Using electronic patient-reported measures to characterize symptoms and improvement in inpatient psychiatric units.

Patient-reported measures are an important tool in personalizing care and monitoring clinical outcomes. This work presents results from the routine collection of self-report measures from individuals (n = 753) admitted to depression and anxiety inpatient units at McLean Hospital. 93.7% participated in the Clinical Measurement Initiative (CMI) between September 2020 and February 2022 on the most established unit. The average time between admission and discharge measures was 12.6 days and an attrition rate of 10.4% was observed on this unit. Missingness of discharge assessments was unrelated to symptom severity or comorbidities. We discuss the feasibility of deploying patient-reported measures as part of routine care in an inpatient psychiatric setting. Systematic evaluation of potential treatment modifiers (e.g., personality disorder, trauma history, and substance misuse) may be valuable in better serving those impacted by psychiatric illness.

The Duration in Treatment With Electroconvulsive Therapy Among Patients Screening Positive or Negative for Borderline Personality Disorder Traits: A Retrospective Cohort Study.

OBJECTIVE: While emerging evidence suggests that electroconvulsive therapy (ECT) is an effective treatment for depressive symptoms in patients with co-occurring borderline personality disorder (BPD) traits, it is unclear whether the presence of BPD traits modulates the tolerability of ECT. This study estimates the association between BPD traits and retention in acute course ECT treatment. METHODS: This study used a retrospective cohort of patients receiving ECT between 2015 and 2020 and who were assessed using the McLean Screening Instrument for BPD, the Quick Inventory of Depressive Symptomatology Self-Report 16-item scale, and the Montreal Cognitive Assessment before initiating treatment. RESULTS: One thousand five hundred eight patients received ECT during the study period, of whom 277 (18.4%) screened positive for BPD traits. Borderline personality disorder traits were associated with a higher odds of remaining in ECT for at least 10 treatments (adjusted odds ratio, 1.502; 95% confidence interval, 1.11-2.02; P = 0.007). Among individual symptom domains, only endorsing chronically feeling empty was associated with duration in ECT treatment. CONCLUSIONS: Among patients receiving ECT, screening positive for BPD traits was associated with a higher odds of receiving at least 10 ECT treatments. These results support the overall tolerability of ECT in patients with BPD traits.

First Acute-Course Electroconvulsive Therapy for Moderate-to-Severe Depression Benefits Patients With or Without Accompanying Baseline Cognitive Impairment.

BACKGROUND: Researchers are increasingly investigating therapeutic response associated with new patient subgroups as a way to improve electroconvulsive therapy (ECT) treatment outcomes and reduce adverse events. This study is the first to examine baseline cognitive impairment status as a predictor of clinical outcome in first acute-course ECT patients. METHODS: Baseline cognitive function at various thresholds and serial depressive symptom severity data from first-time ECT patients were examined using generalized linear mixed-effects models. RESULTS: Of 1345 patients who met the inclusion criteria, 617 had available data at their third assessment visit (~15th treatment visit). There was a robust improvement in depression symptoms over time (P < 0.0001), and cognitive function was not associated with baseline levels of depressive symptoms or serially measured change in self-reported symptom severity during acute-phase ECT. CONCLUSIONS: These results indicate that an acute course of ECT for the treatment of moderate-to-severe depression benefits patients with or without accompanying baseline cognitive impairment. These findings may be useful in informing shared decision-making discussions about ECT risks and expected benefits.

Behavioral Therapy Teams for Obsessive-Compulsive Disorder: Lessons Learned From a Pilot Randomized Trial in a Community Mental Health Center.

Community mental health centers (CMHCs) provide the majority of mental health services for low-income individuals in the United States. Exposure and response prevention (ERP), the psychotherapy of choice for obsessive-compulsive disorder (OCD), is rarely delivered in CMHCs. This study aimed to establish the acceptability and feasibility of testing a behavioral therapy team (BTT) intervention to deliver ERP in CMHCs. BTT consisted of individual information-gathering sessions followed by 12 weeks of group ERP and concurrent home-based coaching sessions. The sample consisted of 47 low-income individuals with OCD who were randomized to receive BTT or treatment as usual (TAU). Symptom severity and quality-of-life measures were assessed at pretreatment, posttreatment, and 3- and 6-month posttreatment. Feasibility of training CMHC staff was partially successful. CMHC therapists successfully completed rigorous training and delivered ERP with high fidelity. However, training paraprofessionals as ERP coaches was more challenging. ERP was feasible and acceptable to patients. BTT participants were more likely than TAU participants to attend their first therapy session and attended significantly more treatment sessions. A large between-group effect size was observed for reduction in OCD symptoms at posttreatment but differences were not maintained across 3- and 6-month follow-ups. For BTT participants, within-group effect sizes reflecting change from baseline to posttreatment were large. For TAU participants, depression scores did not change during the active treatment phase but gradually improved during follow-up. Results support feasibility and acceptability of ERP for this patient population. Findings also underscore the importance of implementation frameworks to help understand factors that impact training professionals.

