Prospectively assessed summer mood status in major depression, recurrent with seasonal pattern: Evidence for SAD's construct validity.

OBJECTIVE: Seasonal patterns are often undetectable in population-based depression studies, calling into question the existence of winter seasonal affective disorder (SAD). If SAD has construct validity, individuals with SAD should show spontaneous depression remission in the summer. Data are sparse on prospectively assessed summer mood status in confirmed SAD patients. METHOD: We conducted prospective summer followup of community adults who, the winter before, were diagnosed with Major Depression, Recurrent with Seasonal Pattern on the Structured Clinical Interview for DSM-IV Axis I Disorders, developed a current SAD episode on the Structured Interview Guide for the Hamilton Rating Scale for Depression-Seasonal Affective Disorder Version (SIGH-SAD), and enrolled in a clinical trial comparing group cognitive-behavioral therapy for SAD and light therapy. In July/August after treatment, 143/153 (93.5 %) participants provided data on the SIGH-SAD, the Beck Depression Inventory-Second Edition, and the Longitudinal Interval Followup Evaluation (LIFE). RESULTS: Summer mean depression scores were in the normal range, with the substantial majority in remission across different measures. On the LIFE, 113/143 (79.0 %) experienced complete summer remission, 19/143 (13.3 %) experienced partial summer remission, and 11/143 (7.7 %) had major depression in the summer. Depression scores were significantly lower at summer than post-treatment in both treatments, indicating incomplete treatment response. LIMITATIONS: This was a single-site study with a relatively homogeneous sample. CONCLUSIONS: Supporting construct validity for SAD, the substantial majority experienced complete summer remission, with a minority in partial remission and a very small minority in episode. Both treatments left residual symptoms at treatment endpoint compared to summer.

Elucidating treatment targets and mediators within a confirmatory efficacy trial: study protocol for a randomized controlled trial of cognitive-behavioral therapy vs. light therapy for winter depression.

BACKGROUND: This study is a confirmatory efficacy trial of two treatments for winter seasonal affective disorder (SAD): SAD-tailored group cognitive-behavioral therapy (CBT-SAD) and light therapy (LT). In our previous efficacy trial, post-treatment outcomes for CBT-SAD and LT were very similar, but CBT-SAD was associated with fewer depression recurrences two winters later than LT (27.3% in CBT-SAD vs. 45.6% in LT). CBT-SAD engaged and altered a specific mechanism of action, seasonal beliefs, which mediated CBT-SAD's acute antidepressant effects and CBT-SAD's enduring benefit over LT. Seasonal beliefs are theoretically distinct from LT's assumed target and mechanism: correction of circadian phase. This study applies the experimental therapeutics approach to determine how each treatment works when it is effective and to identify the best candidates for each. Biomarkers of LT's target and effect include circadian phase angle difference and the post-illumination pupil response. Biomarkers of CBT-SAD's target and effect include decreased pupillary and sustained frontal gamma-band EEG responses to seasonal words, which are hypothesized as biomarkers of seasonal beliefs, reflecting less engagement with seasonal stimuli following CBT-SAD. In addition to determining change mechanisms, this study tests the efficacy of a "switch" decision rule upon recurrence to inform clinical decision-making in practice. METHODS: Adults with SAD (target N = 160) will be randomzied to 6-weeks of CBT-SAD or LT in winter 1; followed in winter 2; and, if a depression recurrence occurs, offered cross-over into the alternate treatment (i.e., switch from LT➔CBT-SAD or CBT-SAD➔LT). All subjects will be followed in winter 3. Biomarker assessments occur at pre-, mid-, and post-treatment in winter 1, at winter 2 follow-up (and again at mid-/post-treatment for those crossed-over), and at winter 3 follow-up. Primary efficacy analyses will test superiority of CBT-SAD over LT on depression recurrence status (the primary outcome). Mediation analyses will use parallel process latent growth curve modeling. DISCUSSION: Consistent with the National Institute of Mental Health's priorities for demonstrating target engagement at the level of Research Domain Criteria-relevant biomarkers, this work aims to confirm the targets and mechanisms of LT and CBT-SAD to maximize the impact of future dissemination efforts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03691792 . Registered on October 2, 2018.

