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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.

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.)

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.)

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.

Background: Some patients with major depression continue to demonstrate deficits in health-related quality of life (HRQL) following remission. No data exist, however, regarding HRQL in remitted psychotic depression. In this study, we aimed to characterize HRQL in patients with psychotic depression receiving controlled pharmacotherapy., Methods: This is a secondary analysis of a randomized controlled trial studying continuation pharmacotherapy of psychotic depression. We compared participants' HRQL (measured using the SF-36) between baseline and remission and to population norms. We also compared SF-36 scores stratified by age and gender and examined the correlation between SF-36 scores and medical burden, depression score and neuropsychological performance in remission., Results: SF-36 scores were significantly lower than population norms at baseline, but improved following remission to the level of population norms. Neither SF-36 scores nor magnitude of SF-36 improvement differed substantially between genders or between younger and older participants. In remission, depression scores were correlated with most SF-36 scales and medical burden was correlated with SF-36 scales measuring physical symptoms. Neuropsychological measures were generally not correlated with SF-36 scores., Limitations: This study was a secondary analysis not powered specifically to measure HRQL as an outcome variable and the SF-36 was the only HRQL measure used., Conclusions: Participants with remitted psychotic depression demonstrated levels of HRQL comparable to population norms, despite marked impairment in HRQL when acutely ill. This finding suggests that, when treated in a rigorous manner, many patients with this severe illness improve significantly from a clinical and HRQL perspective., (Copyright © 2019. Published by Elsevier B.V.)

Importance: Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission., Objective: To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent., Design, Setting, and Participants: Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017., Interventions: Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline., Main Outcomes and Measures: The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A1c (HbA1c)., Results: Among 126 participants who were randomized (mean [SD] age, 55.3 years [14.9 years]; 78 women [61.9%]), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P < .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, -0.01 to 0.10), high-density lipoprotein cholesterol (-0.01 mg/dL; 95% CI, -0.03 to 0.01), triglyceride (-0.153 mg/dL; 95% CI, -0.306 to 0.004), glucose (-0.02 mg/dL; 95% CI, -0.12 to 0.08), or HbA1c levels (-0.0002 mg/dL; 95% CI, -0.0021 to 0.0016)., Conclusions and Relevance: Among patients with psychotic depression in remission, continuing sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks. This benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain., Trial Registration: ClinicalTrials.gov Identifier: NCT01427608.

