy. Research is needed to determine how best to optimize the outcome of psychotic MDDPsy with residual symptoms.

Background: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites., Methods: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups., Results: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate., Conclusions: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine., (© 2023. The Author(s).)

Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis., (© 2024 World Psychiatric Association.)

The effect of antipsychotic medication on resting state functional connectivity in major depressive disorder (MDD) is currently unknown. To address this gap, we examined patients with MDD with psychotic features (MDDPsy) participating in the Study of the Pharmacotherapy of Psychotic Depression II. All participants were treated with sertraline plus olanzapine and were subsequently randomized to continue sertraline plus olanzapine or be switched to sertraline plus placebo. Participants completed an MRI at randomization and at study endpoint (study completion at Week 36, relapse, or early termination). The primary outcome was change in functional connectivity measured within and between specified networks and the rest of the brain. The secondary outcome was change in network topology measured by graph metrics. Eighty-eight participants completed a baseline scan; 73 completed a follow-up scan, of which 58 were usable for analyses. There was a significant treatment X time interaction for functional connectivity between the secondary visual network and rest of the brain (t = -3.684; p = 0.0004; pFDR = 0.0111). There was no significant treatment X time interaction for graph metrics. Overall, functional connectivity between the secondary visual network and the rest of the brain did not change in participants who stayed on olanzapine but decreased in those switched to placebo. There were no differences in changes in network topology measures when patients stayed on olanzapine or switched to placebo. This suggests that olanzapine may stabilize functional connectivity, particularly between the secondary visual network and the rest of the brain., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Psychomotor disturbance is common in psychotic depression and is associated with relapse. In this analysis, we examined whether white matter microstructure is associated with relapse probability in psychotic depression and, if so, whether white matter microstructure accounts for the association between psychomotor disturbance and relapse., Methods: We used tractography to characterize diffusion-weighted MRI data in 80 participants enrolled in a randomized clinical trial that compared efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo in the continuation treatment of remitted psychotic depression. Cox proportional hazard models tested the relationships between psychomotor disturbance (processing speed and CORE score) at baseline, white matter microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) in 15 selected tracts at baseline, and relapse probability., Results: CORE was significantly associated with relapse. Higher mean MD was significantly associated with relapse in the each of the following tracts: corpus callosum, left striato-frontal, left thalamo-frontal, and right thalamo-frontal. CORE and MD were each associated with relapse in the final models., Limitations: As a secondary analysis with a small sample size, this study was not powered for its aims, and is vulnerable to types I and II statistical errors. Further, the sample size was not sufficient to test the interaction of the independent variables and randomized treatment group with relapse probability., Conclusions: While both psychomotor disturbance and MD were associated with psychotic depression relapse, MD did not account for the relationship between psychomotor disturbance and relapse. The mechanism by which of psychomotor disturbance increases the risk of relapse requires further investigation., Clinical Trial Registration: Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II); NCT01427608. URL: https://clinicaltrials.gov/ct2/show/NCT01427608., Competing Interests: Declaration of competing interest K.S. Bingham receives grant support from the University of Toronto. N. Calarco has no disclosures. E.W. Dickie receives grant support from the Brain and Behavior Research Foundation. G.S. Alexopoulos has received NIMH grants and has served in the speakers' bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, Sunovion. M.A. Butters receives research financial support from NIH. P. Marino received research support from the NIMH at the time this work was done. B.S. Meyers received research support from the NIMH at the time this work was done. B.H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has been an unpaid consultant to Myriad Neuroscience. N.H. Neufeld has received grant support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, and the University of Toronto. A.J. Rothschild has received grant or research support from Janssen, the National Institute of Mental Health, Otsuka, Praxis, Eli-Lilly (medications for a NIH-funded clinical trial), Pfizer (medications for a NIH-funded clinical trial), and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry, is a consultant to Alkermes, Janssen, Sage Therapeutics, Xenon Pharmaceuticals and several generic medication companies, has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012; and, UpToDate® and has received honorarium from Wolters Kluwer (Journal Editor). E.M. Whyte received grant support from the NIMH and HRSA at the time that this study was completed. A.J. Flint has received grant support from the U.S. National Institutes of Health, Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, Brain Canada, Ontario Brain Institute, Alzheimer's Association, AGE-WELL, and the Canadian Foundation for Healthcare Improvement. A.N. Voineskos has