Detecting Critical Decision Points during Cognitive-Behavioral Therapy and Light Therapy for Winter Depression Nonremission and Recurrence.

Using data from a clinical trial comparing cognitive-behavioral therapy (CBT-SAD) and light therapy (LT) for winter seasonal affective disorder (SAD; N = 177), we explored critical decision points, or treatment weeks, that predict likelihood of nonremission at post-treatment and depression recurrence following treatment. In receiver operator characteristic (ROC) curve analyses, we used weekly Structured Clinical Interview for the Hamilton Rating Scale for Depression-SAD Version (SIGH-SAD) scores during treatment to predict nonremission at post-treatment (Week 6) and recurrence one winter later (Winter 1), two winters later (Winter 2), and any recurrence. Although several C-statistics of ≥ .70 were found, only Week 4 SIGH-SAD scores in CBT-SAD for nonremission had enough predictive ability to inform clinical decision-making (C-statistic = .80; sensitivity = .91; specificity = .68). Week 4 of CBT-SAD may be a critical time point to identify likely nonremitters who need tailoring of intervention, based on SIGH-SAD cutpoint score ≥ 13. This study illustrates how clinical trial data can inform detecting optimal decision points in treatment for identifying patients unlikely to remit, a critical first step to developing adaptive treatment strategies using decision rules to operationalize when and for whom treatment should change to maximize clinical benefit.

A measure of cognitions specific to seasonal depression: Development and validation of the Seasonal Beliefs Questionnaire.

We introduce the Seasonal Beliefs Questionnaire (SBQ), a self-report inventory of maladaptive thoughts about the seasons, light availability, and weather conditions, proposed to constitute a unique cognitive vulnerability to winter seasonal affective disorder (SAD; Rohan, Roecklein, & Haaga, 2009). Potential items were derived from a qualitative analysis of self-reported thoughts during SAD-tailored cognitive-behavioral therapy (CBT-SAD) and subsequently refined based on qualitative feedback from 48 SAD patients. In the psychometric study (N = 536 college students), exploratory and confirmatory factor analyses pruned the items to a 26-item scale with a 5-factor solution, demonstrating good internal consistency, convergent and divergent validity, and 2-week test-retest reliability. In a known groups comparison, the SBQ discriminated SAD patients (n = 86) from both nonseasonal major depressive disorder (MDD) patients (n = 30) and healthy controls (n = 110), whereas a generic measure of depressogenic cognitive vulnerability (the Dysfunctional Attitudes Scale [DAS]) discriminated MDD patients from the other groups. In a randomized clinical trial comparing CBT-SAD with light therapy (N = 177), SBQ scores improved at twice the rate in CBT-SAD than in light therapy. Greater change in SBQ scores during CBT-SAD, but not during light therapy, was associated with a lower risk of depression recurrence 2 winters later. In contrast, DAS scores improved comparably during CBT-SAD and light therapy, and DAS change was unrelated to recurrence following either treatment. These results support using the SBQ as a brief assessment tool for a SAD-specific cognitive vulnerability and as a treatment target in CBT-SAD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium.

