An answered call for aid? Cannabinoid clinical framework for the opioid epidemic.

BACKGROUND: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. MAIN BODY: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. CONCLUSION: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.

Modification of the Association Between Severe Hypoglycemia and Ischemic Heart Disease by Surrogates of Vascular Damage Severity in Type 1 Diabetes During ∼30 Years of Follow-up in the DCCT/EDIC Study.

OBJECTIVE: Literature suggests that severe hypoglycemia (SH) may be linked to cardiovascular events only in older individuals with high cardiovascular risk score (CV-score). Whether a potential relationship between any-SH and cardiovascular disease exists and whether it is conditional on vascular damage severity in a young cohort with type 1 diabetes (T1D) without apparent macrovascular and no or mild-to-moderate microvascular complications at baseline is unknown. RESEARCH DESIGN AND METHODS: We evaluated data of 1,441 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study volunteers (diabetes duration 1-15 years) followed for ∼30 years. Time-dependent associations between any-SH and ischemic heart disease (IHD: death, silent/nonfatal myocardial infarct, revascularization, or confirmed angina) and associations between interactions of any-SH with surrogates of baseline micro-/macrovascular damage severity and IHD were analyzed. Diabetes duration, steps on DCCT Early Treatment Diabetic Retinopathy Study severity scale (DCCT-ETDRS), Diabetes Complications Severity Index (DCSI), and CV-scores were considered as surrogates of baseline micro-/macrovascular damage severity. RESULTS: Without interactions, in the minimally adjusted model controlling for confounding bias by age and HbA1c, SH was a significant IHD factor (P = 0.003). SH remained a significant factor for IHD in fully adjusted models (P < 0.05). In models with interactions, interactions between SH and surrogates of microvascular complications severity, but not between SH and CV-score, were significant. Hazard ratios for IHD based on SH increased 1.19-fold, 1.32-fold, and 2.21-fold for each additional year of diabetes duration, DCCT-ETDRS unit, and DCSI unit, respectively. At time of IHD event, ∼15% of 110 participants with SH had high CV-scores. CONCLUSIONS: In a young cohort with T1D with no baseline macrovascular complications, surrogates of baseline microvascular damage severity impact the effect of SH on IHD. Older age with high CV-score per se is not mandatory for an association of SH with IHD. However, the association is multifactorial.

Methimazole-Induced Pleural Effusion in the Setting of Graves' Disease.

Methimazole is a thionamide drug that inhibits the synthesis of thyroid hormones by blocking the oxidation of iodine in the thyroid gland. We report a case of methimazole-induced recurrent pleural effusion. A 67-year-old female with recently diagnosed Graves' disease on methimazole 20mg daily was admitted with dyspnea and new onset atrial fibrillation with rapid ventricular rate. Chest X-ray revealed a unilateral right pleural effusion, which was consistent with a transudate on thoracocentesis. She was managed as a case of congestive heart failure and methimazole dose was increased to 30 mg daily. She was readmitted twice with recurrent right pleural effusion. The fluid revealed an exudative process on repeat thoracocentesis. CT scan of the chest with contrast showed mediastinal lymphadenopathy and a diffuse ground glass process involving the right lower lobe suggestive of pneumonitis. Bronchoalveolar lavage showed neutrophil predominant fluid, and cytology and adenosine deaminase were negative. Patient also had an endobronchial ultrasound guided biopsy of the lymph nodes (EBUS). She was treated empirically with steroids 40 mg for 10 days and the methimazole was also discontinued. The antinuclear antibodies (ANA) came back positive with a speckled pattern; antineutrophil cytoplasmic antibody (c-ANCA) and antimyeloperoxidase were also positive. The effusion resolved but recurred on rechallenge with methimazole. She was referred for urgent thyroidectomy. The patient's repeat chest X-ray showed complete resolution of the pleural effusion after stopping the methimazole. Few weeks later, repeat ANCA and antimyeloperoxidase antibody were both negative. Our case report highlights the importance of the recognition of a rare side effect of methimazole. Timely diagnosis would ensure that appropriate treatment is given.