receives funding from the NIMH, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Psychotic depression has a high rate of relapse. The study aims were to identify a prediction model of risk of relapse of psychotic depression and examine whether predictors moderated the effect of treatment on relapse. One hundred and twenty-six men and women aged 18-85 years, who experienced sustained remission or near-remission of psychotic depression with sertraline plus olanzapine, participated in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse (NCT01427608). Cox regression analyses were performed to identify significant predictors of relapse and to model the combined role of significant predictors. Concordance statistic was calculated to determine the accuracy of the best fit multivariable models in predicting relapse. Finally, interaction terms were tested for each significant predictor to examine whether they moderated the effect of treatment on risk of relapse. Lifetime number of depressive episodes, severity of residual depressive symptoms at the time of randomization, and psychomotor disturbance both at acute enrollment when participants were depressed and at the time of randomization predicted risk of relapse. Multivariable models had 69-70% accuracy in predicting relapse. Psychomotor disturbance was associated with increased risk of relapse in the sertraline plus olanzapine group compared with sertraline plus placebo, whereas the other predictors did not moderate the effect of treatment on relapse. Future research is needed to determine whether a combination of clinical and biological variables can further increase the accuracy of prediction of relapse of psychotic depression., Competing Interests: Declaration of competing interest A.J. Flint has received grant support from the U.S. National Institutes of Health, Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, Brain Canada, Ontario Brain Institute, Alzheimer's Association, AGE-WELL, and the Canadian Foundation for Healthcare Improvement. K.S. Bingham receives grant support from the University of Toronto. N.H Neufeld has received grant support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, and University of Toronto. G.S. Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, Sunovion. P. Marino received research support from the NIMH at the time this work was done. B.H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received research support during the past three years from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past three years, he has also been an unpaid consultant to Myriad Neuroscience. A.J. Rothschild has received grant or research support from Allergan, Janssen, the National Institute of Mental Health, Otsuka, Praxis, Eli-Lilly (medications for a NIH-funded clinical trial), Pfizer (medications for a NIH-funded clinical trial), and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry, is a consultant to Alkermes, Janssen, Sage Therapeutics, Xenon Pharmaceuticals, and several generic medication companies; has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®; Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009; The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010; The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012; and, UpToDate® and has received honorarium from Wolters Kluwer (Journal Editor). E.M. Whyte receives grant support from the NIMH and HRSA. A.N. Voineskos has received funding from the NIMH, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto. B.S. Meyers received research support from the NIMH at the time this work was done., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this placebo response rate has not been systematically reassessed. We undertook a systematic review of randomized controlled trials (RCTs) that have used a placebo or sham control group for MDD-Psy., Methods: We searched MEDLINE and identified 9 relevant publications reporting on 10 studies comparing a placebo or sham interventions versus an active intervention. We extracted reported rates of response or of dropout for all causes associated with placebo versus active intervention(s) and aggregated response and dropout rates across trials., Results: Two sham-controlled electroconvulsive therapy (ECT) trials did not provide response rates. In the 3 pharmacotherapy studies published in the 1980s, 0 of 12 participants (0%) responded to placebo versus 13 of 38 (34.2%) responding to the active interventions. In contrast, 5 RCTs published in the 2000s, 114 of 339 participants (33.6%) randomized to placebo responded versus 149 of 373 participants (39.9%) randomized to active interventions; dropout rates were 71/236 (30.1%) for placebo versus 84/282 (29.8%) for the active interventions., Conclusions: As expected, response rates to placebo pills in RCTs for MDD-Psy increased markedly from the 1980s to the 2000s. Methodological issues in the design and conduct of more recent RCTs may have contributed to the high placebo response. However, one needs to consider this placebo response rate when interpreting the result of recent trials of MDD-Psy, which typically have not included a "pure" placebo condition., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The CORE instrument is commonly used to measure psychomotor disturbance. We examined the factor structure of the CORE in 266 adults with an acute episode psychotic depression, a disorder with a high rate of psychomotor disturbance. Exploratory factor analysis identified a two-factor solution: Factor 1 corresponded to the CORE's retardation and non-interactiveness items and Factor 2 corresponded to its agitation items. Internal consistency was excellent for Factor 1 but questionable for Factor 2. These findings suggest that the CORE's retardation and non-interactiveness items should be combined in one subscale when assessing patients with an acute episode of psychotic depression., (Copyright © 2022. Published by Elsevier B.V.)