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: We conducted a 12-week double-blind study of stabilization pharmacotherapy in patients with remitted psychotic depression (PD)., Methods: Seventy-one persons aged 18 years or older who had achieved remission of PD when randomized to either olanzapine plus sertraline or olanzapine plus placebo were continued on the double-blind treatment associated with remission. Symptoms of depression and psychosis, and weight, were measured once every 4 weeks. Cholesterol, triglycerides, and glucose were measured at stabilization phase baseline and Week 12/termination., Results: The effect of treatment did not significantly change with time for depression, weight, or metabolic measures in the stabilization phase. Eight of the 71 participants (11.3%; 95% CI: 5.8, 20.7) experienced a relapse of major depression, psychosis, or both. Treatment groups did not differ in the frequency of relapse. In the entire study group, the adjusted estimate for change in weight was an increase of 1.66 kg (95% CI: 0.83, 2.48) and the adjusted estimate for change in total cholesterol was a decrease of 14.8 mg/dL (95% CI: 3.5, 26.1) during the 12-week stabilization phase; the remaining metabolic measures did not significantly change., Conclusion: Continuation of acute treatment was associated with stability of remission., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To examine the association between baseline suicidality and outcome of major depression in a randomized controlled trial of the pharmacotherapy of psychotic depression and to explore the interaction of suicidality, randomized treatment assignment, and depression outcome., Methods: This study was a secondary analysis of data from 258 persons aged 18 years or older with DSM-IV-defined major depressive disorder with psychotic features who participated in a 12-week randomized controlled trial (RCT) comparing olanzapine plus sertraline with olanzapine plus placebo (the Study of the Pharmacotherapy of Psychotic Depression [STOP-PD], which ran from 2002 to 2007). The independent variable was baseline suicidality, defined by 4 groups (suicide attempt in the current episode, active suicidal ideation, passive suicidal ideation, and no suicidality). The outcome variables were change in 16-item Hamilton Depression Rating Scale (HDRS₁₆) total score (excluding the suicide item) over time and remission of psychotic depression over time., Results: Suicidality groups did not significantly differ on baseline HDRS₁₆ total score. Baseline suicidality group was significantly associated with change in HDRS₁₆ score over time in the sample as a whole (F₃,₁₃₉₄ = 8.17; P < .0001), but was not significantly associated with probability of remission over time. Among participants assigned to olanzapine and placebo, persons with no suicidality had a significantly greater reduction in HDRS₁₆ total score compared to those with passive suicidal ideation (7.5-point difference in change scores between the 2 groups; 95% CI, 4.3-10.7 t₁₃₉₄ = 4.61, P < .0001), active suicidal ideation (4.4 points; 95% CI, 1.4-7.4; t₁₃₉₄ = 2.85, P = .0176), or suicide attempts (6.1 points; 95% CI, 2.8-9.4; t₁₃₉₄ = 3.66, P = .0015). The 12-week change from baseline in HDRS₁₆ score for patients with no suicidality was not significantly different between the 2 treatment arms. However, the 12-week HDRS₁₆ improvement was significantly greater in the olanzapine plus sertraline arm, compared with the olanzapine plus placebo arm, for patients with suicide attempts (8.7-point difference in change scores between the 2 groups; 95% CI, 5.1-12.4; t₁₃₉₄ = 4.75, P < .0001), active suicidal ideation (8.1 points; 95% CI, 4.5-11.7; t₁₃₉₄ = 4.38, P < .0001), or passive suicidal ideation (5.7 points; 95% CI, 2.2-9.2; t₁₃₉₄ = 3.23, P = .0012), respectively., Conclusions: Baseline suicidality predicted worse acute treatment outcome of psychotic depression. However, participants with suicidality had a better outcome when treated with the combination of olanzapine and sertraline than when treated with olanzapine plus placebo., Trial Registration: ClinicalTrials.gov identifier: NCT00056472​., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Objective: To characterize cognitive function at baseline and investigate the relationship between change in cognition, depression, and psychosis after treatment among older adults with major depressive disorder with psychotic features., Methods: This was a secondary analysis of a double-blind, randomized, controlled treatment trial at inpatient and outpatient settings at four academic health centers on "Young Old" (aged 60-71 years, N = 71) and "Older" (aged 72-86 years, N = 71) participants diagnosed with psychotic depression. Olanzapine plus sertraline or olanzapine plus placebo were given until week 12 or termination., Results: At baseline, Young Old and Older participants did not differ on measures of depression severity or global cognition, information processing speed, and executive function. Improvement in depressive and psychotic symptoms from baseline to treatment end was similar in both the Young Old and Older groups. However, improvement in depressive symptoms was significantly associated with improvement in global cognitive function in Young Old participants but not in Older participants., Conclusion: Cognitive dysfunction was not a detriment to improvement in symptoms of psychotic