Treatment Outcomes of Electroconvulsive Therapy for Depressed Patients With and Without Borderline Personality Disorder: A Retrospective Cohort Study.

BACKGROUND: Electroconvulsive therapy (ECT) is the gold-standard treatment for refractory depression. Borderline personality disorder (BPD) is generally considered a poor predictor of treatment response. We sought to assess symptom-severity outcomes among depressed patients with (BPD+) and without (BPD-) comorbid BPD undergoing acute phase ECT. METHODS: The study sample consisted of at least moderately depressed patients who received an acute course of ECT from January 2011 to December 2016 at an academic, freestanding psychiatric hospital. Participants completed a DSM-IV-validated BPD screening instrument at baseline. Measures of DSM-IV depressive symptom severity from the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) were taken serially on 4 occasions. Outcomes of interest comprised total QIDS-SR score trajectory, QIDS-SR suicidality subscore, and symptom cluster subscores posited to differentiate response among antidepressant treatments. RESULTS: Of the 693 individuals who met study inclusion criteria, 145 (20.9%) screened positive for BPD. Overall, ECT was associated with significant improvement of depressive symptoms (χ²1 = 504.8, P < .0001). Despite differing from BPD- individuals on key baseline features, BPD+ individuals responded to ECT with similar improvement in overall depression severity (χ²1 = 0.22, P = .64), suicidality (χ²1 = 1.63, P = .20), and core emotional (χ²1 = 0.63, P = .43), sleep (χ²1 = 0.20, P = .65), and atypical (χ²1 = 1.30, P = .25) symptoms after 15 treatments. Post hoc analysis indicated a slightly less robust overall response among the BPD+ group by the 15th treatment. CONCLUSIONS: Acute course ECT benefits depressed patients with or without comorbid BPD, although patients with BPD may exhibit less pronounced improvement over time.

Borderline personality traits do not influence response to TMS.

Comorbid personality disorders are common in patients with major depressive disorder (MDD). Individuals with comorbid borderline personality disorder (BPD) may be less responsive to electroconvulsive therapy (ECT), but it remains unclear whether BPD affects responsiveness to transcranial magnetic stimulation (TMS). We sought to investigate the association between BPD and response to TMS. We conducted a retrospective analysis of individuals receiving TMS (n=356) at McLean Hospital. We also included individuals receiving ECT (n=1434) as a control. All individuals completed the McLean Screening Instrument for BPD (MSI-BPD) at baseline. Response to treatment was measured by the Quick Inventory of Depression Symptomatology Self-Report (QIDS-SR). We performed general linear models (GLMs) to assess the effect of BPD on treatment response to TMS and ECT. At baseline, the ECT group had a higher average QIDS-SR score (21.4 vs. 20.3, p<0.05). For both treatment groups, the number of treatments had a significant effect on depression severity. For the TMS group, there was no significant Group x Time interaction on QIDS-SR score (p=0.18). However, for individuals receiving ECT, there was a significant Group x Time interaction on QIDS-SR score (p=0.02), suggesting that BPD significantly impaired response. These results suggest that borderline personality traits did not affect treatment response to TMS for MDD. BPD traits modestly predicted response to ECT, which is consistent with the literature. These results require replication in a clinical trial.

Return to College After a First Episode of Psychosis.

