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Introduction: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. Methods: Genomic analyses were performed in 171 men and women aged 18–85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. Results: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer’s disease had a significantly decreased likelihood of relapse. Conclusion: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.

Psychotic depression has a high rate of relapse. The study aims were to identify a prediction model of risk of relapse of psychotic depression and examine whether predictors moderated the effect of treatment on relapse. One hundred and twenty-six men and women aged 18-85 years, who experienced sustained remission or near-remission of psychotic depression with sertraline plus olanzapine, participated in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse (NCT01427608). Cox regression analyses were performed to identify significant predictors of relapse and to model the combined role of significant predictors. Concordance statistic was calculated to determine the accuracy of the best fit multivariable models in predicting relapse. Finally, interaction terms were tested for each significant predictor to examine whether they moderated the effect of treatment on risk of relapse. Lifetime number of depressive episodes, severity of residual depressive symptoms at the time of randomization, and psychomotor disturbance both at acute enrollment when participants were depressed and at the time of randomization predicted risk of relapse. Multivariable models had 69-70% accuracy in predicting relapse. Psychomotor disturbance was associated with increased risk of relapse in the sertraline plus olanzapine group compared with sertraline plus placebo, whereas the other predictors did not moderate the effect of treatment on relapse. Future research is needed to determine whether a combination of clinical and biological variables can further increase the accuracy of prediction of relapse of psychotic depression.

Objective To examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine. Methods Two hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures. Results Participants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18–59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures. Conclusion Older patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.

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.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.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.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.Residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression in a randomized placebo-controlled trial.

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

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.

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.

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.

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.

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.

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​.

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.

Background: Prescriptions for antipsychotic medications continue to increase, across many brain disorders, including off-label use in children, and the elderly. Recent animal data and uncontrolled human data suggest that antipsychotics may have deleterious effects on brain structure. The present study is the first to assess the effects of antipsychotics on brain structure in humans using a double-blind randomized placebo-controlled design. Methods: Participants were recruited from the multi-centre STudy Of the Pharmacotherapy of Psychotic Depression II (STOP-PD II, clinicaltrials.gov registration number NCT01427608). All participants had major depressive disorder with psychotic features ('psychotic depression') and were prescribed olanzapine and sertraline for a period of 12-20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue on this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Those who consented to the imaging study completed an MRI scan at the time of randomization and a second MRI scan at the end of the 36-week period, or sooner if the participant experienced a relapse. 88 participants completed a baseline scan; 75 completed a follow-up scan of which 72 were useable. Using mixed model regression, we assessed changes in gray matter morphology, and changes in white matter using diffusion-weighted MRI. We also explored the effects of illness relapse on the same measures. Findings: There was a significant treatment group by time interaction in cortical thickness, but not surface area, and thalamic, but not striatal or hippocampal volume. A similar interaction was found in mean diffusivity of white matter, but not fractional anisotropy. When the analysis was restricted to those who sustained remission only (controlling for effects of active illness and time), exposure to olanzapine compared to placebo was associated with significant decreases in cortical thickness and cortical surface area, but not subcortical volumes, no change in fractional anisotropy, but significant increase in mean diffusivity of white matter. Post-hoc analyses showed that those who relapsed on placebo experienced decreases in cortical thickness compared to those who sustained remission, suggesting effects of illness on brain structure. Interpretation: Antipsychotic medication can have deleterious effects on brain structure. Our results, along with reports of increased risk of death, suggest reconsideration of prescribing practice, particularly where alternatives are present. However, potentially adverse effects of relapse on brain structure support antipsychotic treatment during active illness. Trial Registration: Clinicaltrials.gov Registry ID: NCT01427608 Funding Statement: The present study was funded by the NIMH R01MH099167 grant. The STOP-PD II clinical trial from which participants were recruited was funded by USPHS grants MH 62446, MH 62518, MH 62565, and MH 62624 from the National Institute of Mental Health (NIMH). In that trial, Eli Lilly provided olanzapine and matching placebo pills and Pfizer provided sertraline; neither company provided funding for the study Declaration of Interests: A.N. Voineskos receives funding from the National Institute of Mental Health, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto. B.H. Mulsant has received: research funding from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, and the US National Institutes of Health (NIH); research support from Bristol-Myers Squibb (medications for a NIH-funded clinical trial), Eli-Lilly (medications for a NIH-funded clinical trial), Pfizer (medications for a NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He directly own stocks of General Electric (less than $5,000). E. Dickie receives grant support from the Brain and Behavior Research Foundation N. Neufeld receives grant support from the Physicians’ Services Incorporated Foundation and the University of Toronto A.J. Rothschild has received grant or research support from Allergan, Janssen, the National Institute of Mental Health, Takeda, 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, GlaxoSmithKline, Sage Therapeutics, and Sanofi-Aventis, and 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®. E.M. Whyte receives grant support from the NIMH and HRSA. B.S. Meyers received research support from the NIMH at the time this work was done. G.S. Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, Sunovion. M.J. Hoptman has received NIMH grants during the conduct of this study. J. Lerch receives grant support from CIHR and the Ontario Brain Institute. A.J. Flint has received grant support from the U.S. National Institutes of Health, the PatientCentered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and Alzheimer’s Association. Ethics Approval Statement: Using procedures approved by local institutional review boards, written informed consent was obtained from all participants or their substitute decision maker prior to the initiation of any research procedures.