Role of adipokines and inflammatory markers in postmenopausal hypertension.

BACKGROUND: The role of inflammatory markers and adipokines contributing to the development of postmenopausal hypertension, has not been established. The aim of our study was to assess the complex association between blood pressure, obesity, menopausal status, adipokines and inflammatory mediators in postmenopausal women. METHODS: We recruited 38 women seen at our Endocrinology Clinic and collected anthropometric measures and blood pressure and obtained serum samples for inflammatory markers and adipokine levels. Out of 38 women, 23 (60%) were postmenopausal. RESULTS: In the pre-menopausal and postmenopausal women, there were no significant differences in measured adipokines and inflammatory markers based on hypertensive status. When obesity was eliminated, significantly higher levels of EGF, IL-8, MCP1 and TNF-α and lower levels of IL-1α and IL-3 were observed in the postmenopausal group (P<0.05). Women with higher waist-to-hip ratio (WHR) had a significant trend towards lower adiponectin levels as compared to those with lower WHR (P=0.014 and P=0.04, respectively). CONCLUSIONS: There was a significant difference in pro-inflammatory markers in non-obese, pre- and post-menopausal women. These higher inflammatory markers might play a role in the development of post-menopausal hypertension.

Blunted HPA axis activity prior to suicide attempt and increased inflammation in attempters.

BACKGROUND: Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation is associated with increased risk for suicidal behavior. However, it is not clear whether such dysregulation exists prior to or is a consequence of attempt. Studies also show an activation of inflammatory responses in suicidal behavior but often combine attempters with those with ideation. METHODS: The sample consisted of psychiatric inpatients, aged 15-30 years, admitted for suicide attempt (SA, n=38), inpatients admitted for suicidal ideation with no prior history of attempts (SI, n=40), and healthy controls (n=37). We compared SA, SI, and controls on hair cortisol concentrations (HCC), which provides retrospective levels of cortisol and thus prior to the attempt in SA. We also compared them on the expression of genes in the HPA axis and inflammatory pathways previously implicated in suicidal behavior (GR or NR3C1, SKA2, FKBP5, IL-1ß, TNF-α); plasma C-Reactive Protein (CRP); and cellular measures of glucocorticoid receptor (GR) sensitivity and stimulated production of IL-6. RESULTS: We found lower HCC [ß=-0.55, 95% CI (-0.96, -0.13), p=0.01, ES=-0.54] in first-time SA compared to SI and controls. In addition, SA showed lower GR or NR3C1 (α isoform) mRNA [ß=-5.11, 95% CI (-10.9, 0.73), p=0.09, ES=-0.46], higher CRP [ß=0.94, 95% CI (-0.004, 1.9), p=0.05, ES=0.60], and higher TNF-α mRNA [ß=26.4, 95% CI (7.7, 45.2), p=0.006, ES=0.73]. CONCLUSIONS: This is the first study to differentiate youth who attempt suicide from those with suicidal ideation on HCC and to show that low HCC precedes suicide attempt. Suicide attempters also showed a distinct biological profile on several markers in both the HPA axis and inflammatory pathways. Future longitudinal studies are needed to examine the ability of these biomarkers to predict suicidal behavior.

Protective Effects of Cerium Oxide Nanoparticles on MC3T3-E1 Osteoblastic Cells Exposed to X-Ray Irradiation.