A first episode of psychosis (FEP) can derail a patient's educational goals, including attainment of a college education, and this can have lasting ramifications for socioeconomic and health outcomes. Despite this, few studies have examined return to college, which is an important index of real-world educational success after a FEP. In this study, we conducted a longitudinal medical record review of patients in a transdiagnostic outpatient FEP program and performed survival analysis, setting return to college as the endpoint, among the subset of patients whose college education was interrupted. We found that 82% (93/114) of college-enrolled FEP individuals experienced disruptions to their education after FEP, but that return to college also occurred in a substantial proportion (49/88, 56%) among those on leave who had follow-up data. In this sample, the median time to college return was 18 months. When separated by baseline diagnostic category, FEP patients with affective psychotic disorders (FEAP, n = 45) showed faster time to college return than those with primary psychotic disorders (FEPP, n = 43) (median 12 vs 24 mo; P = .024, unadjusted). When adjusted for having no more than 1 psychiatric hospitalization at intake and absence of cannabis use in the 6 months prior to intake (which were also significant predictors), differences by diagnostic category were more significant (hazard ratio 2.66, 95% CI 1.43-4.94, P = .002). Participation in education is an important outcome for stakeholders, and students with FEP can be successful in accomplishing this goal.

5 Hz Repetitive transcranial magnetic stimulation for posttraumatic stress disorder comorbid with major depressive disorder.

BACKGROUND: Standard clinical protocols for repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) apply 10 Hz pulses over left prefrontal cortex, yet little is known about the effects of rTMS in more diagnostically complex depressed patients. OBJECTIVE/HYPOTHESIS: Posttraumatic stress disorder (PTSD) is commonly comorbid with MDD, and while rTMS has been shown to alleviate PTSD symptoms in preliminary studies, ideal parameters remain unclear. We conducted a prospective, open-label study of 5 Hz rTMS for patients with comorbid PTSD + MDD and hypothesized stimulation would reduce symptoms of both disorders. METHODS: Outpatients (N = 40) with PTSD + MDD and at least moderate global severity were enrolled. 5 Hz rTMS included up to 40 daily sessions followed by a 5-session taper. Symptoms were measured using the PTSD Checklist (PCL-5) and Inventory of Depressive Symptomatology, Self-Report (IDS-SR). Baseline-to-endpoint changes were analyzed. RESULTS: The intent-to-treat population included 35 participants. Stimulation significantly reduced PTSD symptoms (PCL-5 baseline mean ±â€¯SD score 52.2 ±â€¯13.1 versus endpoint 34.0 ±â€¯21.6; p < .001); 23 patients (48.6%) met a pre-defined categorical PTSD response criteria. MDD symptoms also improved significantly (IDS-SR, baseline 47.8 ±â€¯11.9 to endpoint 30.9 ±â€¯18.9; p < .001); 15 patients (42.9%) demonstrated categorical response and 12 (34.3%) remitted. PTSD and MDD symptom change was highly correlated (r = 0.91, p < .001). LIMITATIONS: Unblinded single-arm study, with modest sample size. CONCLUSION: Significant and clinically meaningful reductions in both MDD and PTSD symptoms were observed following stimulation. The preliminary efficacy of 5 Hz rTMS for both symptom domains in patients with comorbid disorders supports future controlled studies.

A pilot randomized controlled trial of aerobic exercise as an adjunct to OCD treatment.

OBJECTIVE: The purpose of the current study was to conduct a randomized controlled trial testing the efficacy of aerobic exercise for decreasing OCD symptom severity, other mental health outcomes, and increasing exercise behaviors and cardiorespiratory fitness among individuals with OCD. METHOD: Fifty-six patients (64% female; mean age=38.8years) with OCD and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of 16 or greater despite engaging in OCD treatment were randomized to 12-weeks of supervised plus home-based moderate-intensity aerobic exercise (AE; n=28) or to 12-weeks of health education sessions (HE; n=28). RESULTS: Random intercepts mixed models examined differences between conditions at post-treatment. Though no difference between conditions on outcomes was observed, both AE and HE showed significant reduction in OCD symptom severity, depression and anxiety at post-treatment. Relative to HE, significant increases were noted in amount of exercise and cardiorespiratory fitness for those in the AE condition. At post-treatment, 30.4% of the AE condition (7 of 23) were treatment-responders (using the commonly accepted measure of 35% symptom reduction from baseline). In the HE condition, 7.7% of the sample (2 of 26) met this criterion at post-treatment. CONCLUSION: The results of this preliminary study suggest that exercise and health-focused interventions may be beneficial adjuncts to existing OCD treatment. Future studies with larger samples are needed to more definitively answer questions the efficacy of AE for reducing OCD symptoms and improving related clinical outcomes.

