Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA).

Diabetic retinal disease is envisioned to become the plague of the coming decades with a steep increase of worldwide diabetes incidence followed by a substantial rise in retinal disease. Improvements in diagnostic and therapeutic care have to cope with this dilemma in a clinically and socioeconomically efficient manner. Laser treatment has found a less destructive competitor in pharmacological treatments. As a consequence of recent rigorous clinical trials, laser photocoagulation is no longer recommended for the treatment of diabetic macular edema (DME), and anti-vascular endothelial growth factor therapy has emerged as first-line therapy. Steroids have maintained a role in the management of chronically persistent DME. The paradigm shifts in therapy are accompanied by a substantial break-through in diagnostics. The following guidance for the management of DME has been composed from the best updated knowledge of leading experts in Europe and represents another volume in the series of EURETINA recommendations for the management of retinal disease.

Ranibizumab or Bevacizumab for Neovascular Age-Related Macular Degeneration According to the Lucentis Compared to Avastin Study Treat-and-Extend Protocol: Two-Year Results.

PURPOSE: To compare the efficacy and safety of bevacizumab (Avastin; F. Hoffmann-La Roche Ltd, Basel, Switzerland) versus ranibizumab (Lucentis; Novartis Pharma AG, Basel, Switzerland) for neovascular age-related macular degeneration (nAMD) after 2 years when using a treat-and-extend protocol. DESIGN: Multicenter, randomized, noninferiority trial with a noninferiority limit of 5 letters. PARTICIPANTS: Patients 50 years of age or older with previously untreated nAMD in 1 eye and best-corrected visual acuity 20/25 to 20/320. METHODS: Patients were assigned randomly to receive intravitreal injections with either ranibizumab 0.5 mg or bevacizumab 1.25 mg. Injections were given every 4 weeks until inactive disease was achieved. The treatment interval then was extended by 2 weeks at a time up to a maximum of 12 weeks. In the event of a recurrence, the treatment interval was shortened by 2 weeks at a time. MAIN OUTCOME MEASURE: Mean change in visual acuity at 2 years. RESULTS: Of a total of 441 randomized patients, 339 patients (79%) completed the 2-year visit. According to per-protocol analysis at 2 years, bevacizumab was equivalent to ranibizumab, with 7.4 and 6.6 letters gained, respectively (95% confidence interval [CI] of mean difference, -4.1 to 2.5; P = 0.634). Intention-to-treat analysis was concordant, with a gain of 7.8 letters for bevacizumab and 7.5 letters for ranibizumab (95% CI of mean difference, -3.2 to 2.7; P = 0.873). The 2-year results did not show any significant difference in mean central retinal thickness, with a decrease of -113 µm for bevacizumab and -122 µm for ranibizumab (95% CI of mean difference, -32 to 15; P = 0.476). There was a statistically significant difference between the drugs regarding the number of treatments given, with 18.2 injections for bevacizumab and 16.0 injections for ranibizumab (95% CI of mean difference, -3.4 to -1.0; P ≤ 0.001). The number of serious adverse events was similar between the groups over the course of the study. CONCLUSIONS: At 2 years, bevacizumab and ranibizumab had an equivalent effect on visual acuity and reduction of central retinal thickness when administered according to a treat-and-extend protocol for nAMD. There was no significant difference in the number of serious adverse events between the treatment groups.

Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol.

