Joel R. Sneed

Does study design influence outcome?. The effects of placebo control and treatment duration in antidepressant trials.

Background: Clinicians and researchers synthesize data from randomized controlled trials (RCTs) of antidepressants to make conclusions about the efficacy of medications for depression. All treatments include nonspecific factors in addition to the specific effects of drugs, and study design may influence patient outcomes via nonspecific factors. This study investigated whether placebo control and treatment duration affect the outcome in antidepressant RCTs. Methods: Medline and the Cochrane Database were searched to identify RCTs of antidepressants for major depression approved by the Food and Drug Administration. Included studies enrolled outpatient participants aged 18–65, lasted 6–12 weeks, compared an antidepressant to placebo or another antidepressant and were published in English after 1985. Excluded trials enrolled inpatients, pregnant women and subjects with psychosis or mania. Mixed-effects logistic regression models including study type (placebo-controlled or comparator) and study duration (6, 8 or 12 weeks) as fixed effects determined whether these factors affected response and remission rates. Results: In the 90 trials analyzed, the odds of depression response (OR = 1.79, 95% CI = 1.45–2.17, p < 0.001) and remission (OR 1.53, 95% CI = 1.11–2.11, p < 0.001) were significantly higher in comparator relative to placebo-controlled trials. Trials lasting 8 (OR = 1.37, CI = 1.14–1.64, p = 0.001) and 12 (OR = 1.52, CI = 1.12–2.07, p = 0.008) weeks had significantly greater response rates than 6-week trials without differing themselves. Conclusions: Response and remission rates to antidepressants are significantly affected by study type and duration. Clinicians and researchers must consider the study design when interpreting and designing RCTs of antidepressant medications.

The Vascular Depression Subtype: Evidence of Internal Validity

BACKGROUND Vascular depression has been proposed as a unique diagnostic subtype in late life, yet no study has evaluated whether the specified clinical features associated with the illness are jointly indicative of an underlying diagnostic class. METHODS We applied latent class analysis to two independent clinical samples: the prospective, cohort design, Neurocognitive Outcomes of Depression in the Elderly (NCODE) study and the 8-week, multicenter, double blind, placebo-controlled Old-Old study. RESULTS A two-class model consisting of vascular and nonvascular depressed patients provided an excellent fit to the data in both studies, chi(2)(6) = 2.02, p = .90 in the NCODE study and chi(2)(6) = 7.024, p = .32 in the Old-Old study. Although all of the proposed features of vascular depression were useful in identifying the illness, deep white matter lesion burden emerged with perfect sensitivity (1.00) and near-perfect specificity (.95), making it the only indicator necessary to determine class membership. CONCLUSIONS These findings, replicated across two independent clinical samples, provide the first support for the internal validity of vascular depression as a subtype of late-life depression.

Antidepressant Medication and Executive Dysfunction: A Deleterious Interaction in Late-Life Depression

OBJECTIVES To determine whether there is differential response to placebo or citalopram among older patients with and without deficient response inhibition (DRI). DESIGN This is an 8-week, double-blind, placebo-controlled trial. SETTING Outpatient psychiatry. PARTICIPANTS Unipolar depressed patients aged 75 years and older. INTERVENTION Citalopram (20-40 mg/day) or placebo pill. MEASUREMENTS Baseline Stroop Color-Word Test and weekly 24-item Hamilton Rating Scale for Depression assessments. RESULTS Citalopram-treated patients with DRI did significantly worse than placebo-treated patients with DRI. Conversely, citalopram-treated patients without DRI did significantly better than placebo-treated patients without DRI. CONCLUSION Patients with late-life depression and DRI respond worse to selective serotonin reuptake inhibitor (SSRI) than placebo. These findings suggest that there may be a deleterious interaction between DRI and antidepressant medication in late-life depression and that the mechanism of SSRI and placebo response is different.

Executive dysfunction and treatment response in late-life depression

Executive dysfunction in geriatric depression has been shown to predict poor response to antidepressant medication. The purpose of this review is to clarify which aspects of executive functioning predict poor antidepressant treatment response.

Quantitative approaches for assessment of white matter hyperintensities in elderly populations

White matter hyperintensities (WMH) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI), including fluid attenuated inverse recovery sequences. Total and regional WMH burden (i.e., volume or severity) has been associated with myriad cognitive, neurological, and psychiatric conditions among older adults. In the current report, we illustrate two approaches to quantify periventricular, deep, and total WMH and examine their reliability and criterion validity among 28 elderly patients enrolled in a depression treatment trial. The first approach, an operator-driven quantitative approach, involves visual inspection of individual MRI scans and manual labeling using a three-step series of procedures. The second approach, a fully automated quantitative approach, uses a processing stream that involves image segmentation, voxel intensity thresholding, and seed growing to label WMH and calculate their volume automatically. There was good agreement in WMH quantification between the two approaches (Cronbachs alpha values from 0.835 to 0.968). Further, severity of WMH was significantly associated with worse depression and increased age, and these associations did not differ significantly between the two quantification approaches. We provide evidence for good reliability and criterion validity for two approaches for WMH volume determination. The operator-driven approach may be better suited for smaller studies with highly trained raters, whereas the fully automated quantitative approach may be more appropriate for larger, high-throughput studies.