During the First Gulf War (1991) over 100 servicemen sustained depleted uranium (DU) exposure through wound contamination, inhalation, and shrapnel. The Department of Veterans Affairs has a surveillance program for these Veterans which has included genotoxicity assays. The frequencies of glycosylphosphatidylinositol anchor (GPIa) negative (aerolysin resistant) cells determined by cloning assays for these Veterans are reported in Albertini RJ et al. (2019: Environ Mol Mutagen). Molecular analyses of the GPIa biosynthesis class A (PIGA) gene was performed on 862 aerolysin-resistant T-lymphocyte recovered isolates. The frequencies of different types of PIGA mutations were compared between high and low DU exposure groups. Additional molecular studies were performed on mutants that produced no PIGA mRNA or with deletions of all or part of the PIGA gene to determine deletion size and breakpoint sequence. One mutant appeared to be the result of a chromothriptic event. A significant percentage (>30%) of the aerolysin resistant isolates, which varied by sample year and Veteran, had wild-type PIGA cDNA (no mutation). As described in Albertini RJ et al. (2019: Environ Mol Mutagen), TCR gene rearrangement analysis of these isolates indicated most arose from multiple T-cell progenitors (hence the inability to find a mutation). It is likely that these isolates were the result of failure of complete selection against nonmutant cells in the cloning assays. Real-time studies of GPIa resistant isolates with no PIGA mutation but with a single TCR gene rearrangement found one clone with a PIGV deletion and several others with decreased levels of GPIa pathway gene mRNAs implying mutation in other GPIa pathway genes. Environ. Mol. Mutagen. 60:470-493, 2019. © 2019 Wiley Periodicals, Inc.

Longitudinal study of t-cell somatic mutations conferring glycosylphosphatidylinositol-anchor deficiency in gulf war I veterans exposed to depleted uranium.

Fifty Veterans of the first Gulf War in 1991 exposed to depleted uranium (DU) were studied for glycosylphosphatidylinositol-anchor (GPIa) deficient T-cell mutants on three occasions during the years 2009, 2011, and 2013. GPIa deficiency was determined in two ways: cloning assays employing aerolysin selection and cytometry using the FLAER reagent for positive staining of GPIa cell surface proteins. Subsequent molecular analyses of deficient isolates recovered from cloning assays (Nicklas JA et al. [2019]: Environ Mol Mutagen) revealed apparent incomplete selection in some cloning assays, necessitating correction of original data to afford a more realistic estimate of GPIa deficient mutant frequency (MF) values. GPIa deficient variant frequencies (VFs) determined by cytometry were determined in the years 2011 and 2013. A positive but nonsignificant association was observed between MF and VF values determined on the same blood samples during 2013. Exposure to DU had no effect on either GPIa deficient MF or VFs. Environ. Mol. Mutagen. 60:494-504, 2019. © 2019 Wiley Periodicals, Inc.

Influence of Age and Comorbidity on Colorectal Cancer Screening in the Elderly.

INTRODUCTION: Expert recommendations differ for colorectal cancer screening in the elderly. Recent studies suggest that healthy adults aged >75 years may benefit from screening. This study examined screening use and follow-up, and how they varied by health status within age strata, among a large cohort of elderly individuals in community settings. METHODS: A population-based, longitudinal cohort study was conducted among health plan members aged 65-89 years enrolled during 2011-2012 in three integrated healthcare systems participating in the Population-Based Research Optimizing Screening through Personalized Regimens consortium. Comorbidity measurements used the Charlson index. Analyses, conducted in 2015, comprised descriptive statistics and multivariable modeling that estimated age by comorbidity-specific percentages of patients for two outcomes: colorectal cancer screening uptake and follow-up of abnormal fecal blood tests. RESULTS: Among 846,267 patients, 72% were up-to-date with colorectal cancer screening. Of patients with a positive fecal blood test, 65% received follow-up colonoscopy within 3 months. Likelihood of being up-to-date and receiving timely follow-up was significantly lower for patients aged ≥76 years than their younger counterparts (p<0.001). Comorbidity was less influential than age and more strongly related to timely follow-up than being up-to-date. In all age groups, considerable numbers of patients with no/low comorbidity were not up-to-date or did not receive timely follow-up. CONCLUSIONS: In three integrated healthcare systems, many older, relatively healthy patients were not screening up-to-date, and some relatively young, healthy patients did not receive timely follow-up. Findings suggest a need for re-evaluating age-based screening guidelines and improving screening completion among the elderly.

Outcomes One and Two Winters Following Cognitive-Behavioral Therapy or Light Therapy for Seasonal Affective Disorder.

