Christine M. Ulbricht

Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder. METHOD Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of ≥ 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects. RESULTS 84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (β = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes. CONCLUSIONS This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00344682.

Improving Mental Health Treatments Through Comparative Effectiveness Research

There is a pressing need for comparative effectiveness research to improve mental health treatments. Although U.S. mental health spending has increased dramatically, mainly because of the rapid adoption of newer psychotropic medications, fewer than a quarter of people with serious mental illnesses receive appropriate care. Because of a general lack of information on the relative effectiveness of different treatments, payers are uncertain about the value of current spending, which in turn may deter new investments to reduce unmet need. We use several recent comparative effectiveness trials to illustrate the potential value of such research for improving practice and policy.

The association between latent depression subtypes and remission after treatment with citalopram: A latent class analysis with distal outcome.

BACKGROUND The objectives were to characterize latent depression subtypes by symptoms, evaluate sex differences in and examine correlates of these subtypes, and examine the association between subtype and symptom remission after citalopram treatment. METHODS Latent class analysis was applied to baseline data from 2772 participants in the Sequenced Treatment Alternatives to Relieve Depression trial. Indicators were from the Quick Inventory of Depressive Symptomatology. Separate multinomial logistic models identified correlates of subtypes and the association between subtype and the distal outcome of remission. RESULTS Four latent subtypes were identified: Mild (men: 37%, women: 27%), Moderate (men: 24%, women: 21%), Severe with Increased Appetite (men: 13%, women: 22%), and Severe with Insomnia (men: 26%, women: 31%). Generalized anxiety disorder, bulimia, and social phobia were correlated with Severe with Increased Appetite and generalized anxiety disorder, post-traumatic stress disorder, and social phobia with Severe with Insomnia. Relative to those with the Mild subtype, those with Severe with Increased Appetite (odds ratiomen (OR): 0.48; 95% confidence interval (CI): 0.25-0.92; OR women: 0.59; 95% CI: 0.41-0.86) and those with Severe Depression with Insomnia (ORmen: 0.65; 95% CI: 0.41-1.02; ORwomen: 0.45; 95% CI: 0.32-0.64) were less likely to achieve remission. LIMITATIONS The sample size limited exploration of higher order interactions. CONCLUSIONS Insomnia and increased appetite distinguished latent subtypes. Sex and psychiatric comorbidities differed between the subtypes. Remission was less likely for those with the severe depression subtypes. Sleep disturbances, appetite changes, and other mental disorders may play a role in the etiology and treatment of depression.

Pain and Pharmacologic Pain Management in Long-Stay Nursing Home Residents

Abstract Previous studies estimate that >40% of long-stay nursing home (NH) residents experience persistent pain, with 20% of residents in pain receiving no analgesics. Strengthened NH surveyor guidance and improved pain measures on the Minimum Data Set 3.0 were introduced in March 2009 and October 2010, respectively. This study aimed to provide estimates after the important initiatives of (1) prevalence and correlates of persistent pain; and (2) prevalence and correlates of untreated or undertreated persistent pain. We identified 1,387,405 long-stay residents in U.S. NHs between 2011 and 2012 with 2 Minimum Data Set assessments 90 days apart. Pain was categorized as persistent (pain on both assessments), intermittent (pain on either assessment), or none. Pharmacologic pain management was classified as untreated pain (no scheduled or as needed medications received) or potentially undertreated (no scheduled received). Modified Poisson models adjusting for resident clustering within NHs provided adjusted prevalence ratios (APRs) estimates and 95% confidence intervals (CIs). The prevalence of persistent and intermittent pain was 19.5% and 19.2%, respectively, but varied substantially by age, sex, race and ethnicity, cognitive impairment, and cancer. Of residents in persistent pain, 6.4% and 32.0% were untreated and undertreated, respectively. Racial and ethnic minorities (non-Hispanic blacks vs whites, APR = 1.19, 95% CI: 1.13-1.25) and severely cognitively impaired residents (severe vs no/mild APR = 1.51, 95% CI: 1.44-1.57) had an increased prevalence of untreated and undertreated pain. One in 5 NH residents has persistent pain. Although this estimate is greatly improved, many residents may be undertreated. The disturbing disparities in untreated and undertreated pain need to be addressed.