BACKGROUND/AIMS: Exposure to ionizing radiation can result in bone damage, including decreased osteocyte number and suppressed osteoblastic activity. However, molecular mechanisms remain to be elucidated, and effective prevention strategies are still limited. This study was to investigate whether cerium oxide nanoparticles (CeO2 NP) can protect MC3T3-E1 osteoblast-like cells from damaging effects of X-ray irradiation, and to study the underpinning mechanism(s). METHODS: MC3T3-E1, a osteoblast-like cell line, was exposed to X-ray irradiation and treated with different concentration of CeO2 nanoparticles. The micronucleus frequency was counted under a fluorescence microscope. Cell viability was evaluated using MTT assay. The effects of irradiation and CeO2 nanoparticles on alkaline phosphatase activity and MC3T3-E1 mineralization were further assayed. RESULTS: We found that the ratio of micronuclei to binuclei was dose-dependently increased with X-ray irradiation (from 2 to 6 Gy), but diminished with the increased concentration of CeO2 NP treatment (from 50 to 100 nM). Exposure to X-rays (6 Gy) decreased cell viability, differentiation and the mineralization, but CeO2 NP treatment (100 nM) attenuated the deteriorative effects of irradiation. Both intracellular reactive oxygen species (ROS) production and extracellular H2O2 concentration were increased after X-ray irradiation, but reduced following CeO2 NP treatment. Similar to irradiation, exposure to H2O2 (10 µM) elevated the frequency of micronuclei and diminished cell viability and mineralization, while these changes were ameliorated following CeO2 NP treatment. CONCLUSIONS: Taken together, our findings suggest that CeO2 nanoparticles exhibit astonishing protective effects on irradiation-induced osteoradionecrosis in MC3T3-E1 cells, and the protective effects appear to be mediated, at least partially, by reducing oxidative stress.

Femoral Neck Bone Mineral Density in Persons Over 50 Years Performing Shiftwork: An Epidemiological Study.

OBJECTIVE: Shiftwork has been associated with bone loss due to hormonal fluctuations. Our aim was to assess the femoral neck bone mineral density and content in persons over 50 years performing shiftwork. METHODS: We performed analysis on the femoral neck bone mineral parameters in persons over age 50 years from the National Health and Nutrition Examination Survey cross-sectional data for 2010 to 2011 in regular and shiftworkers. We also assessed the degree of moderate physical activity and smoking in both groups. RESULTS: Middle-aged men performing shiftwork had significantly higher total femur bone mineral content (37.33 ±â€Š11.00 vs 34.09 ±â€Š10.45, P = 0.01) and femoral neck bone mineral content (4.57 ±â€Š1.07 vs 4.29 ±â€Š1.0, P = 0.03). This difference was not seen in middle aged women. CONCLUSIONS: Shiftwork does not seem to affect bone mineral density in those performing moderate physical activity.

Gene expression classifier for the diagnosis of indeterminate thyroid nodules: a meta-analysis.

Prior studies demonstrate that a novel genomic test, the gene expression classifier (GEC), could identify a benign gene expression signature in those nodules with indeterminate cytology with a negative predictive value of greater than 95 %. Examine the performance of the AFIRMA gene expression classifier in predicting benign and malignant nodules in patients with cytologically indeterminate nodules. MEDLINE and EMBASE search for studies meeting eligibility criteria between January 1, 2005, and August 30, 2015. A total of 58 studies identified. After excluding duplicates, case reports, reviews, commentary, insufficient data, a total of seven studies selected for analysis. We combined individual patient data from seven studies that examined the GEC test for indeterminate thyroid nodules. The reference standard for determination of benign or malignant nodules was the histopathology of the thyroidectomy specimen. A QUADAS-2 report for all studies included in the final analysis was tabulated for risk of bias and applicability. The pooled sensitivity of the GEC was 95.7 % (95 % CI 92.2-97.9, I (2) value 45.4 %, p = 0.09), and the pooled specificity was 30.5 % (95 % CI 26.0-35.3, I (2) value 92.1 %, p < 0.01). Overall, the diagnostic odds ratio was 7.9 (95 % CI 4.1-15.1). Patients with benign GEC were not followed long enough to ascertain the actual false-negative rates of the index test. Our meta-analysis revealed a high pooled sensitivity and a low specificity for the AFIRMA-GEC test for indeterminate thyroid nodules. This makes it an excellent tool to rule out malignancy.

Severe hypoglycemia and coronary artery calcification during the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study.