Background: Little is known about the relationship between psychomotor disturbance (PMD) and treatment outcome of psychotic depression. This study examined the association between PMD and subsequent remission and relapse of treated psychotic depression., Methods: Two hundred and sixty-nine men and women aged 18-85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission or near-remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine (n = 64) with sertraline plus placebo (n = 62). PMD was measured with the psychiatrist-rated sign-based CORE at acute phase baseline and at RCT baseline. Spearman's correlations and logistic regression analyses were used to analyze the association between CORE total score at acute phase baseline and remission/near-remission and CORE total score at RCT baseline and relapse., Results: Higher CORE total score at acute phase baseline was associated with lower frequency of remission/near-remission. Higher CORE total score at RCT baseline was associated with higher frequency of relapse, in the RCT sample as a whole, as well as in each of the two randomized groups., Conclusions: PMD is associated with poorer outcome of psychotic depression treated with sertraline plus olanzapine. Future research needs to examine the neurobiology of PMD in psychotic depression in relation to treatment outcome.

Importance: Prescriptions for antipsychotic medications continue to increase across many brain disorders, including off-label use in children and elderly individuals. Concerning animal and uncontrolled human data suggest antipsychotics are associated with change in brain structure, but to our knowledge, there are no controlled human studies that have yet addressed this question., Objective: To assess the effects of antipsychotics on brain structure in humans., Design, Setting, and Participants: Prespecified secondary analysis of a double-blind, randomized, placebo-controlled trial over a 36-week period at 5 academic centers. All participants, aged 18 to 85 years, were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019., Interventions: Those who consented to the imaging study completed a magnetic resonance imaging (MRI) scan at the time of randomization and a second MRI scan at the end of the 36-week period or at time of relapse., Main Outcomes and Measures: The primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter., Results: Eighty-eight participants (age range, 18-85 years) completed a baseline scan; 75 completed a follow-up scan, of which 72 (32 men and 40 women) were useable for final analyses. There was a significant treatment-group by time interaction in cortical thickness (left, t = 3.3; P = .001; right, t = 3.6; P < .001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t = -2.6, P = .01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t34.4 = 4.7; P <.001), and the right hemisphere (β [SE], 0.03 [0.009]; t35.1 = 3.6; P <.001). Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness., Trial Registration: ClinicalTrials.gov Identifier: NCT01427608.

Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique-non-negative matrix factorization-and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.

During word and object recognition, extensive activation has consistently been observed in the left ventral occipito-temporal cortex (vOT), focused around the occipito-temporal sulcus (OTs). Previous studies have shown that there is a hierarchy of responses from posterior to anterior vOT regions (along the y-axis) that corresponds with increasing levels of recognition - from perceptual to semantic processing, respectively. In contrast, the functional differences between superior and inferior vOT responses (i.e. along the z-axis) have not yet been elucidated. To investigate, we conducted an extensive review of the literature and found that peak activation for reading varies by more than 1 cm in the z-axis. In addition, we investigated functional differences between superior and inferior parts of left vOT by analysing functional MRI data from 58 neurologically normal skilled readers performing 8 different visual processing tasks. We found that group activation in superior vOT was significantly more sensitive than inferior vOT to the type of task, with more superior vOT activation when participants were matching visual stimuli for their semantic or perceptual content than producing speech to the same stimuli. This functional difference along the z-axis was compared to existing boundaries between cytoarchitectonic areas around the OTs. In addition, using dynamic causal modelling, we show that connectivity from superior vOT to anterior vOT increased with semantic content during matching tasks but not during speaking tasks whereas connectivity from inferior vOT to anterior vOT was sensitive to semantic content for matching and speaking tasks. The finding of a functional dissociation between superior and inferior parts of vOT has implications for predicting deficits and response to rehabilitation for patients with partial damage to vOT following stroke or neurosurgery., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The neurobiological basis of bipolar disorders (BD) has received increased attention and several brain regions and brain circuits have been correlated with clinical symptoms. These brain regions and circuits may represent targets for neuromodulation techniques such as transcranial Direct Current Stimulation (tDCS). We systematically reviewed the literature to explore the risks and benefits of tDCS in BD and examined all mood states. Following the PRISMA guidelines, a systematic literature search using several databases was performed from April 2002 to June 2017. From the 135 eligible studies, we retained 19 relevant articles for the systematic review, including 170 patients with BD treated by tDCS. Data from 10 studies suggest that tDCS improves depressive symptoms in BD. One case report of add-on-tDCS reported a significant positive response on manic symptoms. In 4 studies, tDCS impacted specific neurocognitive functions in euthymic patients. There is also preliminary evidence that tDCS improves neurological soft signs and sleep quality in euthymia. Side effects were predominantly transient and low-intensity, although 6 cases of hypomanic/manic affective switches have been reported. The majority of studies have been open trials with few patients. More sufficiently powered randomized controlled trials are needed to clarify the effectiveness of tDCS. Preliminary data suggests that tDCS holds promise as a treatment for BD, especially during depressive episodes. Perhaps most promising are emerging data suggesting tDCS may impact neurocognition and sleep quality in euthymia and be useful for relapse prevention.

