There is significant association between obesity and depression. Naltrexone/Bupropion (NB) is indicated for treatment of overweight and obesity (BMI ≥27 kg/m2 with a comorbidity or ≥30 kg/m2). This post-hoc analysis examines safety and efficacy of NB and placebo among individuals with overweight or obesity who were also taking antidepressant therapy during the LIGHT trial (N=8910). Subjects were divided into four subgroups: NB + antidepressants (n=1150), NB without antidepressants (n=3300), placebo + antidepressants (n=1127) and placebo without antidepressants (n=3317). Among subjects taking NB, the combined incidence of serious adverse events (AEs) and AEs leading to treatment discontinuation was not significantly different between those on antidepressants and those who were not. The key weight-loss efficacy analyses were performed on NB or placebo-treated subjects who remained on study therapy through 104 weeks and who did or did not have documented antidepressant use at each of the baseline, week 52 and week 104 visits (Completers: N=1811; 47.0% female, 86.9% white, mean age of 61 years, mean baseline BMI 37.4 kg/m2). The mean adjusted weight change in subjects taking antidepressants was numerically, but not significantly greater for NB vs. placebo (-6.3% vs. -4.3%). For those subjects not on antidepressants, weight loss was significantly greater for NB vs. PL (-6.8% vs. -3.6%). NB is generally well tolerated in patients with overweight or obesity who are on antidepressants and is effective in promoting weight loss regardless of antidepressant use. These results show that for patients on antidepressant therapy, NB may be an effective option for obesity management.
INTRODUCTION: The British Columbia Ministry of Health launched a Smoking Cessation Program on September 30, 2011, providing financial coverage for smoking cessation pharmacotherapies. Although pharmacotherapies have been shown to have a moderate short-term benefit as a quitting aid, substantial cardiovascular and neuropsychiatric safety concerns have been identified in adverse-reporting databases, leading to prescription label warnings by Health Canada and the U.S. Food and Drug Administration. However, recent studies indicate these warnings may be without merit. This study examined the comparative safety of medications commonly used to aid smoking cessation.
AIMS AND METHODS: Population-based retrospective cohort study using B.C. administrative data to assess the relative safety between varenicline, bupropion, and nicotine replacement therapies (NRTs). The primary outcome was a composite of cardiovascular hospitalizations. Secondary outcomes included mortality, a composite of neuropsychiatric hospitalizations, and individual components of the primary outcome. Statistical analysis used propensity score-adjusted log-binomial regression models. A sensitivity analysis excluded patients with a history of cardiovascular disease.
RESULTS: The study included 116 442 participants. Compared with NRT, varenicline was associated with a 10% 1-year relative risk decrease of cardiovascular hospitalization (adjusted risk ratio [RR] = 0.90, 95% confidence interval (CI): 0.82 to 1.00), a 20% 1-year relative risk decrease of neuropsychiatric hospitalization (RR: 0.80, CI: 0.7 to 0.89), and a 19% 1-year relative risk decrease of mortality (RR: 0.81, CI: 0.71 to 0.93). We found no significant association between NRT and bupropion for cardiovascular hospitalizations, neuropsychiatric hospitalizations, or mortality.
CONCLUSIONS: Compared with NRT, varenicline is associated with fewer serious adverse events and bupropion the same number of serious adverse events.
IMPLICATIONS: This study addresses the need for comparative safety evidence in a real-world setting of varenicline and bupropion against an active comparator. Compared with NRT, varenicline was associated with a decreased risk of mortality, serious cardiovascular events, and neuropsychiatric events during the treatment, or shortly after the treatment, in the general population of adults seeking pharmacotherapy to aid smoking cessation. These results provide support for the removal of the varenicline boxed warning for neuropsychiatric events and add substantively to the cardiovascular safety findings of previous observational studies and randomized clinical trials.
BACKGROUND: Extended-release naltrexone/bupropion (NB) is indicated for chronic weight management. Incretin agents are recommended for patients with type 2 diabetes. This analysis looked at the add-on of NB to incretins to see if weight loss could occur in patients already stabilized on incretin agents.