AIM: Recently, major attention has been paid to the role of hypoglycemia as a cardiovascular risk factor. While EURODIAB-investigators concluded that severe hypoglycemia is not a cardiovascular risk factor in type 1 diabetes, other investigators found the opposite. The primary purpose of this study was to investigate the role of severe hypoglycemia in atherosclerosis during the DCCT- and EDIC-years with special attention to overall glycemic levels. RESEARCH DESIGN AND METHODS: The effect of severe hypoglycemic rates on coronary artery calcification (CAC) was evaluated for the entire cohort (n = 1205) and glycemic stratified cohorts (HbA1C < 7.5% [58 mmol/mol], HbA1C ≥ 7.5%). RESULTS: The association between CAC and mean DCCT-hypoglycemia rate was stronger than the association between CAC and mean EDIC-hypoglycemia rate. Although the DCCT-severe hypoglycemia rate without HbA1C-stratification was not significantly associated with a CAC-score ≥ 100 Agatston units (p = 0.093), the interaction between above glycemic ranges and DCCT-hypoglycemic rate was significant (p < 0.05). A sub-analysis of patients belonging to the lower glycemic range (HbA1C < 7.5%), adjusted for baseline age, gender, baseline diabetes duration, baseline neuropathy, baseline albumin excretion rate, systolic blood pressure, LDL-cholesterol, smoking status, body mass index and DCCT-A1C, indicated significant (p = 0.02) associations between DCCT-severe hypoglycemia rate and CAC-score ≥ 100. One unit increase in the natural logarithm transformed DCCT-severe hypoglycemia rate increased the risk of having a CAC ≥ 100 by 30%. CONCLUSIONS: Our results suggest a cumulative effect of hypoglycemic events on cardiovascular risk. They provide a possible link between above mentioned contradictory reports. Our findings support the relevance of personalizing glycemic goals in diabetes management beyond HbA1C.

Acetaminophen attenuates obesity-related renal injury through ER-mediated stress mechanisms.

BACKGROUND/AIMS: Obesity is an independent risk factor for the development of kidney disease. The purpose of this study was to determine how obesity may contribute to renal damage and whether acetaminophen ingestion can diminish obesity-associated renal cell injury in the obese Zucker rat model. METHODS: Male obese Zucker rats (4 weeks old, n=6) were treated with acetaminophen (30 mg / kg body weight / day) for 26 weeks. Age matched obese control (OC), obese vehicle (OV, 0.073 mL DMSO/kg/d), and lean Zucker rats (LC) were used to determine the effects of treatment and obesity. RESULTS: Compared to lean control rats, renal lipid deposition, expression of the endoplasmic reticulum (ER) stress protein GRP78 and activation of the ER stress-related eIF2α-ATF4-CHOP, caspase 12, and JNK-MAPK signaling pathways were increased in the obese control and obese vehicle rats. These alterations were associated with the elevated renal cell apoptosis and urinary albumin excretion. Acetaminophen treatment decreased renal lipid deposition, ER-stress related signaling, apoptosis and albuminuria. CONCLUSION: These data suggest that the protective effects of low dose acetaminophen on renal injury are mediated, at least in part, through attenuation of ER stress.

Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission.

OBJECTIVE: To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression. METHOD: This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM-IV) who responded partially (17-item Hamilton Rating Scale for Depression [HAM-D-17] score of 11 to 15) or not at all (HAM-D score > 15) to a 16-week trial of escitalopram (up to 20 mg/day), followed by either duloxetine (up to 120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks. Subjects received 2.5 to 15 mg per day of adjunctive aripiprazole (mean dose, 9.0 mg/day) for 12 weeks. The criterion for remission during treatment with aripiprazole was a HAM-D score < or = 10 for 2 consecutive weeks. RESULTS: Of 24 subjects in the intent-to-treat study group, 19 completed 12 weeks of augmentation with aripiprazole, 12 of 24 (50%) met criteria for remission, and 2 of 24 discontinued due to side effects (sedation, akathisia). The mean (SD) HAM-D score decreased significantly by 6.4 (5.8) points (paired t test for means, p < .01, df = 16). There were no relapses among the 12 subjects who participated in continuation treatment over a median period of 27.6 weeks. CONCLUSIONS: In older adults with MDD with incomplete response to SSRI and SNRI pharmacotherapy, aripiprazole was well tolerated, and symptoms of depression improved significantly during treatment with aripiprazole. A randomized, double-blind, placebo-controlled trial of adjunctive aripiprazole for incomplete response in late-life depression is warranted to further evaluate benefit and risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00177671.