major depression in our geriatric patients. Young Old and Older patients improved to a similar degree on measures of depression and delusions from baseline to treatment end. However, improvement in cognition over the course of treatment was more prominent in the Young Old group than in the Older group., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We recently reported an unexpected interaction between olanzapine and sertraline in a population being treated for psychotic depression. Contrary to knowledge of cytochrome p450 interactions sertraline increased apparent clearance of olanzapine by 30%. Here we examined the pharmacokinetics of sertraline in the same population. Existing studies suggest that sertraline apparent clearance is significantly increased in male subjects and suggested an age/sex interaction., Methods: We studied subjects undergoing combination of sertraline/olanzapine treatment for psychotic depression in the Study of the Pharmacotherapy of Psychotic Depression. Nonlinear mixed effect modelling software was used to examine the sertraline pharmacokinetics, evaluating age, sex, race, and olanzapine exposure as covariates., Results: Eighty-seven subjects (median age 62 years, 28 male subjects, 11 African-Americans) provided 138 samples for sertraline concentration. Olanzapine exposure had a 14.8-fold range. A one compartment model with combined residual error described the sertraline concentration data adequately. Half-life and sex effect on sertraline apparent clearance (males averaging 50% higher (p < 0.005); 96.6 l/h vs 64.8 in female subjects) were similar to previous reports. No other covariate (age, race or olanzapine exposure) had a significant impact on apparent clearance, and no age/sex interaction emerged., Conclusion: Sertraline pharmacokinetics were similar to historical descriptions in populations not taking antipsychotics. Unlike our unexpected finding that sertraline increases olanzapine apparent clearance, olanzapine exposure had no impact on sertraline pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: The Psychotic Depression Assessment Scale (PDAS) is a rating scale dedicated to the measurement of severity in psychotic depression (PD). The aim of this study was to establish the PDAS cut-off for remission of PD as well as PDAS score-ranges for mild, moderate, and severe PD. The secondary aim was to test how remission, as defined by the PDAS, would perform as outcome measure when applied to the data from a large randomized controlled trial (RCT) in PD., Methods: The study was based on data from the Study of Pharmacotherapy in Psychotic Depression (STOP-PD). The cut-off for remission on the PDAS and the severity-ranges for mild, moderate, and severe PD were defined using the Clinical Global Impression - Severity scale (CGI-S) as reference by means of pair-wise receiver operating characteristic (ROC) analyses. Subsequently, it was tested whether remission on the PDAS could separate the effects of Olanzapine+Sertraline vs. Olanzapine+Placebo through an intention-to-treat, mixed-effects logistic regression of the data from STOP-PD., Results: According to the ROC analyses, the ideal cut-off for remission of PD was a PDAS total score <8, while the severity-ranges for mild, moderate and severe PD were 8-15, 16-23, and >23 respectively. When applying the PDAS total score <8 (remission) as outcome on the STOP-PD data, treatment with Olanzapine+Sertraline performed significantly better than Olanzapine+Placebo (p<0.001)., Limitations: The STOP-PD was not designed specifically to answer the research questions of the present study., Conclusions: According to this study, a total score <8 on the PDAS corresponds to remission of PD., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To examine whether cerebrovascular risk, executive function, and processing speed are associated with acute treatment outcome of psychotic depression in older adults., Methods: The authors analyzed data from 142 persons aged 60 years or older with major depression with psychotic features who participated in a 12-week randomized controlled trial (RCT) comparing olanzapine plus sertraline with olanzapine plus placebo. The independent variables were baseline cerebrovascular risk (Framingham Stroke Risk Score), baseline executive function (Stroop interference score and the initiation/perseveration subscale of the Mattis Dementia Rating Scale), and baseline processing speed (color and word reading components of the Stroop). The outcome variable was change in severity of depression, measured by the 17-item Hamilton Depression Rating Scale total score, during the course of the RCT., Results: Greater baseline cerebrovascular risk was significantly associated with less improvement in depression severity over time, after controlling for pertinent covariates. Neither executive function nor processing speed predicted outcome., Conclusion: This study suggests an association of cerebrovascular risk, but not executive function or processing speed, with treatment outcome of major depression with psychotic features in older adults., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods., Methods: The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration., Results: Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25-35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance., Conclusions: Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.