PURPOSE: To compare the efficacy and safety of bevacizumab versus ranibizumab when administered according to a treat-and-extend protocol for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, randomized, noninferiority trial with a noninferiority limit of 5 letters. PARTICIPANTS: Patients aged ≥ 50 years with previously untreated neovascular AMD in 1 eye and best-corrected visual acuity (BCVA) between 20/25 and 20/320. METHODS: Patients were randomly assigned to receive ranibizumab 0.5 mg or bevacizumab 1.25 mg intravitreal injections. Monthly injections were given until inactive disease was achieved. The patients were then followed with a gradual extension of treatment interval by 2 weeks at a time up to a maximum of 12 weeks. If signs of recurrent disease appeared, the treatment interval was shortened by 2 weeks at a time. MAIN OUTCOME MEASURES: Change in visual acuity at 1 year. RESULTS: Between March 2009 and July 2012, 441 patients were randomized at 10 ophthalmological centers in Norway. The 1-year visit was completed by 371 patients. In the per protocol analysis at 1 year, bevacizumab was equivalent to ranibizumab, with 7.9 and 8.2 mean letters gained, respectively (95% confidence interval [CI] of mean difference, -2.4 to 2.9; P = 0.845). The intention-to-treat analysis was concordant. There was no significant difference in measured central retinal thickness (CRT), with a mean decrease of -112 µm for bevacizumab and -120 µm for ranibizumab (95% CI of mean difference, -13 to 28; P = 0.460). There was a statistically significant difference (P = 0.001) between the drugs regarding the number of treatments: 8.9 for bevacizumab and 8.0 for ranibizumab. There were fewer arteriothrombotic events in the bevacizumab group (1.4%) than in the ranibizumab group (4.5%) (P = 0.050) and significantly more cardiac events in the ranibizumab group (P = 0.036). However, patients treated with ranibizumab more often had a history of myocardial infarction (P = 0.021). CONCLUSIONS: Bevacizumab and ranibizumab had equivalent effects on visual acuity at 1 year when administered according to a treat-and-extend protocol. The visual acuity results at 1 year were comparable to those of other clinical trials with monthly treatment. The numbers of serious adverse events were small.

The interaction of active substance use, depression, and antiretroviral adherence in methadone maintenance.

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) remains crucial in successfully treating HIV. While active substance use and depression are both associated with each other and with HAART nonadherence, little is known about their interaction. An understanding of the interaction of substance use and depressive symptoms on HAART adherence can inform adherence-enhancing interventions as well as interventions that target substance use and depression. PURPOSE: We tested an interaction between substance use and depression on HAART adherence among methadone maintenance patients. METHOD: We assessed substance use, depressive symptoms, and HAART adherence among 100 HIV-infected individuals receiving methadone maintenance in The Bronx, New York. Regressions were performed on adherence using an interaction term comprised of substance use and depressive symptoms. MODPROBE was used to assess significant interactions. RESULTS: Any use of illicit substances was associated with HAART nonadherence (p = 0.043). Cannabis was the single substance of abuse most strongly associated with nonadherence (p = 0.003). Depressive symptoms approached significance in bivariate analysis (p = 0.066). In regression analysis, a significant interaction was found between illicit substance use and depressive symptoms [OR (95% CI) 1.23 (1.06-1.44), p = 0.007], where illicit substance use was associated with nonadherence in individuals with lower depressive symptoms, but not among those with depressive symptoms at higher levels. No individual substances interacted with depressive symptoms on adherence. CONCLUSION: Though substance use and depressive symptoms interacted on HAART adherence, they did not have a synergistic effect. Continued substance use (51% of the sample) suggests an unmet need for treatment, even in methadone maintenance. Further examinations of the interplay of substance use and depression on HAART adherence are warranted.

Differential medication nonadherence and illness beliefs in co-morbid HIV and type 2 diabetes.

Increased antiretroviral availability has decreased mortality and increased rates of comorbid chronic illnesses, including type 2 diabetes, among people living with HIV. Little work has compared within-person adherence rates for HIV and comorbid conditions. Sixty-two adults with HIV and type 2 diabetes reported adherence rates, illness representations, beliefs about medications, symptoms, side-effects, and negative mood states. Adherence to antiretrovirals was better than diabetes medication (95 vs. 90 %, z = -2.05, p = 0.04). Participants reported better control over diabetes compared to HIV (t = 1.98, p = 0.05) while antiretrovirals were considered more necessary than diabetes medication (t = -2.79, p < 0.05). In adjusted analyses, antiretroviral nonadherence was associated with antiretroviral concerns (OR = 0.24, 95 % CI 0.08-0.67) and diabetes medication nonadherence with diabetes-related symptom burden (OR = 0.69, 95 % CI 0.53-0.89). Results indicate that medication nonadherence varies within individuals across comorbid illnesses and suggest this variation may depend on symptom attribution and medication concerns.

Pain Management in Older Adults Before and During the First Year of COVID-19 Pandemic: Prevalence, Trends, and Correlates.