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

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.

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

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.

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.

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.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.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.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: 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.

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 A(1c) (HbA(1c)). 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

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.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.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.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.ClinicalTrials.gov identifier: NCT00056472.

Tardive dyskinesia (TD) is a debilitating adverse effect associated with antipsychotic treatment. Older age and the presence of mood disorder have been identified as risk factors for the development of TD. Thus, we assessed the incidence of TD in younger and older patients with major depressive disorder with psychotic features who participated in a 12-week clinical trial comparing olanzapine plus sertraline versus olanzapine plus placebo. All subjects (n = 259) were assessed with the Abnormal Involuntary Movement Scale at baseline and after 4, 8, and 12 weeks of treatment (or at termination). We used 7 different published criteria to estimate the prevalence of TD at baseline and the incidence over the duration of the trial. We compared the incidence of TD in subjects 60 years or older and those younger than 60 years. The overall prevalence and incidence of TD varied almost 10-fold, depending on the criteria (prevalence range, 1.2%-8.9%; incidence range, 0.0%-5.9%). Tardive dyskinesia was observed as a clinical adverse event in only 1 subject (0.4%). Whereas older subjects had a higher prevalence of TD at baseline, the incidence in younger and older subjects did not differ significantly. The incidence of TD was relatively low in both younger and older patients with major depressive disorder with psychotic features treated acutely with olanzapine. However, the estimate of the risk of TD varies widely, depending on the criteria used to define TD.

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 23 respectively. When applying the PDAS total score 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

Objectives Determine rates and demographic, clinical, and functional correlates of antidepressants (ADs) in home healthcare patients. Methods Year 2007 cross-sectional National Home Health and Hospice Care Survey (N = 3,226) of patients 65 years or older (mean 80.11, confidence interval [CI] = 79.65–80.57). Results Overall 33.50% used ADs. Among the 6.76% with depression, 70.84% used ADs compared with 29.15% who used ADs without a documented depression diagnosis. In a regression, controlling for depression, blacks used less ADs than whites (odds ratio [OR] = 0.41, CI=0.24–0.70). Younger age (OR = 0.96, CI=0.94–0.98), activities of daily living impairments (OR = 1.15, CI=1.05–1.26), benzodiazepines (OR = 2.63, CI=1.88–3.69), antipsychotics (OR = 2.08, CI=1.29–3.36), and nonpsychotropics (OR = 1.07, CI=1.04–1.10) were related to AD use. Conclusion Among home healthcare patients, more than one-third took ADs including patients without depression. Blacks used fewer ADs than whites. Increased use was associated with younger age, disability, and nonpsychotropics.

High levels of depressive symptoms are common and contribute to poorer clinical outcomes even in geriatric patients who are already taking antidepressant medication. The Depression CARE for PATients at Home (Depression CAREPATH) intervention was designed to meet the needs of medical and surgical patients who suffer from depression. The intervention’s clinical protocols are designed to guide clinicians in managing depression as part of routine home care.

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.