Background: Insight into delusional beliefs varies in patients with major depressive disorder (MDD) with psychotic features ("psychotic depression"). The relationship between impaired insight and illness severity and its impact on treatment outcomes has not been studied in psychotic depression. As such, the aim of this analysis was to explore the relationship among impaired insight, patient characteristics (ie, illness severity, cognition, suicidality, and social functioning), and treatment outcome (ie, remission) during acute treatment of psychotic depression., Method: This secondary analysis is based on the data from the Study of Pharmacotherapy for Psychotic Depression (STOP-PD) in which 259 participants meeting DSM-IV criteria for MDD with psychotic features enrolled between December 2002 and June 2007 (including 142 aged ≥ 60 years) in a 4-center, 12- week, double-blind, randomized controlled trial funded by the US National Institutes of Health. Insight into delusions was assessed using the Delusion Assessment Scale (DAS). The primary outcomes were the predictive utility of insight into illness (ie, Hamilton Depression Rating Scale [HDRS] insight item) and insight into delusions (conviction factor derived from the DAS) on final treatment outcome at 12 weeks of treatment (ie, full remission, partial remission, and nonremission)., Results: At baseline, impaired insight into delusions was positively associated with illness severity (HDRS-16 which excluded the insight item, r = 0.15, P = .016) and negatively correlated with measures of cognition (P < .05). Improvement in insight was not associated with changes in cognition, suicidality, or social functioning after adjusting for covariates. Independent of the severity of depression or psychosis, impaired insight into delusions at baseline (χ² = 11.65, P = .020) and after 3 (χ² = 9.62, P = .047), 6 (χ² = 6.97, P = .031), and 8 (χ² = 9.08, P = .011) weeks of treatment predicted remission at the end of the trial., Conclusions: Impaired insight into delusions appears to be an independent predictor of remission in MDD with psychotic features during acute treatment, suggesting that more attention should be paid to this symptom. Longitudinal studies are required to determine the impact of impaired insight into delusions on long-term outcomes, including relapse., Trial Registration: ClinicalTrials.gov identifier: NCT00056472., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Background: There are conflicting results on the impact of anxiety on depression outcomes. The impact of anxiety has not been studied in major depression with psychotic features ("psychotic depression")., Aims: We assessed the impact of specific anxiety symptoms and disorders on the outcomes of psychotic depression., Methods: We analyzed data from the Study of Pharmacotherapy for Psychotic Depression that randomized 259 younger and older participants to either olanzapine plus placebo or olanzapine plus sertraline. We assessed the impact of specific anxiety symptoms from the Brief Psychiatric Rating Scale ("tension", "anxiety" and "somatic concerns" and a composite anxiety score) and diagnoses (panic disorder and GAD) on psychotic depression outcomes using linear or logistic regression. Age, gender, education and benzodiazepine use (at baseline and end) were included as covariates., Results: Anxiety symptoms at baseline and anxiety disorder diagnoses differentially impacted outcomes. On adjusted linear regression there was an association between improvement in depressive symptoms and both baseline "tension" (coefficient=0.784; 95% CI: 0.169-1.400; p=0.013) and the composite anxiety score (regression coefficient = 0.348; 95% CI: 0.064-0.632; p=0.017). There was an interaction between "tension" and treatment group, with better responses in those randomized to combination treatment if they had high baseline anxiety scores (coefficient=1.309; 95% CI: 0.105-2.514; p=0.033). In contrast, panic disorder was associated with worse clinical outcomes (coefficient=-3.858; 95% CI: -7.281 to -0.434; p=0.027) regardless of treatment., Conclusions: Our results suggest that analysis of the impact of anxiety on depression outcome needs to differentiate psychic and somatic symptoms., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: There is no established psychometric instrument dedicated to the measurement of severity in psychotic depression (PD). The aim of this study was to investigate whether a new composite rating scale, the Psychotic Depression Assessment Scale (PDAS), covering both the psychotic and the depressive domains of PD, could detect differences in effect between two psychopharmacological treatment regimens., Methods: We reanalyzed the data from the Study of Pharmacotherapy of Psychotic Depression (STOP-PD), which compared the effect of Olanzapine+Sertraline (n=129) versus Olanzapine+Placebo (n=130). The response to the two regimens was compared using both a mixed effects model and effect size statistics on the total scores of three rating scales: the 17-item Hamilton Depression Rating Scale (HAM-D17), its 6-item melancholia subscale (HAM-D6), and the 11-item PDAS consisting of the HAM-D6 plus five items from the Brief Psychiatric Rating Scale covering psychotic symptoms., Results: According to both statistical approaches, the PDAS, the HAM-D17 and the HAM-D6 were all able to detect significant differences in treatment effect between Olanzapine+Sertraline and Olanzapine+Placebo (Olanzapine+Sertraline being superior). Notably, 45% of the trial participants were at least "probable psychotic" at their last assessment in the trial., Limitations: The STOP-PD was not designed specifically to answer the research questions of the present study., Conclusions: The Psychotic Depression Assessment Scale (PDAS) is a sensitive measure of treatment response in PD. The fact that 45% of the patients still experienced psychotic symptoms at their last trial assessment emphasizes the need to include items pertaining to psychotic symptoms in rating scales for PD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Observational studies report that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with an increased risk of falls in the elderly, but these studies may overestimate drug-specific risk because of confounding. A randomized controlled trial (RCT) is the optimal way to assess the causal relationship between use of an SSRI and falls. We therefore analyzed data from a RCT of the treatment of psychotic depression, to examine whether combined olanzapine and sertraline