BACKGROUND: There is limited knowledge on whether and how health care access restrictions imposed by the coronavirus disease of 2019 pandemic have affected utilization of both opioid and nonpharmacological treatments among US older adults living with chronic pain. METHODS: We compared prevalence of chronic pain and high impact chronic pain (ie, chronic pain limiting life or work activities on most days or every day in the past 6 months) between 2019 (pre-pandemic) and 2020 (first year of pandemic) and utilization of opioids and nonpharmacological pain treatments among adults aged ≥65 years enrolled in the National Health Interview Survey, a nationally representative sample of noninstitutionalized civilian U.S. adults. RESULTS: Of 12 027 survey participants aged ≥65 (representing 32.6 million noninstitutionalized older adults nationally), the prevalence of chronic pain was not significantly different from 2019 (30.8%; 95% confidence interval [CI], 29.7%-32.0%) to 2020 (32.1%; 95% CI, 31.0%-33.3%; p = .06). Among older adults with chronic pain, the prevalence of high impact chronic pain was also unchanged (38.3%; 95% CI, 36.1%-40.6% in 2019 versus 37.8%; 95% CI, 34.9%-40.8% in 2020; p = .79). Use of any nonpharmacological interventions for pain management decreased significantly from 61.2% (95 CI, 58.8%-63.5%) in 2019 to 42.1% (95% CI, 40.5%-43.8%) in 2020 (p < .001) among those with chronic pain, as did opioid use in the past 12 months from 20.2% (95% CI, 18.9%-21.6%) in 2019 to 17.9% (95% CI, 16.7%-19.1%) in 2020 (p = .006). Predictors of treatment utilization were similar in both chronic pain and high-impact chronic pain. CONCLUSION: Use of pain treatments among older adults with chronic pain declined in the first year of coronavirus disease of 2019 pandemic. Future research is needed to assess long-term effects of coronavirus disease of 2019 pandemic on pain management in older adults.

Comparison of antiretroviral adherence questions.

Our objective was to compare antiretroviral adherence questions to better understand concordance between measures. Among 53 methadone maintained HIV-infected drug users, we compared five measures, including two single item measures using qualitative Likert-type responses, one measure of percent adherence, one visual analog scale, and one multi-item measure that averaged responses across antiretrovirals. Responses were termed inconsistent if respondents endorsed the highest adherence level on at least one measure but middle levels on others. We examined ceiling effects, concordance, and correlations with VL. Response distributions differed markedly between measures. A ceiling effect was less pronounced for the single-item measures than for the measure that averaged responses for each antiretroviral: the proportion with 100% adherence varied from 22% (single item measure) to 58% (multi-item measure). Overall agreement between measures ranged from fair to good; 49% of participants had inconsistent responses. Though responses correlated with VL, single-item measures had higher correlations. Future studies should compare single-item questions to objective measures.

Impact of adherence counseling dose on antiretroviral adherence and HIV viral load among HIV-infected methadone maintained drug users.

Adherence counseling can improve antiretroviral adherence and related health outcomes in HIV-infected individuals. However, little is known about how much counseling is necessary to achieve clinically significant effects. We investigated antiretroviral adherence and HIV viral load relative to the number of hours of adherence counseling received by 60 HIV-infected drug users participating in a trial of directly observed antiretroviral therapy delivered in methadone clinics. Our adherence counseling intervention combined motivational interviewing and cognitive-behavioral counseling, was designed to include six 30 minute individual counseling sessions with unlimited "booster" sessions, and was offered to all participants in the parent trial. We found that, among those who participated in adherence counseling, dose of counseling had a significant positive relationship with antiretroviral adherence measured after the conclusion of counseling. Specifically, a liner mixed-effects model revealed that each additional hour of counseling was significantly associated with a 20% increase in post-counseling adherence. However, the number of cumulative adherence counseling hours was not significantly associated with HIV viral load, also measured after the conclusion of counseling. Our findings suggest that more intensive adherence counseling interventions may have a greater impact on antiretroviral adherence than less intensive interventions; however, it remains unknown how much counseling is required to impact HIV viral load.

Assessment of Hypothetical Out-of-Pocket Costs of Guideline-Recommended Medications for the Treatment of Older Adults With Multiple Chronic Conditions, 2009 and 2019.