METHODS: This was a post-hoc analysis of NB vs. placebo (PL) among subjects with type 2 diabetes stable on an incretin agent prior to randomization in a double-blind, PL-controlled cardiovascular outcome trial (N = 1317).
RESULTS: Over 1 year, mean weight loss was significantly greater among NB patients vs. PL among those taking DPP-4i (mean absolute difference 4.6% [p < 0.0001]) and those taking GLP-1RAs (mean absolute difference 5.2%, p < 0.0001). Proportions of subjects achieving 5% weight loss were significantly greater for NB vs. PL at weeks 26 and 52 among those taking DPP-4is or GLP-1RAs. There were no significant differences in effectiveness observed between NB + DPP-4i and NB + GLP-1RA or between PL + DPP-4i and PL + GLP-1RA in any of the analyses. Serious adverse events were reported by 9.1% and 11.1% for PL + DPP-4i and PL + GLP-1RA, respectively, and 13.3% and 12.4% of NB + DPP-4i and NB + GLP-1RA, respectively.
CONCLUSION: NB appears to be effective in reducing weight in patients with T2DM and obesity/overweight who are taking DPP-4ihibitors or GLP-1RA. The SAE rates in all arms of this analysis were lower than have been reported in other cardiovascular outcome trials in type 2 diabetes.
OBJECTIVE: To investigate the impact of antidepressants (ATDs) on the risk of myocardial infarction (MI) among patients with diabetes mellitus (DM).
METHODS: This was a retrospective population-based cohort study that used data obtained from the National Health Insurance Research Database in Taiwan. The study cohort included diabetic patients who were older than 50 years from 1997 to 2010. We then randomly assigned individuals to the matched cohort at a 1:1 ratio according to their demographic data. Both study and matched cohorts were followed up to compare the risk of MI between patients with and without ATD use from 2000 until the end of 2013. Multivariate Cox proportional hazards models were used to evaluate the relationship between ATD treatment and the occurrence of MI.
RESULTS: After adjustment for confounders, patients with ATD use of more than 180 days had a lower risk of MI than those without ATD use in the matched cohort (adjusted hazard ratio [HR] = 0.68, 95% confidence interval [CI], 0.66-0.71). The adjusted HRs of MI were 0.77 (95% CI, 0.73-0.81) and 0.56 (95% CI, 052.-0.60) in patients with DM and ATD use of 180 > cDDD ≥ 28 and cDDD ≥ 180, respectively. When the duration of ATD treatment was 180 days or longer, MI risk was significantly reduced (after adjustment) for all classes of ATD except bupropion.
CONCLUSIONS: Most ATDs, but not bupropion, were associated with significantly reduced risk of MI among the DM population.
BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.
METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.
RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.
CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).
BACKGROUND: Few published research studies have examined the effectiveness of extended-release naltrexone (XR-NTX) for the treatment of opioid use disorder (OUD) among adolescents and young adults.
METHODS: This two-group randomized controlled trial recruited 288 youth, ages 15-21, with moderate/severe OUD from a residential addiction treatment program in Baltimore, Maryland. The study randomized the youth within the first week of treatment entry to receive either XR-NTX or treatment-as-usual (TAU; either buprenorphine maintenance treatment or treatment without OUD medication following medically managed withdrawal) prior to discharge, with continued treatment in the community for 6 months. However, due to various reasons spanning patients' and caregivers' preferences and constraints, considerable participant nonadherence to randomized condition occurred (i.e., only 30% of the participants randomized to XR-NTX received an initial injection, while 27% of participants randomized to TAU received an XR-NTX injection at treatment discharge, instead of their assigned treatment). The study used generalized linear mixed modeling (GLiMM) to examine self-reported 90-day opioid, cocaine, marijuana, and alcohol use as well as DSM-5 OUD criteria on "intention-to-treat" (as randomized), "as-received" (XR-NTX vs. not XR-NTX), and "as-medicated" (XR-NTX vs. buprenorphine vs. no medication) bases.