OBJECTIVE: The central public health challenge for winter seasonal affective disorder (SAD) is recurrence prevention. Preliminary studies suggest better long-term outcomes following cognitive-behavioral therapy tailored for SAD (CBT-SAD) than light therapy. The present study is a large, randomized head-to-head comparison of these treatments on outcomes one and two winters after acute treatment. METHOD: Community adults with major depression, recurrent with seasonal pattern (N=177) were followed one and two winters after a randomized trial of 6 weeks of CBT-SAD (N=88) or light therapy (N=89). Prospective follow-up visits occurred in January or February of each year, and major depression status was assessed by telephone in October and December of the first year. The primary outcome was winter depression recurrence status on the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD). Other outcomes were depression severity on the SIGH-SAD and the Beck Depression Inventory-Second Edition (BDI-II), remission status based on severity cutoff scores, and major depression status from tracking calls. RESULTS: The treatments did not differ on any outcome during the first year of follow-up. At the second winter, CBT-SAD was associated with a smaller proportion of SIGH-SAD recurrences (27.3% compared with 45.6%), less severe symptoms on both measures, and a larger proportion of remissions defined as a BDI-II score ≤8 (68.3% compared with 44.5%) compared with light therapy. Nonrecurrence at the next winter was more highly associated with nonrecurrence at the second winter among CBT-SAD participants (relative risk=5.12) compared with light therapy participants (relative risk=1.92). CONCLUSIONS: CBT-SAD was superior to light therapy two winters following acute treatment, suggesting greater durability for CBT-SAD.

Mutagenicity monitoring following battlefield exposures: Longitudinal study of HPRT mutations in Gulf War I veterans exposed to depleted uranium.

A total of 70 military Veterans have been monitored for HPRT T-cell mutations in five separate studies at 2-year intervals over an 8-year period. Systemic depleted uranium (DU) levels were measured at the time of each study by determining urinary uranium (uU) excretion. Each HPRT study included 30-40 Veterans, several with retained DU-containing shrapnel. Forty-nine Veterans were evaluated in multiple studies, including 14 who were in all five studies. This permitted a characterization of the HPRT mutation assay over time to assess the effects of age, smoking and non-selected cloning efficiencies, as well as the inter- and intra-individual variability across time points. Molecular analyses identified the HPRT mutation and T-cell receptor (TCR) gene rearrangement in 1,377 mutant isolates. An unexpected finding was that in vivo clones of HPRT mutant T-cells were present in some Veterans, and could persist over several years of the study. The calculated HPRT mutant frequencies (MFs) were repeatedly elevated in replicate studies in three outlier Veterans with elevated urinary uranium excretion levels. However, these three outlier Veterans also harbored large and persistent in vivo HPRT mutant T-cell clones, each of which was represented by a single founder mutation. Correction for in vivo clonality allowed calculation of HPRT T-cell mutation frequencies (MutFs). Despite earlier reports of DU associated increases in HPRT MFs in some Veterans, the results presented here demonstrate that HPRT mutations are not increased by systemic DU exposure. Additional battlefield exposures were also evaluated for associations with HPRT mutations and none were found.

Mutagenicity monitoring following battlefield exposures: Molecular analysis of HPRT mutations in Gulf War I veterans exposed to depleted uranium.

Molecular studies that involved cDNA and genomic DNA sequencing as well as multiplex PCR of the HPRT gene were performed to determine the molecular mutational spectrum for 1,377 HPRT mutant isolates obtained from 61 Veterans of the 1991 Gulf War, most of whom were exposed to depleted uranium (DU). Mutant colonies were isolated from one to four times from each Veteran (in 2003, 2005, 2007, and/or 2009). The relative frequencies of the various types of mutations (point mutations, deletions, insertions, etc.) were compared between high versus low DU exposed groups, (based on their urine U concentration levels), with HPRT mutant frequency (as determined in the companion paper) and with a database of historic controls. The mutational spectrum includes all classes of gene mutations with no significant differences observed in Veterans related to their DU exposures.