interacted with older age to increase the risk of falling compared with olanzapine plus placebo., Design: Double-blind placebo-controlled RCT., Setting: Four academic medical centers., Participants: Two hundred fifty-nine patients with major depressive disorder with psychotic features (N = 117 aged 18-59 years and N = 142 aged 60 years or older)., Intervention: Twelve weeks of randomized double-blind treatment with olanzapine plus sertraline or olanzapine plus placebo., Measurements: Proportion of participants who fell at least once., Results: Older participants were significantly more likely than younger participants to fall. Among older participants, the odds ratio of falling with olanzapine plus sertraline versus olanzapine plus placebo was 1.56 (95% confidence interval: 0.63-3.83). There was not a statistically significant treatment effect or treatment × age interaction with respect to the proportion of participants falling. These negative results may have been due to low statistical power., Conclusion: Evaluating the association between SSRIs and falls in a RCT is limited by the large sample size that is required. An alternative approach is to examine the effect of an SSRI on measures of postural stability and gait that are valid markers of risk of falling., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Gender differences exist in psychiatric disorders; however, gender has not been well studied in psychotic depression. This analysis of the largest clinical trial in psychotic depression examined the effects of age and gender on clinical characteristics and predictors of treatment outcome and treatment-associated changes in body mass index (BMI) and metabolic measures., Method: Secondary analyses were performed on data from 259 subjects with major depressive disorder with psychotic features (DSM-IV-TR) aged 18-93 years in the double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression (Study of Pharmacotherapy of Psychotic Depression). Sociodemographic factors, clinical characteristics, treatment outcome, and treatment-associated changes in BMI and metabolic measures were analyzed by gender and age. Subjects were enrolled from December 2002 to June 2007., Results: Female gender was associated with divorced (χ(2)(1) = 5.3, P = .03) or widowed (χ(2)(1) = 8.1, P ≤ .01) marital status. Comorbid anxiety disorders were more common in women than in men (χ(2)(1) = 4.9, P = .03). Hallucinations (χ(2)(1) = 7.8, P = .005) and delusions with disorganization (t(257) = -2.10, P = .04) were significantly associated with female gender, as were higher cholesterol measures (χ(2)(1) = 7.15, P = .008). There were no significant interactions between treatment and gender in terms of change in BMI. Gender was not associated with treatment response., Discussion: This study is the first analysis of gender and age as predictors of treatment outcome and treatment-associated changes in BMI and metabolic adverse effects in psychotic depression. Gender differences exist in patients with psychotic depression, most notably with regard to the presence of hallucinations. Female gender was associated with metabolic measures. Future studies with larger sample sizes may detect small gender differences in treatment outcome and treatment-associated changes in BMI and metabolic measures in psychotic depression., Trial Registration: ClinicalTrials.gov identifier: NCT00056472., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Having failed to respond to an adequate antidepressant treatment course predicts poorer treatment outcomes in patients with major depression. However, little is known about the impact of prior treatment on the outcome of major depression with psychotic features (MDpsy). We examined the effect of prior treatment history on the outcome of pharmacotherapy of MDpsy in patients who participated in the STOPD-PD study, a randomized, double-blind, clinical trial comparing a combination of olanzapine plus sertraline vs. olanzapine plus placebo. The strength of treatment courses received prior to randomization was classified using a validated method. A hierarchy of outcomes was hypothesized based on treatments received prior to randomization and randomized treatment. A high remission rate was observed in subjects with a history of no prior treatment or inadequate treatment who were treated with a combination of olanzapine and sertraline. A low remission rate was observed in subjects who had previously failed to respond to an antidepressant alone and who were treated with olanzapine monotherapy. A low remission rate was also observed in subjects who had previously failed to respond to a combination of an antipsychotic and an antidepressant. Similar to patients with major depression, these results emphasize the impact of prior pharmacotherapy on treatment outcomes in patients with MDpsy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To compare the frequency of anxiety disorders in older and younger persons with major depressive disorder with psychotic features., Design: Cross-sectional., Setting: University medical centers., Participants: Two hundred fifty-nine persons (N = 117 aged 18-59 years and N = 142 aged > or =60 years) with major depressive disorder with psychotic features who were enrolled in the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD)., Measurements: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) defined anxiety disorders were determined by Structured Clinical Interview for DSM-IV interview at baseline assessment. Younger and older participants were compared on the frequencies of any current anxiety disorder and any lifetime anxiety disorder, as well as the frequencies of individual anxiety disorders., Results: Older persons had significantly lower frequencies of any current anxiety disorder and any lifetime anxiety disorder, even after controlling for relevant demographic and clinical variables. With respect to specific anxiety disorders, older persons had significantly lower frequencies of current and lifetime panic disorder, current and lifetime social anxiety disorder, and current and lifetime posttraumatic stress disorder., Conclusion: The findings of this study are consistent with those of community-based epidemiologic surveys that anxiety disorders are less prevalent in older than younger adults. Because of the rigorous assessment used in STOP-PD, our findings suggest that the age-related decline in the prevalence of anxiety disorders is not simply due to a failure to detect cases in older people, as has been previously suggested.

