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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.

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.)

Background: Impaired insight into delusions is associated with a lower probability of remission of psychotic depression, independent of illness severity. The relationship between participant characteristics and impaired insight into delusions in remitted psychotic depression, and whether impaired insight is associated with risk of relapse of psychotic depression during continuation pharmacotherapy were examined., Methods: Data were analyzed from 126 participants in the STOP-PD II study who experienced sustained remission of psychotic depression during 8-week stabilization treatment with sertraline plus olanzapine and were then randomized to 36 weeks of continuation treatment with sertraline plus either olanzapine or placebo. Insight into delusions was assessed with the Resolution of Delusions Scale (RODS). Linear regression analyses examined the associations between participant characteristics and insight into delusions. Cox proportional-hazards models examined whether i) change in RODS during stabilization treatment; or ii) RODS at the end of stabilization treatment predicted risk of relapse during 36 weeks of continuation treatment., Results: Severity of psychosis before initiation of treatment was the only participant characteristic associated with the change in insight during stabilization treatment. Neither change in insight during stabilization treatment nor insight at the end of stabilization treatment was associated with risk of relapse., Limitations: Insufficient statistical power and the lack of variability in RODS scores at the time of randomization may have contributed to the absence of a relationship between RODS and risk of relapse., Conclusion: Residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression in a randomized placebo-controlled trial., Competing Interests: Conflict of interest J. Song has no disclosures. 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. M. Sanches has no disclosures. G.S. Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, and participated in advisory boards of Eisai and Janssen. 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. A.J. Rothschild has received grant or research support from Janssen, the National Institute of Mental Health, Otsuka, and Praxis, and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry, is a consultant to Alkermes, 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). 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 received grant support from the NIMH and HRSA at the time that this work was done. 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. P. Gerretsen reports receiving research support from the Canadian Institute of Health Research (CIHR), Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), the Centre for Addiction and Mental Health (CAMH), CAMH Foundation, and an Academic Scholars Award from the Department of Psychiatry, University of Toronto., (Copyright © 2022. Published by Elsevier B.V.)

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.)

Purpose/background: Electroconvulsive therapy (ECT) is effective in the treatment of acute episodes of psychotic depression. However, no adequately powered studies have directly investigated the efficacy of antipsychotic pharmacotherapy in relapse prevention of psychotic depression after ECT. In the absence of such literature, we reviewed the clinical practice of 4 academic medical centers that have made research contributions in the treatment of psychotic depression over the past 20 years., Methods/procedures: We reviewed medical records of patients with a diagnosis of psychotic depression who received 1 or more acute courses of ECT over the span of 3 years. Chi-square tests were used to compare pharmacotherapy prescribed at the time of completion of ECT., Findings/results: A total of 163 patients received 176 courses of ECT for separate episodes of psychotic depression. The combination of an antidepressant plus an antipsychotic was the most common regimen, ranging from 61.9% to 85.5% of all prescriptions. One center added lithium in 45.5% of cases treated with the combination of an antidepressant plus an antipsychotic. An antipsychotic alone was prescribed in less than 10% of cases. An antidepressant alone or other drug combinations were rare., Implications/conclusions: The combination of an antidepressant plus an antipsychotic was the most commonly prescribed regimen at the completion of ECT for relapse prevention in patients with psychotic depression acutely treated with ECT. Although this report offers a view of the clinical practice of 4 academic medical centers, it also points to the need of randomized controlled trials on continuation pharmacotherapy after treatment of psychotic depression with ECT., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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 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 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.

Objective: Unipolar psychotic depression (PD) is a severe and debilitating syndrome, which requires intensive monitoring. The objective of this study was to provide an overview of the rating scales used to assess illness severity in PD., Method: Selective review of publications reporting results on non-self-rated, symptom-based rating scales utilized to measure symptom severity in PD. The clinical and psychometric validity of the identified rating scales was reviewed., Results: A total of 14 rating scales meeting the predefined criteria were included in the review. These scales grouped into the following categories: (i) rating scales predominantly covering depressive symptoms, (ii) rating scales predominantly covering psychotic symptoms, (iii) rating scales covering delusions, and (iv) rating scales covering PD. For the vast majority of the scales, the clinical and psychometric validity had not been tested empirically. The only exception from this general tendency was the 11-item Psychotic Depression Assessment Scale (PDAS), which was developed specifically to assess the severity of PD., Conclusion: In PD, the PDAS represents the only empirically derived rating scale for the measurement of overall severity of illness. The PDAS should be considered in future studies of PD and in clinical practice., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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: 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.

Context: Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression (MD) with psychotic features., Objectives: To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy; and to compare response by age., Design: Twelve-week, double-blind, randomized, controlled trial., Setting: Clinical services of 4 academic sites. Patients Two hundred fifty-nine subjects with MD with psychotic features randomized by age (<60 or > or =60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 younger adults vs 71.7 [7.8] years in 142 geriatric participants). Intervention Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day. Main Outcome Measure Remission rates of MD with psychotic features., Results: Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (chi(2)(1) = 9.53, P = .002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09-1.66; P = .01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001)., Conclusions: Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features. Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks., Trial Registration: clinicaltrials.gov Identifier: NCT00056472.

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: 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: Decreased dopamine beta-hydroxylase (DBH) activity has been reported in unipolar psychotic depression. DBH comparisons between elderly delusional and nondelusional depressives and controls and determination of whether pretreatment group differences persist have not been reported. Our objective was to compare DBH activity in elderly delusional major depressives with that of nondelusional depressives and normal control subjects before and after hospital treatment., Methods: Enzyme activity was assessed after hospital admission. A subsample had predischarge assessments. Treatment was not controlled but accounted for in analyses. Electroconvulsive therapy subjects were medication-free for posttreatment assays., Results: Baseline and predischarge DBH assays were lower in subjects with delusional depression than in either comparison group. Despite high intraindividual correlation, treatment was associated with significant increases in activity in the clinical groups., Conclusions: Patients with late-life delusional depression have lower DBH activity before and after hospital treatment than age-matched nondelusional patients or normal controls.