Randomized Trial of Cognitive-Behavioral Therapy Versus Light Therapy for Seasonal Affective Disorder: Acute Outcomes.

OBJECTIVE: Whereas considerable evidence supports light therapy for winter seasonal affective disorder (SAD), data on cognitive-behavioral therapy for SAD (CBT-SAD) are promising but preliminary. This study estimated the difference between CBT-SAD and light therapy outcomes in a large, more definitive test. METHOD: The participants were 177 adults with a current episode of major depression that was recurrent with a seasonal pattern. The randomized clinical trial compared 6 weeks of CBT-SAD (N=88) and light therapy (N=89). Light therapy consisted of 10,000-lux cool-white florescent light, initiated at 30 minutes each morning and adjusted according to a treatment algorithm based on response and side effects. CBT-SAD comprised 12 sessions of the authors' SAD-tailored protocol in a group format and was administered by Ph.D. psychologists in two 90-minute sessions per week. Outcomes were continuous scores on the Structured Interview Guide for the Hamilton Rating Scale for Depression-SAD Version (SIGH-SAD, administered weekly) and Beck Depression Inventory-Second Edition (BDI-II, administered before treatment, at week 3, and after treatment) and posttreatment remission status based on cut points. RESULTS: Depression severity measured with the SIGH-SAD and BDI-II improved significantly and comparably with CBT-SAD and light therapy. Having a baseline comorbid diagnosis was associated with higher depression scores across all time points in both treatments. CBT-SAD and light therapy did not differ in remission rates based on the SIGH-SAD (47.6% and 47.2%, respectively) or the BDI-II (56.0% and 63.6%). CONCLUSIONS: CBT-SAD and light therapy are comparably effective for SAD during an acute episode, and both may be considered as treatment options.

Cognitive-behavioral therapy vs. light therapy for preventing winter depression recurrence: study protocol for a randomized controlled trial.

BACKGROUND: Seasonal affective disorder (SAD) is a subtype of recurrent depression involving major depressive episodes during the fall and/or winter months that remit in the spring. The central public health challenge in the management of SAD is prevention of winter depression recurrence. Light therapy (LT) is the established and best available acute SAD treatment. However, long-term compliance with daily LT from first symptom through spontaneous springtime remission every fall/winter season is poor. Time-limited alternative treatments with effects that endure beyond the cessation of acute treatment are needed to prevent the annual recurrence of SAD. METHODS/DESIGN: This is an NIMH-funded R01-level randomized clinical trial to test the efficacy of a novel, SAD-tailored cognitive-behavioral group therapy (CBT) against LT in a head-to-head comparison on next winter outcomes. This project is designed to test for a clinically meaningful difference between CBT and LT on depression recurrence in the next winter (the primary outcome). This is a concurrent two-arm study that will randomize 160 currently symptomatic community adults with major depression, recurrent with seasonal pattern, to CBT or LT. After 6 weeks of treatment in the initial winter, participants are followed in the subsequent summer, the next winter, and two winters later. Key methodological issues surround timing study procedures for a predictably recurrent and time-limited disorder with a focus on long-term outcomes. DISCUSSION: The chosen design answers the primary question of whether prior exposure to CBT is associated with a substantially lower likelihood of depression recurrence the next winter than LT. This design does not test the relative contributions of the cognitive-behavioral treatment components vs. nonspecific factors to CBT's outcomes and is not adequately powered to test for differences or equivalence between cells at treatment endpoint. Alternative designs addressing these limitations would have required more patients, increased costs, and reduced power to detect a difference in the primary outcome. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01714050.

Cognitive Change across Cognitive-Behavioral and Light Therapy Treatments for Seasonal Affective Disorder: What Accounts for Clinical Status the Next Winter?