IMPORTANCE: Most adults 65 years or older have multiple chronic conditions. Managing these conditions with prescription drugs can be costly, particularly for older adults with limited incomes. OBJECTIVE: To estimate hypothetical out-of-pocket costs associated with guideline-recommended outpatient medications for the initial treatment of 8 common chronic diseases among older adults with Medicare prescription drug plans (PDPs). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study used 2009 and 2019 Medicare prescription drug plan formulary files to estimate annual out-of-pocket costs among hypothetical patients enrolled in Medicare Advantage or stand-alone Medicare Part D plans. A total of 3599 PDPs in 2009 and 3618 PDPs in 2019 were included after inclusion and exclusion criteria were applied. Costs associated with guideline-recommended medications for 8 of the most common chronic diseases (atrial fibrillation, chronic obstructive pulmonary disease [COPD], heart failure with reduced ejection fraction, hypercholesterolemia, hypertension, osteoarthritis, osteoporosis, and type 2 diabetes), alone and in 2 clusters of commonly comorbid conditions, were examined. MAIN OUTCOMES AND MEASURES: Annual out-of-pocket costs for each chronic condition, inflation adjusted to 2019 dollars. RESULTS: Among 3599 Medicare PDPs in 2009, 1998 were Medicare Advantage plans and 1601 were stand-alone plans; among 3618 Medicare PDPs in 2019, 2719 were Medicare Advantage plans and 899 were stand-alone plans. For an older adult enrolled in any Medicare PDP in 2019, the median annual out-of-pocket costs for individual conditions varied, from a minimum of $32 (IQR, $6-$48) for guideline-recommended management of osteoporosis (a decrease from $128 [IQR, $102-$183] in 2009) to a maximum of $1579 (IQR, $1524-$2229) for guideline-recommended management of atrial fibrillation (an increase from $91 [IQR, $73-$124] in 2009). For an older adult with a cluster of 5 commonly comorbid conditions (COPD, hypertension, osteoarthritis, osteoporosis, and type 2 diabetes) enrolled in any PDP, the median out-of-pocket cost in 2019 was $1999 (IQR, $1630-$2564), a 12% decrease from $2284 (IQR, $1920-$3107) in 2009. For an older adult with all 8 chronic conditions (atrial fibrillation, COPD, diabetes, hypercholesterolemia, heart failure, hypertension, osteoarthritis, and osteoporosis) enrolled in any PDP, the median out-of-pocket cost in 2019 was $3630 (IQR, $3234-$5197), a 41% increase from $2571 (IQR, $2185-$3719) in 2009. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, out-of-pocket costs for guideline-recommended outpatient medications for the initial treatment of 8 common chronic diseases varied by condition. Although costs generally decreased between 2009 and 2019, particularly with regard to conditions for which generic drugs were available, out-of-pocket costs remained high and may have presented a substantial financial burden for Medicare beneficiaries, especially older adults with conditions for which brand-name drugs were guideline recommended.

Lack of sustained improvement in adherence or viral load following a directly observed antiretroviral therapy intervention.

BACKGROUND: Methadone clinic-based directly observed antiretroviral therapy (DOT) has been shown to be more efficacious for improving adherence and suppressing human immunodeficiency virus (HIV) load than antiretroviral self-administration. We sought to determine whether the beneficial effects of DOT remain after DOT is discontinued. METHODS: We conducted a post-trial cohort study of 65 HIV-infected opioid-dependent adults who had completed a 24-week randomized controlled trial of methadone clinic-based DOT versus treatment as usual (TAU). For 12 months after DOT discontinuation, we assessed antiretroviral adherence using monthly pill counts and electronic monitors. We also assessed viral load at 3, 6, and 12 months after DOT ended. We examined differences between DOT and TAU in (1) adherence, (2) viral load, and (3) proportion of participants with viral load of <75 copies/mL. RESULTS: At trial end, adherence was higher among DOT participants than among TAU participants (86% and 54%, respectively; P < .001), and more DOT participants than TAU participants had viral loads of <75 copies/mL (71% and 44%, respectively; P = .03). However, after DOT ended, differences in adherence diminished by 1 month (55% for DOT vs 48% for TAU; P = .33) and extinguished completely by 3 months (49% for DOT vs 50% for TAU; P = .94). Differences in viral load between DOT and TAU disappeared by 3 months after the intervention, and the proportion of DOT participants with undetectable viral load decreased steadily after DOT was stopped until there was no difference (36% for DOT and 34% for TAU; P = .92). CONCLUSIONS: Because the benefits of DOT for adherence and viral load among HIV-infected methadone patients cease after DOT is stopped, methadone-based DOT should be considered a long-term intervention.

Rationale and design of a randomized controlled trial of directly observed hepatitis C treatment delivered in methadone clinics.

