Faculty Bibliography

BACKGROUND: Axis I comorbidity complicates diagnosing axis II personality disorders (PDs). PDs might influence Axis I outcome. No research has examined psychotherapy effects on PDs of treating Axis I comorbidity. Secondary analysis of a randomized controlled trial examined PD diagnostic stability after brief psychotherapy of chronic posttraumatic stress disorder (PTSD). METHODS: Patients with chronic PTSD were randomly assigned to 14 weeks of prolonged exposure, interpersonal psychotherapy, or relaxation therapy. Assessments included the Structured Clinical Interview for DSM-IV, Patient Version (SCID-P) and Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) at baseline, week 14, and for treatment responders (>/=30% clinician-administered PTSD scale improvement, defined a priori) at week 26 follow-up. We hypothesized patients whose PTSD improved would retain fewer baseline PD diagnoses posttreatment, particularly with personality traits PTSD mimics, e.g. paranoid and avoidant. RESULTS: Forty-seven (47%) of 99 SCID-II patients evaluated at baseline received a SCID-II diagnosis: paranoid (28%), obsessive-compulsive (27%), and avoidant (23%) PDs were most prevalent. Among 78 patients who repeated SCID-II evaluations posttreatment, 45% (N = 35) had baseline PD diagnoses, of which 43% (N = 15/35) lost at week 14. Three (7%) patients without baseline PDs acquired diagnoses at week 14; 10 others shifted diagnoses. Treatment modality and PTSD response were unrelated to PD improvement. Of treatment responders reevaluated at follow-up (N = 44), 56% with any baseline Axis II diagnosis had none at week 26. CONCLUSION: This first evaluation of Axis I psychotherapy effects on personality disorder stability found that acutely treating a chronic state decreased apparent trait-across most PDs observed. These exploratory findings suggest personality diagnoses may have limited prognostic meaning in treating chronic PTSD.

Background: The APOE e4 allele, an established risk factor for AD, may act synergistically with depression to increase the risk for progressive cognitive decline and conversion to MCI/AD. However, these findings have been reported inconsistently. Methodological differences across studies, including in the definition of depression, failure to properly diagnose depression or AD, short duration of follow up, and possible inclusion of individuals with preexisting cognitive decline or MCI. These considerations prompted us to conduct a 3-year longitudinal prospective study in cognitively intact elderly individuals, who either had a diagnosis of MDD or were healthy controls, to determine if e4 and depression interacted with respect to progressive cognitive decline. We focused primarily on neurobehavioral tests sensitive to early AD and also examined the CSF total tau/Abeta42 ratio, which has been linked to incident MCI/AD-related decline. Methods: 91 participants were included in this study, age 60 and older, with an MMSE 28 at the beginning of the 3- year longitudinal investigation. 45 participants had a diagnosis of MDD. Participants underwent a comprehensive neuropsychological test battery that included the Buschke Selective Reminding Test and Boston Naming Task at baseline and annually thereafter. APOE status on all and CSFAD biomarkers on a subset of subjects were determined at baseline. Regression analyses examining neuropsych change scores (baseline to follow-up) as functions of baseline characteristics. Results: Adjusting for age and MMSE score, participants with depression and carrying. Conclusions: Our results indicate that cognitively intact depressive e4 carriers have greater decline in selective cognitive tests especially in a confrontation naming task even during a relatively short three year longitudinal period compared to controls. Additionally, increased brain AD pathology as reflected by the CSF tau/Abeta42 ratio appeared to be associated with greater decline in memory performance in all depressives, regardless of APOE e4 status

Background: Volumetric analyses of MRI data have been employed to predict conversion to Alzheimer's disease (AD), and individuals with preclinical AD tend to show atrophy in the right medial temporal lobe, which includes the hippocampus. In this study, we set out to compare a volumetric measurement of the hippocampus to a newly developed measure of hippocampal integrity in their respective potential for prediction of generalized cognitive performance (MMSE) over time. Methods: Ninety participants, who were cognitively intact at baseline and aged 60 or older, were recruited for a study on major depressive disorder (MDD) and tested twice, over three years. Linear regression models were applied to the data with the change in MMSE score as outcome, and hippocampal integrity (HI), hippocampal volume (HV), age and MDD status among the predictors. HI was measured for the left and right hippocampi as the ratio of the parenchymal voxels to the total number of voxels in an automatically determined hippocampus ROI. The ROI was determined by local affine registration of 65 previously delineated hippocampus atlases to the test subject. HVs were extracted from MRI images using an automated volumetric approach. Results: Change in MMSE performance was significantly predicted by both integrity and volume: greater HI and HV values were associated with less decline. However, when comparing predictors' contributions to the models, HI was slightly better than HV for the right side, and explained more of the variance in MMSE performance; HI and HV contributions were largely comparable for the left side. Conclusions: More research is needed to evaluate whether hippocampal integrity or hippocampal volume is a more accurate predictor of cognitive decline, but tentative results from this study appear to suggest that right side HI measures have the potential to be sensitive to future changes in general cognitive ability

