Effect of olanzapine exposure on relapse and brain structure in patients with major depressive disorder with psychotic features.

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

Trajectories of remitted psychotic depression: identification of predictors of worsening by machine learning.

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.

Effects of antipsychotic medication on functional connectivity in major depressive disorder with psychotic features.

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

Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study.

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.

Placebo Effect in Randomized Trials of Major Depressive Disorder With Psychotic Features: A Systematic Review and Descriptive Meta-Analysis.

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

An Internet-Based Self-Management Intervention to Reduce Fatigue Among People With Traumatic Brain Injury: A Pilot Randomized Controlled Trial.

IMPORTANCE: Fatigue is a chronic and distressing sequela of traumatic brain injury (TBI). Little evidence exists for the efficacy of interventions that address post-TBI fatigue. OBJECTIVE: To evaluate the preliminary efficacy of a self-management intervention (Maximizing Energy; MAX) for reducing the impact (primary outcome) and severity of fatigue on daily life, improving fatigue experience, and increasing participation compared with a health education (HE) intervention. DESIGN: Pilot randomized controlled trial (RCT). SETTING: Community. PARTICIPANTS: Forty-one participants randomly assigned to the MAX (n = 20) or HE (n = 21) intervention. INTERVENTIONS: The MAX intervention included problem-solving therapy with energy conservation education to teach participants fatigue management. The HE intervention included diet, exercise, and energy conservation education. Both interventions (30 min/day, 2 days/wk for 8 wk) were delivered online by occupational therapists. OUTCOME AND MEASURES: The primary outcome was the modified Fatigue Impact Scale (mFIS). Outcome measures were collected at baseline, postintervention, and 4- and 8-wk postintervention. RESULTS: At 8 wk postintervention, participants in the MAX group reported significantly lower levels of fatigue impact (mFIS) than those in the HE group, F(1, 107) = 29.54, p = .01; Cohen's d = 0.87; 95% confidence interval [0.18, 1.55]. CONCLUSIONS AND RELEVANCE: These findings provide preliminary evidence that the MAX intervention may decrease the impact of fatigue on daily life among people with post-TBI fatigue. What This Article Adds: An internet-based, self-management intervention combining occupational therapy- delivered energy conservation education with cognitive-behavioral therapy seems to reduce fatigue impact and severity among people with post-TBI fatigue. Future appropriately powered RCTs could positively contribute to the evidence available to occupational therapy practitioners for this chronic, debilitating, and often overlooked symptom.

Association between psychomotor disturbance and treatment outcome in psychotic depression: a STOP-PD II report.

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

Pharmacotherapy Prescriptions for Relapse Prevention of Psychotic Depression After Electroconvulsive Therapy.

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.

Effect of Older vs Younger Age on Anthropometric and Metabolic Variables During Treatment of Psychotic Depression With Sertraline Plus Olanzapine: The STOP-PD II Study.

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.

Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial.

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

Improvement in Depression is Associated with Improvement in Cognition in Late-Life Psychotic Depression.

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.

SSRI-antipsychotic combination in psychotic depression: sertraline pharmacokinetics in the presence of olanzapine, a brief report from the STOP-PD study.

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.

Relationship Between Cerebrovascular Risk, Cognition, and Treatment Outcome in Late-Life Psychotic Depression.

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.

Pilot feasibility of an mHealth system for conducting ecological momentary assessment of mood-related symptoms following traumatic brain injury.

OBJECTIVE: This study assessed pilot feasibility and validity of a mobile health (mHealth) system for tracking mood-related symptoms after traumatic brain injury (TBI). DESIGN: A prospective, repeated measures design was used to assess compliance with daily ecological momentary assessments (EMA) conducted via a smartphone application over an 8-week period. METHODS: An mHealth system was developed specifically for individuals with TBI and utilized previously validated tools for depressive and anxiety symptoms (Patient Health Questionnaire-9, Generalized Anxiety Disorder-7). Feasibility was assessed in 20 community-dwelling adults with TBI via an assessment of compliance, satisfaction and usability of the smartphone applications. The authors also developed and implemented a clinical patient safety management mechanism for those endorsing suicidality. RESULTS: Participants correctly completed 73.4% of all scheduled assessments, demonstrating good compliance. Daily assessments took <2 minutes to complete. Participants reported high satisfaction with smartphone applications (6.3 of 7) and found them easy to use (6.2 of 7). Comparison of assessments obtained via telephone-based interview and EMA demonstrated high correlations (r = 0.81-0.97), supporting the validity of conducting these assessments via smartphone application in this population. CONCLUSIONS: EMA conducted via smartphone demonstrates initial feasibility among adults with TBI and presents numerous opportunities for long-term monitoring of mood-related symptoms in real-world settings.