BACKGROUND: Most methadone-maintained injection drug users (IDUs) have been infected with hepatitis C virus (HCV), but few initiate HCV treatment. Physicians may be reluctant to treat HCV in IDUs because of concerns about treatment adherence, psychiatric comorbidity, or ongoing drug use. Optimal HCV management approaches for IDUs remain unknown. We are conducting a randomized controlled trial in a network of nine methadone clinics with onsite HCV care to determine whether modified directly observed therapy (mDOT), compared to treatment as usual (TAU), improves adherence and virologic outcomes among opioid users. METHODS/DESIGN: We plan to enroll 80 HCV-infected adults initiating care with pegylated interferon alfa-2a (IFN) plus ribavirin, and randomize them to mDOT (directly observed daily ribavirin plus provider-administered weekly IFN) or TAU (self-administered ribavirin plus provider-administered weekly IFN). Our outcome measures are: 1) self-reported and pill count adherence, and 2) end of treatment response (ETR) or sustained viral response (SVR). We will use mixed effects linear models to assess differences in pill count adherence between treatment arms (mDOT v. TAU), and we will assess differences between treatment arms in the proportion of subjects with ETR or SVR with chi square tests. Of the first 40 subjects enrolled: 21 have been randomized to mDOT and 19 to TAU. To date, the sample is 77% Latino, 60% HCV genotype-1, 38% active drug users, and 27% HIV-infected. Our overall retention rate at 24 weeks is 92%, 93% in the mDOT arm and 92% in the TAU arm. DISCUSSION: This paper describes the design and rationale of a randomized clinical trial comparing modified directly observed HCV therapy delivered in a methadone program to on-site treatment as usual. Our trial will allow rigorous evaluation of the efficacy of directly observed HCV therapy (both pegylated interferon and ribavirin) for improving adherence and clinical outcomes. This detailed description of trial methodology can serve as a template for the development of future DOT programs, and can also guide protocols for studies among HCV-infected drug users receiving methadone for opiate dependence.

Strategies to improve access to and utilization of health care services and adherence to antiretroviral therapy among HIV-infected drug users.

We review five innovative strategies to improve access, utilization, and adherence for HIV-infected drug users and suggest areas that need further attention. In addition, we highlight two innovative programs. The first increases access and utilization through integrated HIV and opioid addiction treatment with buprenorphine in a community health center, and the second incorporates adherence counseling for antiretroviral therapy in methadone programs. Preliminary evaluations demonstrated that these strategies may improve both HIV and opioid addiction outcomes and may be appropriate for wider dissemination. Further refinement and expansion of strategies to improve outcomes of HIV-infected drug users is warranted.

Providers' experiences treating chronic pain among opioid-dependent drug users.

BACKGROUND: Successful management of chronic pain with opioid medications requires balancing opioid dependence and addiction with pain relief and restoration of function. Evaluating these risks and benefits is difficult among patients with chronic pain and pre-existing addiction, and the ambiguity is increased for patients on methadone maintenance therapy for opioid dependence. Providers treating both chronic pain and addiction routinely make diagnostic and therapeutic decisions, but decision-making strategies in this context have not been well described. OBJECTIVE: Our objective was twofold. We sought first to explore providers' perceptions of ambiguity, and then to examine their strategies for making diagnostic and treatment decisions to manage chronic pain among patients on methadone maintenance therapy. DESIGN: Qualitative semi-structured interviews. SETTING AND PARTICIPANTS: We interviewed health-care providers delivering integrated medical care and substance abuse treatment to patients in a methadone maintenance program. RESULTS: Providers treating pain and co-morbid addiction described ambiguity in all diagnostic and therapeutic decisions. To cope with this inherent ambiguity, most providers adopted one of two decision-making frameworks, which determined clinical behavior. One framework prioritized addiction treatment by emphasizing the destructive consequences of abusing illicit drugs or prescription medications; the other prioritized pain management by focusing on the destructive consequences of untreated pain. Identification with a decision-making framework shaped providers' experiences, including their treatment goals, perceptions of treatment risks, pain management strategies, and tolerance of ambiguity. Adherence to one of these two frameworks led to wide variation in pain management practices, which created tension among providers. CONCLUSIONS: Providers delivering integrated medical care and substance abuse treatment to patients in a methadone maintenance program found tremendous ambiguity in the management of chronic pain. Most providers adopted one of the two divergent heuristic frameworks we identified, which resulted in significant variations in pain management. To reduce variation and determine best practices, studies should examine clinically relevant endpoints, including pain, illicit drug use, prescription drug abuse, and functional status. Until then, providers managing chronic pain in patients with co-morbid addiction should attempt to reduce tension by acknowledging ambiguity and engaging in open discourse.