A systematic review and meta-analysis on herpes zoster and the risk of cardiac and cerebrovascular events

Background Patients who develop herpes zoster or herpes zoster ophthalmicus may be at risk for cerebrovascular and cardiac complications. We systematically reviewed the published literature to determine the association between herpes zoster and its subtypes with the occurrence of cerebrovascular and cardiac events. Methods/Results Systematic searches of PubMed (MEDLINE), SCOPUS (Embase) and Google Scholar were performed in December 2016. Eligible studies were cohort, case-control, and self-controlled case-series examining the association between herpes zoster or subtypes of herpes zoster with the occurrence of cerebrovascular and cardiac events including stroke, transient ischemic attack, coronary heart disease, and myocardial infarction. Data on the occurrence of the examined events were abstracted. Odds ratios and their accompanying confidence intervals were estimated using random and fixed effects models with statistical heterogeneity estimated with the I2 statistic. Twelve studies examining 7.9 million patients up to 28 years after the onset of herpes zoster met our pre-defined eligibility criteria. Random and fixed effects meta-analyses showed that herpes zoster, type unspecified, and herpes zoster ophthalmicus were associated with a significantly increased risk of cerebrovascular events, without any evidence of statistical heterogeneity. Our meta-analysis also found a significantly increased risk of cardiac events associated with herpes zoster, type unspecified. Conclusions Our results are consistent with the accumulating body of evidence that herpes zoster and herpes zoster ophthalmicus are significantly associated with cerebrovascular and cardiovascular events.

Implementation and reporting of causal mediation analysis in 2015: a systematic review in epidemiological studies.

BackgroundCausal mediation analysis is often used to understand the impact of variables along the causal pathway of an occurrence relation. How well studies apply and report the elements of causal mediation analysis remains unknown.MethodsWe systematically reviewed epidemiological studies published in 2015 that employed causal mediation analysis to estimate direct and indirect effects of observed associations between an exposure on an outcome. We identified potential epidemiological studies through conducting a citation search within Web of Science and a keyword search within PubMed. Two reviewers independently screened studies for eligibility. For eligible studies, one reviewer performed data extraction, and a senior epidemiologist confirmed the extracted information. Empirical application and methodological details of the technique were extracted and summarized.ResultsThirteen studies were eligible for data extraction. While the majority of studies reported and identified the effects of measures, most studies lacked sufficient details on the extent to which identifiability assumptions were satisfied. Although most studies addressed issues of unmeasured confounders either from empirical approaches or sensitivity analyses, the majority did not examine the potential bias arising from the measurement error of the mediator. Some studies allowed for exposure-mediator interaction and only a few presented results from models both with and without interactions. Power calculations were scarce.ConclusionsReporting of causal mediation analysis is varied and suboptimal. Given that the application of causal mediation analysis will likely continue to increase, developing standards of reporting of causal mediation analysis in epidemiological research would be prudent.

An Evidence-Based Systematic Review of Vitamin A by the Natural Standard Research Collaboration

ABSTRACT An evidence-based systematic review of vitamin A by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated and reproducible grading rationale. This paper includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Changes in Depression Subtypes Among Men in STAR*D: A Latent Transition Analysis:

The burden of depression in men is high. Current diagnostic criteria may not fully capture men’s experience with depression. Descriptions of the heterogeneity in depression among men are lacking. The purpose of the study was to characterize latent subtypes of major depression and changes in these subtypes among men receiving citalopram in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Latent transition analysis was applied to data from 387 men who completed baseline and Week 12 study visits in Level 1 of STAR*D. Items from the self-report version of the Quick Inventory of Depressive Symptomatology were used as indicators of latent depression subtypes. Four statuses were identified at baseline and Week 12. Baseline statuses were Mild (10% of men), Moderate (53%), Severe with Psychomotor Slowing (20%), and Severe with Psychomotor Agitation (17%). At Week 12, the statuses were Symptom Resolution (41%), Mild (36%), Moderate (18%), and Severe with Psychomotor Slowing (5%). Men in the Mild status were most likely to transition to Symptom Resolution (probability = 69%). Men in the Severe with Agitation status were least likely to transition to Symptom Resolution (probability = 0%). This work highlights the need to not focus solely on summary rating scores but to also consider patterns of symptoms when treating depression.

Depression and cognitive impairment among newly admitted nursing home residents in the USA

The objective of this study is to describe the prevalence of depression and cognitive impairment among newly admitted nursing home residents in the USA and to describe the treatment of depression by level of cognitive impairment.

Probabilistic bias analysis in pharmacoepidemiology and comparative effectiveness research: a systematic review.

We systematically reviewed pharmacoepidemiologic and comparative effectiveness studies that use probabilistic bias analysis to quantify the effects of systematic error including confounding, misclassification, and selection bias on study results.