Background: There is paucity of neurobiological knowledge about major depressive disorder with psychotic features ("psychotic depression"). This study addresses this knowledge gap by using resting state functional magnetic resonance imaging (R-fMRI) to compare functional connectivity in patients with psychotic depression and healthy controls., Methods: We scanned patients who participated in a randomized controlled trial as well as healthy controls. All patients achieved remission from depressive and psychotic symptoms with sertraline and olanzapine. We employed Independent Component Analysis in independent samples to isolate the default mode network (DMN) and compared patients and controls., Findings: The Toronto sample included 28 patients (mean [SD], age 56·2 [13·7]) and 39 controls (age 55·1 [13·5]). The Replication sample included 29 patients (age 56·1 [17·7]) and 36 controls (age 48·3 [17·9]). Patients in the Toronto sample demonstrated decreased between-network functional connectivity between the DMN and bilateral insular, somatosensory/motor, and auditory cortices with peak activity in the right planum polare (t = 4·831; p = 0·001, Family Wise Error (FWE) corrected). A similar pattern of between-network functional connectivity was present in our Replication sample with peak activity in the right precentral gyrus (t = 4·144; p = 0·003, FWE corrected)., Interpretation: Remission from psychotic depression is consistently associated with an absence of increased DMN-related functional connectivity and presence of decreased between-network functional connectivity. Future research will evaluate this abnormal DMN-related functional connectivity as a potential biomarker for treatment trajectories., Funding: National Institute of Mental Health., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Bipolar disorder (BD) is a severe and recurrent brain disorder that can manifest in manic or depressive episodes. Transcranial Direct Current Stimulation (tDCS) has been proposed as a novel therapeutic modality for patients experiencing bipolar depression, for which standard treatments are often inefficient. While several studies have been conducted in this patient group, there has been no systematic review or meta-analysis that specifically examines bipolar depression. We aimed to address this gap in the literature and evaluated the efficacy and tolerability of tDCS in patients fulfilling DSM-IV-TR criteria for BD I, II, or BD not otherwise specified (NOS)., Methods: We systematically searched the literature from April 2002 to November 2016 to identify relevant publications for inclusion in our systematic review and meta-analysis. Effect sizes for depression rating-scale scores were expressed as the standardized mean difference (SMD) before and after tDCS., Results: Thirteen of 382 identified studies met eligibility criteria for our systematic review. The meta-analysis included 46 patients from 7 studies with depression rating-scale scores pre- and post-tDCS. Parameters of tDCS procedures were heterogeneous. Depression scores decreased significantly with a medium effect size after acute-phase of treatment (SMD 0.71 [0.25-1.18], z=3.00, p=0.003) and at the furthest endpoint (SMD 1.27 [0.57-1.97], z=3.57, p=0.0004). Six cases of affective switching under tDCS treatment protocols were observed., Conclusions: Depressive symptoms respond to tDCS in patients with BD. Additional studies, and particularly randomized controlled trials, are needed to clarify the effectiveness of tDCS in bipolar depression, the frequency of tDCS-emergent hypomania/mania, and which tDCS modalities are most efficient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Helicobacter pylori infects half the global population. Because serious complications can result from this infection, a so-called "triple therapy" is recommended: treatment with a proton-pump inhibitor and clarithromycin, along with amoxicillin or metronidazole. Although these antibiotics have been associated with neuropsychiatric symptoms, it is difficult to disentangle the effects of antibiotics from the effects of acute infections that may precipitate acute neuropsychiatric symptoms. Study of patients with chronic H. pylori infections who undergo antibiotic treatment may provide a clearer view of the associations between acute neuropsychiatric symptoms and antibiotics. The literature concerning this association in patients with H. pylori has not been reviewed. We therefore undertook a review of MEDLINE and postmarket surveillance data concerning this issue and identified 25 cases. Postmarket data indicated that gastrointestinal symptoms