The authors hypothesized that the depression treatment preferences of elderly home care patients would vary by their experience of depression and that preferences for active treatment would be associated with current depression and with antidepressant treatment.The authors conducted cross-sectional secondary analyses of data from the TRIAD study (Training in the Assessment of Depression) of 256 randomly selected elderly patients newly admitted to home care. The study assessed preference for active treatments (medication or psychotherapy) and nonactive or complementary approaches (such as religious activities or doing nothing). Nondepressed patients were asked to choose as if they had serious depression. Two separate indicators of depression experience were used: a current diagnosis of major or minor depression and current or previous antidepressant treatment.Of the 256 patients, 16% (N=41) met criteria for major or minor depression. Forty-seven percent of the sample (N=121) preferred an active treatment as their first choice, and others preferred nonactive or complementary approaches. Logistic regression indicated that current antidepressant use, previous psychotherapy experience, white or Hispanic race-ethnicity (versus black), greater impairment in instrumental activities of daily living, and less personal stigma about depression were independently associated with preference for an active treatment.Elderly home care patients had a variety of treatment preferences, ranging from active treatments, to religious or spiritual activities, to no treatment. Several factors were associated with a preference for active treatment, including treatment experience, physical impairment, race-ethnicity, and attitudes and beliefs. An understanding of patient preferences may help engage older depressed home care patients in treatment.

OBJECTIVE: Identify depression symptoms during active late-life depression (LLD) that predict conversion to dementia. METHODS: We followed a cohort of 290 participants from the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. All participants were actively depressed and cognitively normal at enrollment. Depression symptom factors were derived from prior factor analysis: 1) Anhedonia and Sadness; 2) Suicidality and Guilt; 3) Appetite and Weight Loss; 4) Sleep Disturbance; 5) Anxiety and Tension. Cox regression analysis modeled time to AD and non-AD dementia onset on depression symptom factors, along with age, education, sex, and race. Significant dementia predictors were tested for interaction with age of depression onset. RESULTS: Higher scores on the Appetite and Weight Loss symptom factor were associated with an increased hazard of both AD and non-AD dementia. This factor was moderated by age of first depression onset, such that higher scores were associated with higher risk of non-AD dementia when depression first occurred earlier in life. Other depression symptom factors and overall depression severity were not related to risk of AD or non-AD dementia. CONCLUSIONS: Results suggest greater appetite/weight loss symptoms in active episodes of LLD are associated with increased likelihood of AD and non-AD dementia, but possibly via different pathways moderated by age of first depression onset. Results may help clinicians identify individuals with LLD at higher risk of developing AD and non-AD dementia, and help design interventions that reduce this risk.

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 ≥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.

Objective To identify study-level and treatment group-level characteristics that are associated with attrition in antidepressant trials for the depressed elderly. Methods This meta-analysis used 68 published antidepressant randomized trials for the elderly depressed. Study-level and treatment group-level variables were extracted. The former consisted of: use of placebo arm, number of arms, unbalanced treatment allocation, year conducted, study duration, study location, number of centers, and patient pool. The latter consisted of: assigned treatments, baseline mean Hamilton Depression Rating Scale (HDRS), baseline mean age, gender ratio, attrition size, and sample size. Univariate logistic regressions with attrition as the dependent variable were applied, followed by application of a forward stepwise selection method for identification of independent attrition correlates. Results The 68 studies had a total of 153 treatment groups and 8,385 subjects. Among them, 2,287 subjects were terminated early, resulting in an overall 27.3% attrition rate. The stepwise results showed that higher attrition was significantly associated with active antidepressant groups as opposed to placebo groups, higher baseline HDRS, smaller sample size, unbalanced allocation of treatments, longer duration, and studies conducted in USA. Conclusions The attrition in geriatric antidepressant trials can be affected by study and group-level design characteristics that include severity of depression symptoms and active treatments among others. Copyright © 2009 John Wiley & Sons, Ltd.