Sleeping well, aging well: a descriptive and cross-sectional study of sleep in "successful agers" 75 and older.

OBJECTIVES: To examine diary-based, laboratory-based, and actigraphic measures of sleep in a group of healthy older women and men (> or =75 years of age) without sleep/wake complaints and to describe sleep characteristics which may be correlates of health-related quality of life in old age. DESIGN: Cross-sectional, descriptive study. SETTING: University-based sleep and chronobiology program. INTERVENTION: None. PARTICIPANTS: Sixty-four older adults (30 women, 34 men; mean age 79). MEASUREMENTS: We used diary-, actigraphic-, and laboratory-based measures of sleep, health-related quality of life, mental health, social support, and coping strategies. We used two-group t-tests to compare baseline demographic and clinical measures between men and women, followed by ANOVA on selected EEG measures to examine first-night effects as evidence of physiological adaptability. Finally, we examined correlations between measure of sleep and health-related quality of life. RESULTS: We observed that healthy men and women aged 75 and older can experience satisfactory nocturnal sleep quality and daytime alertness, especially as reflected in self-report and diary-based measures. Polysomnography (psg) suggested the presence of a first-night effect, especially in men, consistent with continued normal adaptability in this cohort of healthy older adults. Continuity and depth of sleep in older women were superior to that of men. Diary-based measures of sleep quality (but not psg measures) correlated positively (small to moderate effect sizes) with physical and mental health-related quality of life. CONCLUSIONS: Sleep quality and daytime alertness in late life may be more important aspects of successful aging than previously appreciated. Good sleep may be a marker of good functioning across a variety of domains in old age. Our observations suggest the need to study interventions which protect sleep quality in older adults to determine if doing so fosters continued successful aging.

Incomplete response in late-life depression: getting to remission.

Incomplete response in the treatment of late-life depression is a large public health challenge: at least 50% of older people fail to respond adequately to first-line antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment-resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of empirical data on how best to manage TRLLD. A pilot study by our group on aripiprazole augmentation in 24 incomplete responders to sequential SSRI and SRNI pharmacotherapy found that 50% remitted over 12 weeks with the addition of aripiprazole, and that remission was sustained in all participants during 6 months of continuation treatment. In addition to controlled assessment, evidence is needed to support personalized treatment by testing the moderating role of clinical (e.g., comorbid anxiety, medical burden, and executive impairment) and genetic (eg, selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while also controlling for variability in drug exposure. Such studies may advance us toward the goal of personalized treatment in late-life depression.

Getting better, getting well: understanding and managing partial and non-response to pharmacological treatment of non-psychotic major depression in old age.