Transcranial magnetic stimulation for treatment-resistant depression: Naturalistic treatment outcomes for younger versus older patients.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) has been shown to be safe and effective for treatment-resistant depression (TRD) in the general adult population. Efficacy among older (≥60 years) patients, who have a greater burden of cognitive, physical, and functional impairment compared to their younger counterparts, remains unclear. The current study aimed to characterize antidepressant response to an acute course of TMS therapy among patients aged ≥60 years compared to those <60 years in naturalistic clinical practice settings. METHODS: Data were retrospectively collected and pooled for adults with TRD (N =231; n =75 aged ≥60 years and n = 156 <60 years) who underwent an acute course of outpatient TMS therapy at two outpatient clinics. Self-report depression scales were administered at baseline and end of acute treatment. Change on continuous measures and categorical outcomes were compared across older vs. younger patients. RESULTS: Both age groups showed significant improvements in depression symptoms. Response and remission rates did not differ between groups. Age group was not a significant predictor of change in depression severity, nor of clinical response or remission, in a model controlling for other predictors (all p>.05). LIMITATIONS: Limitations include reliance on self-report clinical measures and variability in comorbidity and concurrent pharmacotherapy due to the naturalistic nature of the study. CONCLUSIONS: Results suggest that effectiveness of TMS for TRD is not differentially modified by age. Based on these naturalistic data, age alone should not be considered a contraindication or poor prognostic indicator of the antidepressant efficacy of TMS.

61% of unmedicated treatment resistant depression patients who did not respond to acute TMS treatment responded after four weeks of twice weekly deep TMS in the Brainsway pivotal trial.

BACKGROUND: An acute course of dTMS typically involves treatments delivered 5 days a week, for 4 weeks. Should more treatments be given if the patient has not responded? Data are needed to inform decisions about the best next steps for acute non-responders. OBJECTIVE: To characterize response among acute-phase non-responders in a randomized controlled trial of deep repetitive transcranial magnetic stimulation (dTMS) monotherapy for medication-resistant depression. METHODS: Summary statistics and Kaplan-Meier curves were used to characterize outcomes of 33 medication-free Brainsway™ dTMS non-responders to double blind but active treatment at the end of 4 weeks (20 sessions), who then continued double blind but active twice-weekly treatment for up to 12 additional weeks. RESULTS: 24 participants (72.7%) achieved responder status during at least one rating with dTMS continuation -- 20 (60.6%) within four weeks, with 13 (39.4%) consistently meeting response criteria for the duration of the study. 20 (63.6%) achieved remission status at some point during treatment continuation. CONCLUSIONS: A significant proportion of acute course non-responders to dTMS treatment eventually respond with continued treatment. Continuing TMS treatment beyond the acute course for non-responders may result in eventual response in over half of these individuals.

Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review.