Background: Among patients with major depression with psychotic features, little is known about the extent to which those with and without somatic delusions differ., Methods: The first 183 participants in the STOP-PD study were divided into two groups based on the presence or absence of somatic delusions and were compared on multiple demographic and clinical characteristics., Results: In the multivariate analysis, those with somatic delusions reported more somatic symptoms, rated their health as worse, and were less likely to have persecutory delusions., Conclusions: Based on the methods we used, we could not detect meaningful differences between subjects with and without somatic delusions. This suggests that the presence of irrational somatic ideation does not define a distinct clinical subgroup among patients with psychotic depression. This finding needs to be replicated.

Objective: This study examined the rate and predictors of major depression six months after outpatient mental health admission., Methods: Assessments were conducted at admission and three and six months later among 166 participants. Antidepressant treatment adequacy and depression outcomes were assessed at follow-ups., Results: Predictors of major depression at six months included nonremission status at three months (odds ratio [OR]=3.56, p=.003), inadequacy of early pharmacotherapy (OR=2.73, p=.009), worse physical functioning measured by the 36-Item Short-Form Health Survey (OR=.975, p<.001), and being unmarried (OR=2.54, p=.031)., Conclusions: The findings support the effects of baseline physical disability, marital status, early treatment adequacy, and early remission on the course of major depression. The identification of individuals who do not receive intensive pharmacotherapy or who have not recovered by three months may provide opportunities for interventions to optimize six-month outcomes and to prevent the development of a persistent depression.