Efficacious treatments for seasonal affective disorder include light therapy and a seasonal affective disorder-tailored form of cognitive-behavioral therapy. Using data from a parent clinical trial, these secondary analyses examined the relationship between cognitive change over treatment with cognitive-behavioral therapy, light therapy, or combination treatment and mood outcomes the next winter. Sixty-nine participants were randomly assigned to 6-weeks of cognitive-behavioral therapy, light therapy, or combination treatment. Cognitive constructs (i.e., dysfunctional attitudes, negative automatic thoughts, and rumination) were assessed at pre- and post-treatment. Dysfunctional attitudes, negative automatic thoughts, and rumination improved over acute treatment, regardless of modality; however, in participants randomized to solo cognitive-behavioral therapy, a greater degree of improvement in dysfunctional attitudes and automatic thoughts was uniquely associated with less severe depressive symptoms the next winter. Change in maladaptive thoughts during acute treatment appears mechanistic of solo cognitive-behavioral therapy's enduring effects the next winter, but is simply a consequence of diminished depression in light therapy and combination treatment.

Measures of genotoxicity in Gulf war I veterans exposed to depleted uranium.

Exposure to depleted uranium (DU), an alpha-emitting heavy metal, has prompted the inclusion of markers of genotoxicity in the long-term medical surveillance of a cohort of DU-exposed Gulf War veterans followed since 1994. Using urine U (uU) concentration as the measure of U body burden, the cohort has been stratified into low-u (<0.10 µg U/g creatinine) and high-u groups (≥ 0.10 µg U/g creatinine). Surveillance outcomes for this cohort have historically included markers of mutagenicity and clastogenicity, with past results showing generally nonsignificant differences between low- vs. high-U groups. However, mean hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutant frequencies (MFs) have been almost 50% higher in the high-U group. We report here results of a more comprehensive protocol performed in a 2009 evaluation of a subgroup (N = 35) of this cohort. Four biomarkers of genotoxicity [micronuclei (MN), chromosome aberrations, and MFs of HPRT and PIGA] were examined. There were no statistically significant differences in any outcome measure when results were compared between the low- vs. high-U groups. However, modeling of the HPRT MF results suggests a possible threshold effect for MFs occurring in the highest U exposed cohort members. Mutational spectral analysis of HPRT mutations is underway to clarify a potential clonal vs. a threshold uU effect to explain this observation. This study provides a comprehensive evaluation of a human population chronically exposed to DU and demonstrates a relatively weak genotoxic effect of the DU exposure. These results may explain the lack of clear epidemiologic evidence for U carcinogenicity in humans. Environ. Mol. Mutagen., 2011. © 2011 Wiley-Liss, Inc.

Winter depression recurrence one year after cognitive-behavioral therapy, light therapy, or combination treatment.

The central public health challenge in the management of seasonal affective disorder (SAD) is prevention of depression recurrence each fall/winter season. The need for time-limited treatments with enduring effects is underscored by questionable long-term compliance with clinical practice guidelines recommending daily light therapy during the symptomatic months each year. We previously developed a SAD-tailored group cognitive-behavioral therapy (CBT) and tested its acute efficacy in 2 pilot studies. Here, we report an intent-to-treat (ITT) analysis of outcomes during the subsequent winter season (i.e., approximately 1 year after acute treatment) using participants randomized to CBT, light therapy, and combination treatment across our pilot studies (N=69). We used multiple imputation to estimate next winter outcomes for the 17 individuals who dropped out during treatment, were withdrawn from protocol, or were lost to follow-up. The CBT (7.0%) and combination treatment (5.5%) groups had significantly smaller proportions of winter depression recurrences than the light therapy group (36.7%). CBT alone, but not combination treatment, was also associated with significantly lower interviewer- and patient-rated depression severity at 1 year as compared to light therapy alone. Among completers who provided 1-year data, all statistically significant differences between the CBT and light therapy groups persisted after adjustment for ongoing treatment with light therapy, antidepressants, and psychotherapy. If these findings are replicated, CBT could represent a more effective, practical, and palatable approach to long-term SAD management than light therapy.