were the most commonly reported adverse reactions, followed by neurological adverse reactions; neuropsychiatric symptoms were less commonly reported, with variable and nonspecific terminology used to describe them. More specific, yet still variable terminology was found in the literature. Anxiety, delirium, dissociation, mania, and psychosis were reported, with approximately half of these neuropsychiatric symptoms occurring without symptoms of delirium. The use of standardized neuropsychiatric symptom rating scales and the Confusion Assessment Method for monitoring adverse reactions may improve our knowledge of neuropsychiatric symptoms and their association with antibiotics and thus mitigate underreporting. Physicians should remain alert to the possibility that neuropsychiatric symptoms may occur during antibiotic treatment of H. pylori and recognize that rapid resolution typically occurs with discontinuation of the antibiotics.

Background: Electroconvulsive therapy (ECT) remains one of the most effective tools in the psychiatric treatment armamentarium, particularly for refractory depression. Yet, there remains a subset of patients who do not respond to ECT or for whom clinically adequate seizures cannot be elicited, for whom ketamine has emerged as a putative augmentation agent., Methods: We searched EMBASE, PsycINFO, CENTRAL, and MEDLINE from 1962 to April 2014 to identify randomized controlled trials evaluating ketamine in ECT (PROSPERO #CRD42014009035). Clinical remission, response, and change in depressive symptom scores were extracted by two independent raters. Adverse events were recorded. Drop-outs were assessed as a proxy for acceptability. Meta-analyses employed a random effects model., Results: Data were synthesized from 5 RCTs, representing a total of 182 patients with major depressive episodes (n = 165 Major Depressive Disorder, n = 17 Bipolar Disorder). ECT with ketamine augmentation was not associated with higher rates of clinical remission (Risk Difference (RD) = 0.00; 95%CI = -0.08 to 0.10), response (RD = -0.01; 95%CI = -0.11 to 0.08), or improvements in depressive symptoms (SMD = 0.38; 95%CI = -0.41 to 1.17). Ketamine augmentation was associated with higher rates of confusion/disorientation/prolonged delirium (OR = 6.59, 95%CI: 1.28-33.82, NNH = 3), but not agitation, hypertension or affective switches., Conclusion: Our meta-analysis of randomized controlled trials of ketamine augmentation in the ECT setting suggests a lack of clinical efficacy, and an increased likelihood of confusion. Individuals for whom adequate seizures or therapeutic response cannot be obtained have not been studied using randomized controlled designs. Additional research is required to address the role of ketamine in this population., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Randomized and sham-controlled trials (RCTs) on repetitive transcranial magnetic stimulation (rTMS) for treating obsessive-compulsive disorder (OCD) have yielded conflicting results that may be due to limited statistical power among individual studies. We pursued the present systematic review and meta-analysis to assess the efficacy of rTMS for OCD and to generate hypotheses for more robustly powered RCTs., Method: We searched the literature for RCTs on rTMS for OCD from 1995 through December 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and SCOPUS. We then performed an exploratory random-effects meta-analysis with the main outcome measures as pre-post changes in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores, response to treatment and overall dropout rates at study end., Results: Data were obtained from 10 RCTs, totaling 282 subjects with OCD. The pooled Hedges' g for pre-post Y-BOCS scores was 0.59 (z = 2.73, p = 0.006), indicating a significant and medium-sized difference in outcome favoring active rTMS. Furthermore, response rates were 35% and 13% for patients receiving active and sham rTMS, respectively (OR = 3.4, p = 0.002). Sub-group analyses indicated that LF-rTMS and rTMS protocols targeting non-DLPFC regions (i.e., orbitofrontal cortex or supplementary motor area) seem to be the most promising for reducing OCD-related symptoms. No differences on baseline depression scores or dropout rates at study end were observed between active and sham rTMS groups, although OCD severity at baseline was higher in the active group., Conclusions: Our exploratory analyses show that active rTMS seems to be efficacious for treating OCD. Moreover, LF-rTMS and protocols targeting the orbitofrontal cortex or the supplementary motor area seem to be the most promising. Nevertheless, future