The independent association of age and other factors with suicidality in patients with major depression with psychotic features was examined. Of the 183 study participants, 21% had a suicide attempt during the current episode. Male gender, Hispanic background, past suicide attempt, higher depression scores, and higher cognitive scores were each independently associated with greater intensity of current suicidality. Older age was independently associated with a lower risk of a lifetime suicide attempt. These findings reinforce the evidence that patients with psychotic depression are at high risk for suicide and underscore the importance of examining correlates of suicidality specific to patients with psychotic depression.

Background: Major depressive disorder with psychotic features (psychotic depression), though occurring relatively frequently in the general population, is a commonly missed psychiatric diagnosis., Objective: To ascertain accuracy of diagnosis of psychotic depression among inpatients at 4 academic medical centers and explore whether presenting symptoms, treatment setting, and physician's level of training affect the accuracy of diagnosis., Method: The medical records of 65 patients who met DSM-IV criteria for psychotic depression following systematic assessment were analyzed to ascertain the concordance between chart diagnoses and research diagnoses arrived at using the Structured Clinical Interview for DSM-IV. The patients were participants in the National Institute of Mental Health Study of Pharmacotherapy of Psychotic Depression, conducted from December 28, 2002, through June 18, 2004, at 4 academic medical centers. For each patient's hospital visit, separate standardized data forms were completed on the basis of each physician's assessment of the patient prior to screening for the study. Hospital records from the emergency room and from admission to psychiatric units were reviewed. Among these 65 patients, 130 chart diagnoses had been made., Results: Psychotic depression had not been diagnosed prior to research assessments for 27% of the 130 diagnoses in our sample. The 3 most common diagnoses assigned to patients meeting research criteria for psychotic depression were major depressive disorder without psychotic features, depression not otherwise specified, and mood disorder not otherwise specified. Failure to identify psychotic depression was more likely when symptoms of depressed mood, hallucinations, or delusions were not noted in the medical record (all p < .005). The accuracy of diagnoses was greater on inpatient units than in emergency rooms (chi(2) = 7.64, p < .01)., Conclusion: The diagnosis of psychotic depression is frequently missed in emergency room and inpatient settings. The findings of this study are sobering given the serious morbidity and mortality of psychotic depression and the implications for treatment if an inaccurate diagnosis is made., Trial Registration: clinicaltrials.gov Identifier: NCT00056472.

Objective: To determine whether the sensitivity of the Hamilton Depression Rating Scale (HDRS) and Montgomery-Asberg Depression Rating Scale (MADRS) to treatment effects are comparable in geriatric antidepressant randomized controlled trials by developing and validating an equation that links between the two instruments., Methods: Literature search for this meta-analysis was based on three sources: MEDLINE, a recent related meta-analysis, and experts in geriatric antidepressant trials. The search resulted in 11 relevant geriatric antidepressant trial studies that administered both instruments for symptom ratings. The authors used baseline ratings as a model-building sample and postrandomization ratings as a validation sample. HDRS scores were prorated into HDRS17, a 17-item HDRS, for analysis. The development and validation was based on a total number of 1,874 subjects., Results: The correlations were high between baseline mean HDRS17 and MADRS ratings (r = 0.80; Fisher's z = 1.09, N = 25, p <0.0001) and between postrandomization ratings (r = 0.88, Fisher's z = 1.39, N = 65, p <0.0001). The following equation was derived: HDRS17 = -1.58 + 0.86 x MADRS. The difference between observed and estimated HDRS17 in a validation sample consisting of postrandomization follow-up means did not depend on magnitudes of HDRS17., Conclusion: Although generalizability of findings into a broader population could be limited, and the authors could not assess concordance of changes of particular item constructs between HDRS and MADRS ratings, both ratings are comparable in assessing changes in overall depressive symptom severity in response to antidepressants in depressed elderly at aggregated group mean levels.

Objective: Practice guidelines recommend the use of a combination of an antidepressant and an antipsychotic for the pharmacologic treatment of major depressive disorder with psychotic features (MD-Psy). We assessed the extent to which the pharmacotherapy received by patients with MD-Psy under usual care conforms to these recommendations., Method: We assessed the pharmacotherapy received under usual care conditions by 100 patients with MD-Psy prior to enrollment in STOP-PD (Study of the Pharmacotherapy of Psychotic Depression), a 12-week randomized, controlled trial comparing olanzapine plus sertraline to olanzapine plus placebo. Our assessment took place from January 2003 to May 2004. The strength of antidepressant trials was rated using the Antidepressant Treatment History Form (ATHF). The strength of antipsychotic trials or combinations of antidepressants and antipsychotics was rated using a modified version of the ATHF. We also determined whether the strength of antipsychotic or combination trials was associated with age, the duration of the current depressive episode, medical burden, cognitive status, or the severity of depressive or psychotic symptoms., Results: Most patients with MD-Psy were treated with antidepressants (N = 82, 82%) or antipsychotics (N = 65, 65%). About half of the patients (N = 48, 48%) received therapeutic doses of an antidepressant; 10% (N = 10) received an intermediate dose of an antipsychotic, and 6% (N = 6) received a high dose. Overall, only 5% (N = 5) received a combination of an adequate dose of an antidepressant and a high dose of an antipsychotic. The strength of both antipsychotic trials (p = .021) and combination trials (p = .039) was significantly associated only with a longer duration of the current depressive episode., Conclusions: These findings show a persisting low use of antipsychotics in the treatment of MD-Psy. Given the high morbidity rates associated with MD-Psy, it is important to continue to educate clinicians regarding its identification and treatment., Clinical Trials Registration: ClinicalTrials.gov identifier NCT00056472.