RESULTS: The condition x time interactions in the intention-to-treat analyses failed to reach significance for past-90-day self-reported use of illicit opioids, cocaine, marijuana, or alcohol, or in meeting DSM-5 OUD criteria at 3 or 6 months [all ps > 0.05]. However, these findings are of limited interpretive value due to participant nonadherence to their randomized condition. When the study analyzed results by the treatment received at discharge, the "as-received" group x time interaction for illicit opioid use was significant [p = .003], with the XR-NTX group reporting less opioid use in the past 90 days at 3 and 6 months. Participants who received their first XR-NTX dose at inpatient discharge (n = 82) received, on average, 1.3 subsequent injections in the community over the 6-month study follow-up period. Only 2 of the 82 study participants received XR-NTX continuously through the 6-month postdischarge follow-up period. Twelve serious adverse events (SAEs) occurred during the study, but the study determined that only 1 was possibly study related (hepatitis C/elevated liver function test results).
CONCLUSION: None of the condition x time interactions in the intention-to-treat analyses reached significance. Participants' nonadherence may have contributed to the failure to reject the null hypothesis. Irrespective of randomized condition, participants who received XR-NTX for OUD demonstrated low retention in treatment, receiving an average of only 1.3 subsequent injections, yet reported less opioid use at follow-up than participants who did not received XR-NTX. Treatment programs should consider XR-NTX as a treatment option for youth motivated to receive it. Future research should focus on building developmentally informed strategies to improve uptake of and adherence to relapse prevention medication in this population.
IMPORTANCE: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed.
OBJECTIVE: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type.
DESIGN, SETTING, AND PARTICIPANTS: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019.
INTERVENTIONS: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study.
MAIN OUTCOMES AND MEASURES: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks.
RESULTS: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups.
CONCLUSIONS AND RELEVANCE: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood.
TRIAL REGISTRATION: EU Clinical Trials Register Identifier: 2007-005352-17.
Withdrawal syndrome is one of the initial focuses of opioid detoxification. Very low dose naltrexone (VLNTX) has been found to reduce opioid tolerance and dependence in animal and human clinical studies. The aim of this study was to determine the safety and efficacy of VLNTX during early stages of detoxification. In a multi-arm parallel, double-blind, randomized controlled trial, 63 opioid-dependent male participants referring to Imam Reza Rehabilitation Center were allocated to three equal groups using block randomization method. They received 0.125 mg, 0.250 mg of VLNTX or placebo daily for 10 days, together with the routine clonidine-based protocol. Self-reported and observer ratings of withdrawal severity and adverse events were measured on the 1st, 4th and 10th day of treatment. Runny eyes (p = 0.006), anxiety (p = 0.031) and dehydration (p = 0.014) were reduced during the whole 10 days in the 0.125 mg VLNTX-treated group compared to placebo. Only drowsiness (p = 0.043) and dysphoric mood (p < 0.001) were reduced in the 0.250 mg VLNTX-treated group. Results of 1st, 4th, and 10th-day assessment showed that most symptoms reductions were for the 0.125 mg VLNTX and the placebo group in the 1st and 4th days, respectively. On the 10th day, there was not any significant difference between 0.250 mg VLNTX-treated group and placebo group. No adverse effect was observed. In the starting days of detoxification, VLNTX can reduce the withdrawal symptoms, but the efficacy declined by passing time. Further studies are needed to test the utility of this new therapeutic approach.
PURPOSE: Little information is available on the performance of high-dimensional propensity scores (HDPS) in settings with more than two exposure levels. Our objective was to adapt the HDPS algorithm to allow for the inclusion of multilevel treatments and compare estimates obtained via this approach with those obtained via pairwise comparisons in a case study using real-world data.