In general, the pharmacological treatment of non-psychotic major depressive disorder in old age is only partially successful, with only approximately 50% of older depressed adults improving with initial antidepressant monotherapy. Many factors may predict a more difficult-to-treat depression, including coexisting anxiety, low self-esteem, poor sleep and a high coexisting medical burden. Being aware of these and other predictors of a difficult-to-treat depression gives the clinician more reasonable expectations about a patient's likely treatment course. If an initial antidepressant trial fails, the clinician has two pharmacological options: switch or augment/combine antidepressant therapies. About 50% of patients who do not improve after initial antidepressant therapy will respond to either strategy. Switching has several advantages including fewer adverse effects, improved treatment adherence and reduced expense. However, as a general guideline, if patients are partial responders at 6 weeks, they will likely be full responders by 12 weeks. Thus, changing medication is not indicated in this context. However, if patients are partial responders at 12 weeks, switching to a new agent is advised. If the clinician treats vigorously and if the patient and clinician persevere, up to 90% of older depressed patients will respond to pharmacological treatment. Furthermore, electroconvulsive therapy is a safe and effective non-pharmacological strategy for non-psychotic major depression that fails to respond to pharmacotherapy. Getting well and staying well is the goal; thus, clinicians should treat to remission, not merely to response. Subsequently, maintenance treatment with the same regimen that has been successful in relieving the depression strongly improves the patient's chances of remaining depression free.

Noninsulinoma pancreatogenous hypoglycemia syndrome: quantitative and immunohistochemical analyses of islet cells for insulin, glucagon, somatostatin, and pancreatic and duodenal homeobox protein.

OBJECTIVE: To present a case of an elderly man with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and to determine the pathogenesis of this syndrome. METHODS: The pancreas of our patient with NIPHS was immunocytochemically stained for insulin-, glucagon-, and somatostatin-secreting cells and pancreatic and duodenal homeobox protein (PDX-1). The clinical findings and morphologic and immunocytochemical analyses of the islets of our patient are described, along with a review of related published reports. RESULTS: A 78-year-old man presented with hyperinsulinemic hypoglycemia, with episodes unrelated to meals or fasting. An insulinoma could not be localized by preoperative imaging or by intraoperative ultrasonography or palpation. He underwent a 70% distal pancreatectomy. For assessment of the possibility that a nuclear transcription factor regulating islet beta-cell growth and development is overexpressed in this disease and is responsible for diffuse islet hyperfunction and proliferation of beta-cells, pancreatic sections from our patient were stained immunocytochemically for PDX-1, insulin, glucagon, and somatostatin. Morphologic findings were compared with pancreatic sections from normal control patients and normative data reported in the literature. Clinical findings and morphologic analyses were consistent with NIPHS. Islets were arranged in long clusters, both in the pancreatic tissue and in peripancreatic adipose tissue. Islets were small but increased in number, and insulin, glucagon, and somatostatin were present in the islets. The relative intensity of insulin staining was increased in our patient in comparison with that in the control patients, and PDX-1 was not overexpressed. CONCLUSION: The etiopathogenesis of NIPHS in this patient involved (1) an increased number of islets with development of ectopic islets in the peripancreatic adipose tissue; (2) alpha- and delta- as well as beta-cell proliferation; and (3) an early step in the development of the islet not involving overexpression of PDX-1.

Late-onset major depression: clinical and treatment-response variability.

OBJECTIVE: To explore clinical and treatment-response variability in late-onset vs early-onset non-bipolar, non-psychotic major depression. METHODS: We grouped patients from a late-life depression treatment study according to illness-course characteristics: those with early-onset, recurrent depression (n = 59), late-onset, recurrent depression (n = 27), and late-onset, single-episode depression (n = 95). Early-onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late-onset was defined as having a first episode of major depression at age 60 or later. We characterized the three groups of patients with respect to baseline demographic, neuropsychological, and clinical characteristics, use of augmentation pharmacotherapy to achieve response, and treatment outcomes. RESULTS: Rates of response, remission, relapse, and termination were similar in all three groups; however, patients with late-onset, recurrent major depression took longer to respond to treatment than those with late-onset, single-episode depression (12 weeks vs 8 weeks) and had more cognitive and functional impairment. Additionally, patients with recurrent depression (whether early or late) were more likely to require pharmacotherapy augmentation to achieve response than patients with a single lifetime episode. CONCLUSION: Late-onset, recurrent depression takes longer to respond to treatment than late-onset single-episode depression and is more strongly associated with cognitive and functional impairment. Further study of biological, neuropsychologic, and psychosocial correlates of late-onset, recurrent depression is needed.