Objective: Although medical illness and physical disability are strongly associated with depression, the majority of older adults who experience medical illness or disability at any given time are not depressed. The aim of these analyses was to identify risk factors for new onset depression in a sample of medically ill, disabled older adults. Methods: The authors used data from a representative sample of homebound older adults who recently started receiving Medicare home healthcare services for medical or surgical problems (N = 539). The authors report on the rate and baseline predictors of new onset major or minor depression, using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria and assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders, at 1-year follow-up. Our analyses were conducted with a subsample of older adults (N = 268) who did not meet criteria for major or minor depression and were not on an antidepressant medication at our baseline interview. Results: At 1-year follow-up, 10% (28/268) of patients met criteria for either major (3%; 9/268) or minor depression (7%; 19/268). In multivariate analyses, the authors found that worse self-rated health (odds ratio [OR] = 0.53, p=0.042), more somatic depressive symptoms (OR = 1.19, p=0.015), greater number of activities of daily living (ADL) limitations at baseline (OR = 1.63, p=0.014), and greater decline in ADL functioning from baseline to 1 year (OR = 1.59, p=0.022) were all independently associated with onset depression. Conclusion: These findings underscore the significant fluctuations in both depression and disability in high-risk older adults and suggest that both persistent and new onset disability increase the risk of depression. They may also help in designing preventive strategies to promote the ongoing good mental health of these high-risk patients over time.

Among patients with major depression with psychotic features, little is known about the extent to which those with and without somatic delusions differ.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.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.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.

Because falls are highly prevalent, harmful events for older adults, identification of patients at risk is a high priority for home health care agencies. Using routine administrative data, we demonstrated that patients with depressive symptoms on the Outcome and Assessment Information Set are at risk for falls. A prospective case-control study that matched 54 patients who experienced an adverse fall with 854 controls showed that patients who fell had twice the odds of being depressed (odds ratio = 1.90, 95% confidence interval = 1.01 to 3.59). Bowel incontinence, high medical comorbidity, stair use, injury and poisoning, memory deficit, and antipsychotic medication use were also predictors, but no association was found for antidepressant medications. These data suggest the potential benefit of including depression screening for multifactorial fall prevention interventions.

This study examined the rate and predictors of major depression six months after outpatient mental health admission.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.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).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.

Objectives: The objectives of this pilot study were to determine the incidence of Posttraumatic Stress Disorder (PTSD) one to two months after Myocardial Infarction (MI), and to evaluate potential predictors of PTSD symptoms post-MI. Methods: A convenience sample of 31 patients hospitalized for treatment of acute MI was interviewed during hospitalization and one to two months later. The assessments included socio-demographic questions, questions related to clinical history and hospitalization, assessment of depressive symptoms using the Center for Epidemiologic Studies— Depression (CES-D) scale, medical comorbidity using the Charlson Comorbidity Index (CCI), and perceived social support using the Medical Outcomes Study (MOS) scale. Medical records were reviewed for collection of clinical data. Symptoms of PTSD were evaluated using the Structured Clinical Interview for DSM-IV (SCID) and the Impact of Events Scale-Revised (IES-R). Results: While one patient (4.0%) met DSM IV criteria for PTSD; additional 16% of the patients had significant symptoms of PTSD as measured by the IES-R (scoring above 24). Higher scores of PTSD symptoms were significantly associated ( p < 0.05) with younger age, black race, depressive symptoms in baseline, and self-reported anxiety during the MI. Conclusions: The incidence of PTSD following MI was low, but 16% of MI patients developed subsyndromal PTSD. The emotional status of the patients at the time of the MI and their subjective reaction to the event were important factors in the development of PTSD symptoms. Black and younger patients were in increased risk of developing PTSD symptoms post-MI.

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.

Weight gain has often been associated with olanzapine treatment, yet little is known about the influence of patient age or cumulative dose on olanzapine-associated weight gain. The first 118 participants in the National Institutes of Mental Health Study of the Pharmacotherapy of Psychotic Depression randomized clinical trial (Clinical Trials.gov Registration NCT00056472) completing at least 4 weeks of treatment with olanzapine were analyzed to determine the relationship between weight gain, age, and cumulative olanzapine dose. Younger (age 18-59 years) and older (age 60 + years) participants received open-label olanzapine and either sertraline or placebo for up to 12 weeks. Linear mixed effect regression modeling was used to determine the effects of age and cumulative olanzapine dose on weight gain, controlling for potential confounders. Age was observed to have a significant negative association with weight gain (P=0.01), even after controlling for differences in cumulative dose and baseline body mass index. Each 10-year increase in age was associated with a decrease in mean weight gain over 12 weeks of approximately 0.6 kg (95% confidence interval: 0.14-1.05 kg). Cumulative olanzapine dose was also significantly associated with weight gain (P< 0.0001). Approximately 60% of completers of the 12-week trial experienced clinically significant weight gain (≥ 7% of baseline weight).