METHODS: We conducted a retrospective cohort study of cardiovascular events associated with three smoking cessation drugs (varenicline, bupropion, nicotine replacement therapy [NRT]) using the Clinical Practice Research Datalink. We applied the binary HDPS algorithm adjusted for pre-specified and empirically-selected covariates to cohorts formed by each treatment pair. We then constructed multinomial HDPS models on a cohort of new users of any of the three drugs, adjusting for predefined covariates and different combinations of empirically-selected covariates. After trimming the area of non-overlap of the HDPS distributions, the effects of the study drugs on cardiovascular events were estimated with the Cox proportional hazards models adjusted for propensity score category.
RESULTS: Outcome models adjusted for multinomial HDPS estimated treatment effects that were slightly more protective than those estimated in pairwise comparisons (varenicline vs NRT: HRMultinomial = 0.60-0.62, HRPairwise = 0.64; bupropion vs NRT: HRMultinomial = 0.70-0.72, HRPairwise = 0.76). Trimming rates were similar between the two approaches.
CONCLUSIONS: The extension of HDPS to multilevel exposures is a valid and practical approach to confounder control that may be useful when comparing different classes of drugs prescribed for the same indication or different molecules within a given drug class.
BACKGROUND AND OBJECTIVES: Cancer-related fatigue (CRF) is one of the most prevalent complications experienced by cancer patients during and after the process of treatment. Despite conducting a lot of studies, there is no approved therapy to help manage CRF. This study aims to investigate the efficacy of bupropion on CRF.
MATERIALS AND METHODS: In this double-blind randomized placebo-controlled clinical trial, a total of 30 eligible cancer patients suffering from fatigue were randomly divided into two groups (15 patients in each group). Bupropion was administered 75 mg/day for the first three days and 150 mg/day (divided in two doses) till the end of the study at week 6. Fatigue as the primary outcome was measured by BFI (Brief Fatigue Inventory) and FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy) scales. Secondary outcomes included HADS (Hospital Anxiety and Depression Scale) and performance status (PS) measured by Karnofsky and ECOG (Eastern Cooperative Oncology Group) scales. Assessments were done at baseline, end of the second and sixth week.
RESULTS: There was no significant difference between placebo and bupropion at baseline and the end of second week. Significant difference was seen between two groups at the end of week six (P = 0.006 based on BFI) in favor of bupropion. In-group assessment showed improvement in fatigue levels in both groups during study time (P = 0.000 based on BFI for both bupropion and placebo). Secondary outcomes (e.g., HADS and PS) were not different at baseline and the end of second week. However, at the end of week six, the difference was significant in favor of bupropion.
CONCLUSION: A six-week trial of bupropion reduces the CRF and improves the PS of cancer patients.
TRIAL REGISTRATION: Current Controlled Trials IRCT20090613002027N12, registration date: 2018-06-01.
There is significant association between obesity and depression. Naltrexone/Bupropion (NB) is indicated for treatment of overweight and obesity (BMI ≥27 kg/m2 with a comorbidity or ≥30 kg/m2). This post-hoc analysis examines safety and efficacy of NB and placebo among individuals with overweight or obesity who were also taking antidepressant therapy during the LIGHT trial (N=8910). Subjects were divided into four subgroups: NB + antidepressants (n=1150), NB without antidepressants (n=3300), placebo + antidepressants (n=1127) and placebo without antidepressants (n=3317). Among subjects taking NB, the combined incidence of serious adverse events (AEs) and AEs leading to treatment discontinuation was not significantly different between those on antidepressants and those who were not. The key weight-loss efficacy analyses were performed on NB or placebo-treated subjects who remained on study therapy through 104 weeks and who did or did not have documented antidepressant use at each of the baseline, week 52 and week 104 visits (Completers: N=1811; 47.0% female, 86.9% white, mean age of 61 years, mean baseline BMI 37.4 kg/m2). The mean adjusted weight change in subjects taking antidepressants was numerically, but not significantly greater for NB vs. placebo (-6.3% vs. -4.3%). For those subjects not on antidepressants, weight loss was significantly greater for NB vs. PL (-6.8% vs. -3.6%). NB is generally well tolerated in patients with overweight or obesity who are on antidepressants and is effective in promoting weight loss regardless of antidepressant use. These results show that for patients on antidepressant therapy, NB may be an effective option for obesity management.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