Improving the self-report of HIV antiretroviral medication adherence: is the glass half full or half empty?

Self-reports are the most widely used method for measuring antiretroviral adherence. The association between self-reports and viral loads has been repeatedly demonstrated, but this association does not address how well self-reports measure actual medication-taking behaviors. Understanding adherence self-reports requires studying the science of memory and the reporting of behaviors. In the first section of this review, we discuss research in cognitive psychology that pertains to adherence self-reports, focusing primarily on studies that examine cognitive processes respondents use to answer survey questions. In the second section, we review recent articles examining the relationship between self-reports and objective measures of adherence, highlighting the strength of associations and key methodologic issues. We conclude with key questions for future research and methodologic recommendations.

Self-efficacy and depression as mediators of the relationship between pain and antiretroviral adherence.

The goals of this study were to examine the association between pain and antiretroviral adherence and to estimate the mediating effect of adherence self-efficacy and depression symptom severity. Surveys using audio computer-assisted self-interview were conducted among 70 HIV-infected current and former drug users enrolled in a methadone program. We assessed antiretroviral adherence and adherence self-efficacy using questions from the Adult Clinical Trials Group survey. We considered participants adherent if they reported taking at least 95% of prescribed antiretrovirals over the past seven days. We assessed depression symptom severity using the depression subscale of the Brief Symptom Inventory. Participants reported pain of any duration in response to a question from the Brief Pain Inventory. Participants reporting pain were 87% less likely to be classified as adherent compared to those without pain (Unadjusted OR = 0.13, 95%CI: 0.03-0.52). When we examined adherence self-efficacy as a mediator of the relationship between pain and adherence, criteria for partial mediation were met. Adjusting for self-efficacy, the beta coefficient for pain decreased by 23% but the independent relationship between pain and antiretroviral adherence was maintained. Mediation criteria were not met when we examined the mediating effect of depression symptom severity on the relationship between pain and adherence. Adjusting for depression symptom severity, the beta coefficient for pain decreased by 9% and the relationship between pain and antiretroviral adherence remained significant. Our results indicate that neither adherence self-efficacy nor depression symptom severity fully mediated the relationship between pain and adherence. HIV providers should recognize the potential impact of pain on antiretroviral adherence among current and former drug users.

Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults.

OBJECTIVES: To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older. DESIGN: Systematic review and meta-analysis. SETTING: Specialist or generalist outpatient setting, rehabilitation facility, and nursing facilities. PARTICIPANTS: Persons 65 years and older with MDD. INTERVENTION: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine compared with another antidepressant, placebo, or nonpharmacologic therapy. MEASUREMENTS: Adverse events, arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, QTc prolongation, serious adverse events, and withdrawals due to adverse events. RESULTS: Nineteen randomized controlled trials and two observational studies were included. Most studies evaluated treatment of the acute phase (<12 wk) of MDD of moderate severity. SSRIs led to a statistically similar frequency of overall adverse events vs placebo (moderate strength of evidence [SOE]), but SNRIs caused more overall adverse events vs placebo (high SOE) during the acute treatment phase. Both SSRIs and SNRIs led to more study withdrawals due to adverse events vs placebo (SSRIs low SOE; SNRIs moderate SOE). Duloxetine led to a more falls vs placebo (moderate SOE) during 24 weeks of acute and continuation treatment of MDD. CONCLUSION: In patients 65 years of age or older with MDD, treatment of the acute phase of MDD with SNRIs, but not SSRIs, was associated with a statistically greater number of overall adverse events vs placebo. SSRIs and SNRIs led to a greater number of study withdrawals due to adverse events vs placebo. Duloxetine increased the risk of falls that as an outcome was underreported in the literature. Few studies examined head-to-head comparisons, most trials were not powered to evaluate adverse events, and results of observational studies may be confounded. Comparative long-term studies reporting specific adverse events are needed to inform clinical decision making regarding choice of antidepressants in this population. J Am Geriatr Soc 67:1571-1581, 2019.