Effect of sertraline on risk of falling in older adults with psychotic depression on olanzapine: results of a randomized placebo-controlled trial.

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

Reliability and validity of the Executive Interview (EXIT) and Quick EXIT among community dwelling older adults.

OBJECTIVES: To investigate the psychometric properties of the Executive Interview (EXIT) and Quick EXIT in community dwelling older adults. DESIGN: Secondary analysis of data obtained as part of a longitudinal study of cognitive function in late-life depression. SETTING: A university hospital. PARTICIPANTS: Community-dwelling adults (N = 422), aged 59 years and older, with current or recent history of non-psychotic unipolar major depression, and never-depressed comparison subjects. MEASUREMENTS: The EXIT and other measures of executive control functions (ECF), non-executive cognitive domains, and global cognitive function. We calculated Quick EXIT scores from the EXIT. RESULTS: The EXIT demonstrated high inter-rater reliability (Intraclass correlation coefficient = 0.978, F(7, 21) = 174.85, p <0.001), and both the EXIT and Quick EXIT demonstrated moderate internal consistency (α = 0.66 and α = 0.68, respectively). Both tests also demonstrated acceptable convergent validity against several standard tests of ECF (rs -0.399 to 0.322, except for the Trail Making Test B, where rs was 0.057 to 0.063) as well as against measures of multifactorial cognitive function (rs -0.432 to 0.491). Both tests, however, demonstrated inconsistent discriminant validity against a variety of standard non-ECF tests (rs -0.013 to 0.376). CONCLUSIONS: Both the EXIT and the Quick EXIT have adequate reliability and appear to require ECF in this population. However, both the EXIT and the Quick EXIT also reflect non-ECF domains. The EXIT and Quick EXIT should be considered to be measures of global cognitive function rather than pure ECF measures. Given similar reliability and validity, the Quick EXIT is recommended clinically as it is briefer and less burdensome than the full EXIT.

Differential impact of anxiety symptoms and anxiety disorders on treatment outcome for psychotic depression in the STOP-PD study.

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.

Developing complex interventions: lessons learned from a pilot study examining strategy training in acute stroke rehabilitation.

OBJECTIVE: To examine the feasibility of a strategy training clinical trial in a small group of adults with stroke-related cognitive impairments in inpatient rehabilitation, and to explore the impact of strategy training on disability. DESIGN: Non-randomized two-group intervention pilot study. SETTING: Two inpatient rehabilitation units within an academic health centre. PARTICIPANTS: Individuals with a primary diagnosis of acute stroke, who were admitted to inpatient rehabilitation and demonstrated cognitive impairments were included. Individuals with severe aphasia; dementia; major depressive disorder, bipolar, or psychotic disorder; recent drug or alcohol abuse; and anticipated length of stay less than five days were excluded. INTERVENTION: Participants received strategy training or an attention control session in addition to usual rehabilitation care. Sessions in both groups were 30-40 minutes daily, five days per week, for the duration of inpatient rehabilitation. MAIN OUTCOME MEASURES: We assessed feasibility through participants' recruitment and retention; research intervention session number and duration; participants' comprehension and engagement; intervention fidelity; and participants' satisfaction. We assessed disability at study admission, inpatient rehabilitation discharge, 3 and 6 months using the Functional Independence Measure. RESULTS: Participants in both groups (5 per group) received the assigned intervention (>92% planned sessions; >94% fidelity) and completed follow-up testing. Strategy training participants in this small sample demonstrated significantly less disability at six months (M (SE) = 117 (3)) than attention control participants (M(SE) = 96 (14); t 8 = 7.87, P = 0.02). CONCLUSIONS: It is feasible and acceptable to administer both intervention protocols as an adjunct to acute inpatient rehabilitation, and strategy training shows promise for reducing disability.

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

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

The incidence of tardive dyskinesia in the study of pharmacotherapy for psychotic depression.

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.