Background: Although delusions are the hallmark of major depression with psychotic features, a scale to measure the intensity of beliefs across multiple delusional domains in this condition has been unavailable. The development and assessment of the Delusional Assessment Scale (DAS) are described., Methods: Scale items were selected initially based on previous studies of delusional ideation in schizophrenia. A three-point item to assess mood congruence was added. A 15-item scale was assessed in 92 subjects participating in the four-site collaborative study of the pharmacotherapy of major depression with psychotic features. Maximum likelihood method was used to determine scale factors. The internal consistency of these factors was determined. Comparisons between scale scores and ratings from the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) were used to assess convergent and discriminant validity., Results: The data were fit by a five-factors model (impact, conviction, disorganization, bizarreness, and extension). Inter-rater reliability of the five factors ranged from .77 for conviction and .74 for impact to .37 for disorganization. Internal consistency for each of the five factors was > or =.72. Scores on specific domains were significantly correlated with the BPRS unusual thought content item and positive symptom subscale scores., Conclusions: The DAS is a reliable measure of 5 delusional domains.

Objective: Studies in primary care settings have shown that depression is often chronic and associated with negative outcomes among patients with medical illness. The stability of depression among home care recipients has not been investigated. The authors examined the 1-month stability of major depression in a representative sample of elderly adults shortly after their admission to home care., Methods: A group of 539 subjects over age 65, newly admitted to home care for skilled nursing, were interviewed with the Structured Clinical Interview for DSM-IV (SCID-IV). Depression severity, medical comorbidity, pain, functional status, cognitive status, and recent life events were also assessed. Of 84 subjects who met criteria for major depression (MDD) at baseline, 74 were available for 1-month follow-up interview., Results: At 1-month follow-up, 31 subjects (42%) continued to meet MDD criteria; 20 (27%) achieved partial remission; and 23 (31%) were in full remission. Fewer instrumental activity limitations at baseline, experiencing "a great deal" of pain, and absence of a recent stressful life event were associated with full remission at 1-month follow-up., Conclusion: Nearly one-half of newly admitted elderly home care patients who meet criteria for MDD continue to meet full criteria 1 month later. Functional and psychosocial factors affect the short-term course.

Background: Plasma activity of dopamine beta-hydroxylase (DbetaH), the enzyme that converts dopamine to norepinephrine, is reportedly lower in patients with unipolar major depression with psychotic features (UDPF) than in those with nonpsychotic unipolar major depression (UD). Plasma DbetaH is under genetic control by the structural locus encoding DbetaH protein, DBH. This study tested the hypothesis that diagnosis-specific allelic variation at DBH accounts for lower plasma DbetaH in UDPF., Methods: Plasma DbetaH activity was measured in samples from patients with UDPF (n = 33) and UD (n = 45). Genotypes were determined at several functional DBH polymorphisms, including C-1021T, a single nucleotide polymorphism (SNP) in the proximal 5' region that associates with variation in plasma DbetaH activity., Results: Mean plasma DbetaH activity was significantly lower in UDPF than in UD. Genotyping at DBH did not reveal genetic associations distinguishing UDPF from UD. A two-way analysis of variance showed significant effects of genotype and diagnostic group but no significant interaction., Conclusions: Although the effects of the diagnosis of UDPF, and of DBH allele status, on plasma DbetaH activity were replicated, the lower plasma DbetaH in patients with UDPF was not accounted for by DBH genotype. Several explanations for this result are possible. First, other variants at DBH, or at other loci, could account for the findings. Second, nongenetic factors could account for the differences in plasma DbetaH. In this regard, we hypothesize that abnormal regulation of hypothalamic-pituitary-adrenal function in UDPF lowers expression of DbetaH protein, which could in turn alter the ratio of dopamine and norepinephrine in noradrenergic neurons, thereby promoting development of psychotic symptoms.