Vascular depression: A distinct diagnostic subtype?

Vascular depression has been proposed as a unique and valid diagnostic subtype on the basis of studies of external (concurrent and predictive) validity. Validating a diagnostic entity on the basis of external validity is problematic, because it presupposes that the construct is well defined (i.e., the proposed features cluster together to define a distinct patient group). Because such evidence has not been obtained, we propose that the next critical step in evaluating this potential subtype is to establish internal (construct) validity and highlight taxometric analysis and latent class cluster analysis as illustrative multivariate statistical techniques that can be used in this effort. The psychometric approach advocated here (despite its inherent assumptions and limitations) might substantially improve on previous diagnostic efforts (e.g., expert consensus), and vascular depression might serve as a prototype for future psychiatric classification.

MRI signal hyperintensities and failure to remit following antidepressant treatment

BACKGROUND MRI signal hyperintensities predict poor remission to antidepressant treatment. Previous studies using volumetrics in outpatient samples have relied on total lesion volume. The purpose of this study was to test whether remission from geriatric depression depends on lesion volume by region of interest (ROI). METHOD Thirty-eight patients received baseline MRIs as part of a larger 12-week, randomized clinical trial comparing sertraline and nortriptyline in the treatment of late-life depression. MRIcro was used to quantify MRI-hyperintensity volume into total hyperintensity, deep white matter hyperintensity (DWMH), and periventricular hyperintensity (PVH) volumes. High versus low total, DWMH, and PVH volumes were defined based on the highest quartile of their respective distributions. Remission from depression was defined as a 24-item Hamilton Rating Scale for Depression score ≤ 7 for two consecutive weeks. RESULTS Patients classified as having high DWMH were 7.14 times more likely not to remit following antidepressant treatment compared to patients classified as having low DWMH (p=0.02). Similar odds ratios were obtained for PVH (OR=4.17, p=0.16) and total volumes (OR=5.00, p=0.05). Importantly, adjusting for age did not change the magnitude of these effects. LIMITATIONS A small and predominantly White sample. CONCLUSIONS This is the first study to test whether remission from geriatric depression depends on lesion volume by ROI in an outpatient sample. The pattern of remission rates and odds ratios was similar when patients were classified as having high DWMH, PVH or total volume suggesting that lesion location may not be critical.

Social Role and Birth Cohort Influences on Gender-Linked Personality Traits in Women: A 20-Year Longitudinal Analysis

Growth curve modeling was used to examine the impact of social role experiences (e.g., marital support, occupational prestige) and birth cohort on mean-level differences and age-related changes in positive personality traits indicative of either femininity or masculinity in 758 mothers heterogeneous in age, assessed 4 times over 2 decades. Both femininity and masculinity increased significantly from mean ages 39 through 59; each was predictive of an age change in the other. Low masculinity was associated with a more rapid increase in femininity, whereas high occupational prestige decreased the magnitude of association between masculinity and femininity. Femininity increased with more marital support but decreased with unmarried status, more children at home, and working full or part time; among full-time workers, that effect was modified by marital support. Masculinity increased with full-time work and high occupational prestige. A trend for differing levels of femininity, and contrasting associations of masculinity with femininity and marital conflict in women born after 1944 compared with those born earlier, suggests shifting social norms and gender relations in the marital role.

The Dynamic Interdependence of Developmental Domains Across Emerging Adulthood

Emerging adulthood is a period in which profound role changes take place across a number of life domains including finance, romance, and residence. On the basis of dynamic systems theory, change in one domain should be related to change in another domain, because the concept of development according to this approach is a relational one. To evaluate this hypothesis dynamic systems analysis was applied to data from narrative interviews of 200 respondents covering the years between 17 and 27 to examine how change in one domain affects change in another domain. In each dyad, the fit of the model significantly deteriorated when the coupling between domains was removed providing support for the assumption of interdependency. On average, assuming greater responsibility in one domain was associated with assuming greater responsibility in the other domain. However, imbalances were also observed in which role assumption in one domain far exceeded role assumption in another domain. These imbalances can have detrimental effects and indicate the utility of a balanced approach to development. The findings underscore the importance of studying the relational unit between domains, which is critical to understanding development over time within domains.

MRI-defined vascular depression: a review of the construct.

To review the construct of MRI‐defined vascular depression and to examine the substantive and methodological issues that bear on its validity as a distinct subtype of depression in late life.