BACKGROUND: The effect and association of omega-3 fatty acids (n-3 FA) intake and biomarker levels with cardiovascular (CV) clinical and intermediate outcomes remains controversial. We update prior Evidence Reports of n-3 FA and clinical and intermediate CV disease (CVD) outcomes. OBJECTIVES: Evaluate the effect of n-3 FA on clinical and selected intermediate CV outcomes and the association of n-3 FA intake and biomarkers with CV outcomes. The n-3 FA under review include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), stearidonic acid (SDA), and alphalinolenic acid (ALA). DATA SOURCES: MEDLINE®, Embase®, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CAB Abstracts from 2000 or 2002 to June 8, 2015, and eligible studies from the original reports and relevant existing systematic reviews. REVIEW METHODS: We included randomized controlled trials (RCTs) of any n-3 FA intake compared to no, lower, or other n-3 FA intake with an outcome of interest conducted in healthy adults, those at risk for CVD, or those with CVD. We also included prospective observational studies of the association between baseline n-3 FA intake or biomarker level and followup outcomes. We required 1 year or more of followup for clinical outcomes and 4 weeks for intermediate outcomes (blood pressure [BP] and lipids). RESULTS: From 11,440 citations (from electronic literature searches and existing systematic reviews), 829 abstracts met basic eligibility criteria; 61 RCTs and 37 longitudinal observational studies (in 147 articles) were included. Most RCTs and observational studies had few risk-of-bias concerns.Total n-3 FA: There is low strength of evidence (SoE) of no association between total n-3 FA intake and stroke death or myocardial infarction. There is insufficient evidence for other outcomes.Marine oils, total: There is moderate to high SoE that higher marine oil intake lowers triglycerides (Tg), raises high density lipoprotein cholesterol (HDL-c), and lowers the ratio of total cholesterol to HDL-c but raises low density lipoprotein cholesterol (LDL-c); also that higher marine oil intake does not affect major adverse CV events, all-cause death, total stroke, sudden cardiac death, coronary revascularization, atrial fibrillation, or BP. There is low SoE of associations between higher marine oil intake and decreased risk of CVD death, coronary heart disease (CHD), myocardial infarction, ischemic stroke, and congestive heart failure (CHF). There is low SoE of no association with CHD death or hemorrhagic stroke. There is insufficient evidence for other outcomes.Marine oil FA individually: There is low SoE of no associations between EPA or DHA intake (separately) and CHD, and between EPA or DPA and atrial fibrillation. There is low SoE of no association between EPA biomarkers and atrial fibrillation, but moderate SoE of no effect of purified DHA supplementation on BP or LDL-c. There is insufficient evidence for other specific marine oil FA and outcomes.ALA: There is moderate SoE of no effect of ALA intake on BP, LDL-c, HDL-c, or Tg. There is low SoE of no association between ALA intake or biomarker level and CHD, CHD death, atrial fibrillation, and CHF. There is insufficient evidence for other outcomes.Other n-3 FA analyses: There is insufficient evidence comparing n-3 FA with each other or for SDA.Subgroup analyses: Nineteen of 22 studies found no interaction of sex on any effect of n-3 FA. Likewise, 19 of 20 studies found no differential effect by statin co-use. Within 16 studies evaluating diabetes subgroups, 2 found statistically significant beneficial effects of n-3 FA in those with diabetes but not in those without diabetes, but no test of interaction was reported. CONCLUSIONS: The 61 RCTs mostly compared marine oil supplements with placebo on CVD outcomes in populations at risk for CVD or with CVD, while the 37 observational studies mostly examined associations between various individual n-3 FA and long-term CVD events in generally healthy populations. Compared with the prior report on n-3 FA and CVD, there is more robust RCT evidence on ALA and on clinical CV outcomes; also, by design there are newly added data on associations between n-3 FA biomarkers and CV outcomes. However, conclusions regarding the effect of n-3 FA intake on CV outcomes or associations with outcomes remain substantially unchanged. Marine oils statistically significantly raise HDL-c and LDL-c by similar amounts (≤2 mg/dL), while lowering Tg in a dose-dependent manner, particularly in individuals with elevated Tg; they have no significant effect on BP. ALA has no significant effect on intermediate outcomes. Limited data were available from RCTs on the effect of n-3 FA on clinical CVD outcomes. Observational studies suggest that higher marine oil intake (including from dietary fish) is associated with lower risk of several CVD outcomes. No clear differences in effects or associations were evident based on population, demographic features, or cointerventions. Future RCTs would be needed to establish adequate evidence of the effect of n-3 FA on CVD outcomes or to clarify differential effects in different groups of people. However, future trials are unlikely to alter conclusions about the effects of n-3 FA supplementation on intermediate cardiovascular outcomes (BP, LDL-c, HDL-c, or Tg).

Predicting course of illness in patients with severe obsessive-compulsive disorder.

OBJECTIVE: Few data are available to inform clinical expectations about course and prognosis of severe obsessive-compulsive disorder (OCD). Such information is necessary to guide clinicians and to inform criteria for invasive interventions for severe and intractable OCD. This study sought to examine course and prospective predictors of a chronic course in patients with severe OCD over 5 years. METHOD: A selected subset of adults in the Brown Longitudinal Obsessive-Compulsive Study (BLOCS) was included. Adult BLOCS participants were enrolled between 2001 and 2006. All participants in the current study (N = 113) had DSM-IV OCD diagnosis, severe OCD symptoms at baseline, and at least 1 year of follow-up data. RESULTS: Cox proportional hazard models were used to examine the general pattern of course in the severe OCD sample based on Longitudinal Interval Follow-Up Evaluation (LIFE) psychiatric status ratings, as well as test predictors of chronically severe course. Results indicated that approximately half of patients with severe OCD at baseline had illness drop to a moderate or lower range of severity during 5 years of follow-up (50.4%) and that marked improvement was rare after 3 years of severe illness. The only unique predictor of a more chronically severe course was patient report of ever having been housebound for a week or more due to OCD symptoms (P < .05). CONCLUSIONS: Findings of this study were 3-fold: (1) half of participants with severe OCD have symptom improvement over 5 years of follow-up, (2) the majority of participants that drop out of the severe range of symptom severity do so within the first 3 years of follow-up, and (3) patient-reported history of being housebound for 1 week or more due to OCD is a significant predictor of OCD's remaining severe over the 5-year follow-up.