RCTs on rTMS for OCD should include larger sample sizes and be more homogeneous in terms of demographic/clinical variables as well as stimulation parameters and brain targets., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The left ventral occipito-temporal cortex (LvOT) is thought to be essential for the rapid parallel letter processing that is required for skilled reading. Here we investigate whether rapid written word identification in skilled readers can be supported by neural pathways that do not involve LvOT. Hypotheses were derived from a stroke patient who acquired dyslexia following extensive LvOT damage. The patient followed a reading trajectory typical of that associated with pure alexia, re-gaining the ability to read aloud many words with declining performance as the length of words increased. Using functional MRI and dynamic causal modelling (DCM), we found that, when short (three to five letter) familiar words were read successfully, visual inputs to the patient's occipital cortex were connected to left motor and premotor regions via activity in a central part of the left superior temporal sulcus (STS). The patient analysis therefore implied a left hemisphere "reading-without-LvOT" pathway that involved STS. We then investigated whether the same reading-without-LvOT pathway could be identified in 29 skilled readers and whether there was inter-subject variability in the degree to which skilled reading engaged LvOT. We found that functional connectivity in the reading-without-LvOT pathway was strongest in individuals who had the weakest functional connectivity in the LvOT pathway. This observation validates the findings of our patient's case study. Our findings highlight the contribution of a left hemisphere reading pathway that is activated during the rapid identification of short familiar written words, particularly when LvOT is not involved. Preservation and use of this pathway may explain how patients are still able to read short words accurately when LvOT has been damaged., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Functional imaging studies of brain damaged patients offer a unique opportunity to understand how sensorimotor and cognitive tasks can be carried out when parts of the neural system that support normal performance are no longer available. In addition to knowing which regions a patient activates, we also need to know how these regions interact with one another, and how these inter-regional interactions deviate from normal. Dynamic causal modeling (DCM) offers the opportunity to assess task-dependent interactions within a set of regions. Here we review its use in patients when the question of interest concerns the characterization of abnormal connectivity for a given pathology. We describe the currently available implementations of DCM for fMRI responses, varying from the deterministic bilinear models with one-state equation to the stochastic non-linear models with two-state equations. We also highlight the importance of the new Bayesian model selection and averaging tools that allow different plausible models to be compared at the single subject and group level. These procedures allow inferences to be made at different levels of model selection, from features (model families) to connectivity parameters. Following a critical review of previous DCM studies that investigated abnormal connectivity we propose a systematic procedure that will ensure more flexibility and efficiency when using DCM in patients. Finally, some practical and methodological issues crucial for interpreting or generalizing DCM findings in patients are discussed.

Holter monitoring was used to detect the underlying mechanism among 53 patients referred for dizziness, fainting and/or syncope. The complaints were unexplained on clinical grounds in 38, suggestive of SSS in 11, and of pacemaker dysfunction in 4 patients who underwent pacemaker implantation for symptomatic A-V block. Occult dysrhythmias were revealed in 24 of 38 (61%) of the first group; the clinical impression of SSS was confirmed in 8 of 11 (72%) in the second, and ineffective pacing confirmed in 2 of 4 in the third group. Thus, the diagnosis was clarified in 34 of 53 (64%) of patients. It is concluded that Holter monitoring is most useful for detecting the underlying mechanism in the above mentioned conditions, especially in elderly subjects whose syncopal attacks remained unexplained despite routine cardiological and neurological examination. Holter monitoring should be carried out for at least 36 hours before ruling out dysrhythmias as a cause of dizziness and/or syncopal attacks.