Background: Numerous studies have suggested that the APOE e4 allele, an established risk factor for AD, may act synergistically with depression to increase the risk for progressive cognitive decline and conversion to MCI/AD. However, these findings remain controversial and have been reported inconsistently. A possible reason for these conflicting results is differences in methodologies across studies, including differences in the definition of depression, failure to properly diagnose depression or AD, short duration of follow up, differences in age, and possible inclusion of individuals with preexisting cognitive decline or MCI. These considerations prompted us to conduct a 3-year longitudinal prospective study in cognitively intact elderly individuals, who either had a diagnosis of MDD or were healthy controls, to determine if e4 and depression interacted with respect to progressive cognitive decline. We focused primarily on neurobehavioral tests sensitive to early AD and also examined the CSF total tau/Ab42 ratio, which has been linked to incident MCI/AD-related decline. Methods: 91 participants were included in this study, 60 older and with an MMSE score of at least 28 at the beginning of the 3-year longitudinal investigation. 45 participants had a diagnosis of MDD. APOE status and CSF AD biomarkers were determined at baseline and participants underwent a comprehensive neuropsychological test battery that included the Buschke Selective Reminding Test and the Boston Naming Task. Regression models examining change scores from baseline to follow-up were employed to test our hypotheses. Results: Adjusting for age and MMSE score, elderly participants with depression and carrying APOE e4 showed greater decline on average in the Boston Naming Task (p < 0.01) and a trend with high imagery performance (p = 0.05). A higher CSF total tau/Ab42 ratio was associated with decline in memory performance among depressed subjects (r =-0.45, p = 0.03, n = 23), regardless of APOE status, but not in controls. Conclusions: Our results indicate that cognitively intact depressive e4 carriers have greater decline in selective cognitive tests especially in a confrontation naming task even during a relatively short three year longitudinal period compared to controls. Additionally, increased brain AD pathology as reflected by the CSF tau/Ab42 ratio appeared to be associated with greater decline in memory performance in all depressives, regardless of APOE e4 status

The amount and complexity of patient-level data being collected in randomized-controlled trials offer both opportunities and challenges for developing personalized rules for assigning treatment for a given disease or ailment. For example, trials examining treatments for major depressive disorder are not only collecting typical baseline data such as age, gender, or scores on various tests, but also data that measure the structure and function of the brain such as images from magnetic resonance imaging (MRI), functional MRI (fMRI), or electroencephalography (EEG). These latter types of data have an inherent structure and may be considered as functional data. We propose an approach that uses baseline covariates, both scalars and functions, to aid in the selection of an optimal treatment. In addition to providing information on which treatment should be selected for a new patient, the estimated regime has the potential to provide insight into the relationship between treatment response and the set of baseline covariates. Our approach can be viewed as an extension of "advantage learning" to include both scalar and functional covariates. We describe our method and how to implement it using existing software. Empirical performance of our method is evaluated with simulated data in a variety of settings and also applied to data arising from a study of patients with major depressive disorder from whom baseline scalar covariates as well as functional data from EEG are available.

To date, only one study has examined test-retest reliability of resting state fMRI (R-fMRI) in children, none in clinical developing groups. Here, we assessed short-term test-retest reliability in a sample of 46 children (11-17.9 years) with attention-deficit/hyperactivity disorder (ADHD) and 57 typically developing children (TDC). Our primary test-retest reliability measure was the intraclass correlation coefficient (ICC), quantified for a range of R-fMRI metrics. We aimed to (1) survey reliability within and across diagnostic groups, and (2) compare voxel-wise ICC between groups. We found moderate-to-high ICC across all children and within groups, with higher-order functional networks showing greater ICC. Nearly all R-fMRI metrics exhibited significantly higher ICC in TDC than in children with ADHD for one or more regions. In particular, posterior cingulate and ventral precuneus exhibited group differences in ICC across multiple measures. In the context of overall moderate-to-high test-retest reliability in children, regional differences in ICC related to diagnostic groups likely reflect the underlying pathophysiology for ADHD. Our currently limited understanding of the factors contributing to inter- and intra-subject variability in ADHD underscores the need for large initiatives aimed at examining their impact on test-retest reliability in both clinical and developing populations.

BACKGROUND: Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. METHODS: We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620. FINDINGS: We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35.7% (SD 17.8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7.6 [SEM 1.4] for D-serine group vs 11.3 [1.2] for placebo group; d=0.68, p=0.03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). INTERPRETATION: This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. FUNDING: National Institutes of Health.