Basal ganglia MR relaxometry in obsessive-compulsive disorder: T2 depends upon age of symptom onset.

Dysfunction in circuits linking frontal cortex and basal ganglia (BG) is strongly implicated in obsessive-compulsive disorder (OCD). On MRI studies, neuropsychiatric disorders with known BG pathology have abnormally short T2 relaxation values (a putative biomarker of elevated iron) in this region. We asked if BG T2 values are abnormal in OCD. We measured volume and T2 and T1 relaxation rates in BG of 32 adults with OCD and 33 matched controls. There were no group differences in volume or T1 values in caudate, putamen, or globus pallidus (GP). The OCD group had lower T2 values (suggesting higher iron content) in the right GP, with a trend in the same direction for the left GP. This effect was driven by patients whose OCD symptoms began from around adolescence to early adulthood. The results suggest a possible relationship between age of OCD onset and iron deposition in the basal ganglia.

Risk factors for incident dementia in England and Wales: The Medical Research Council Cognitive Function and Ageing Study. A population-based nested case-control study.

OBJECTIVE: To investigate a number of prospectively collected factors (sociodemographic, medical and behavioural) and their association with incident dementia in a population-based cohort. DESIGN: Nested case-control analysis (at 2 and 6 years) of a population-based cohort study. SETTING: Individuals aged 65 years and above from five centres in England and Wales: two rural (Cambridgeshire and Gwynedd) and three urban (Nottingham, Newcastle and Oxford). PARTICIPANTS: A total of 4,075 individuals from a detailed assessment group, with risk measured at baseline. MAIN OUTCOME MEASURE: Incident dementia at 2 and 6 years. METHODS: Logistic regression was used to calculate crude odds ratios (ORs) for various risk factors and ORs adjusted for age, sex, education and social class. RESULTS: Age (90+ versus 65-69 years OR = 25.6, 95% confidence interval (CI) = 11.6-56.9) and sex (women versus men OR = 1.6, 95% CI = 1.1-2.4) were directly associated with dementia, with a trend by years of education (P(trend) = 0.02) but not social class. Poor self-perceived health (versus good) increased the risk for incident dementia (OR = 3.9, 95% CI = 2.2-6.9). Alcohol and smoking (never, past and current) were neither strongly protective nor predictive. Stroke was strongly related to incident dementia (OR = 2.1, 95% CI = 1.1-4.2), as was Parkinson's disease (OR = 3.5, 95% CI = 1.3-9.3), and exposure to general anaesthesia (GA) was inversely associated with dementia development (OR = 0.6, 95% CI = 0.4-0.9, with a trend with increasing GA exposure; P = 0.003). CONCLUSION: In this large multicentre and long-term population-based study, some well-known risk factors for dementia, of vascular and Alzheimer's type, are confirmed but not others. The association between self-perceived health-a robust predictor of later health outcomes-and incident dementia, independently of other potential risks, warrants further study.

Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE Study.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID) use may protect against Alzheimer's disease (AD) risk. We sought examine the association between NSAID use and risk of AD, and potential effect modification by APOE-epsilon4 carrier status and ethnicity. METHODS: The MIRAGE Study is a multi-center family study of genetic and environmental risk factors for AD. Subjects comprised 691 AD patients (probands) and 973 family members enrolled at 15 research centers between 1996 and 2002. The primary independent and dependent variables were prior NSAID use and AD case status, respectively. We stratified the dataset in order to evaluate whether the association between NSAID use and AD was similar in APOE-epsilon4 carriers and non-carriers. Ethnicity was similarly examined as an effect modifier. RESULTS: NSAID use was less frequent in cases compared to controls in the overall sample (adjusted OR = 0.64; 95% CI = 0.38-1.05). The benefit of NSAID use appeared more pronounced among APOE-epsilon4 carriers (adjusted OR = 0.49; 95% CI = 0.24-0.98) compared to non-carriers, although this association was not statistically significant. The pattern of association was similar in Caucasian and African Americans. CONCLUSIONS: NSAID use is inversely associated with AD and may be modified by APOE genotype. Prospective studies and clinical trials of sufficient power to detect effect modification by APOE-epsilon4 carrier status are needed.

Empirically derived phenotypic subgroups - qualitative and quantitative trait analyses.

BACKGROUND: The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits. METHODS: Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis. RESULTS: We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 x 10(-6)) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23). CONCLUSION: This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.