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In a randomized trial involving participants with methamphetamine use disorder, the response among those who received bupropion and naltrexone was 11 percentage points higher than that among participants who received placebo. Adverse events included gastrointestinal disorders.

Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9–12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline–placebo and bupropion–placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were −1·28 (95% CI −2·40 to −0·15) and −0·08 (−1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were −1·07 (−2·21 to 0·08) and 0·13 (−1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline–placebo and bupropion–placebo RDs were 1·59 (95% CI −0·42 to 3·59) and 1·78 (−0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (−0·81 to 3·25) and 1·42 (−0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. Pfizer and GlaxoSmithKline.

In a pragmatic trial involving older persons with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole was better than augmentation with bupropion or a switch to bupropion.

Although clinicians frequently add a second medication to an ineffective antidepressant, randomized trials comparing augmentation medications are lacking. In this study, adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to sustained-release bupropion or buspirone and had similar remission rates on the basis of clinician and self-reports. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to bupropion or buspirone and had similar remission rates. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Numerous studies, 1 – 7 including one by Rush et al. 8 reported elsewhere in this issue of the Journal, have shown that major depressive disorder often requires more than one step of treatment to elicit a remission of symptoms. Frequently, a second medication is added to augment the first. 4 , 6 Augmentations of an initial selective serotonin-reuptake inhibitor (SSRI) with sustained-release bupropion, buspirone, mirtazapine, or dopamine agonists (e.g., pramipexole, dextroamphetamine, and methylphenidate) have been evaluated largely in open case series conducted in symptomatic volunteers with few psychiatric or general medical coexisting illnesses. 9 No randomized, controlled, prospective trials have directly compared two or more . . .

BackgroundExtended-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.MethodsThis 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).ResultsOver 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.ConclusionNB 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.

The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons 1 – 3 . It is a pharmacological target for various antidepressants and analgesic drugs 4 , 5 . Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlA EM ), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na + and Cl − undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlA EM provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design. Cryo-electron microscopy structures of the noradrenaline transporter (NET) reveal binding modes of adrenaline, coordination of sodium and chloride ion binding and the binding sites and mechanisms of inhibition by conotoxin, bupropion and ziprasidone.

Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types 1 . Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane 2 . Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants. The cryo-electron microscopy structures of the human noradrenaline transporter in both the apo state and bound to substrates or antidepressant drugs are resolved.

Adult outpatients with a nonpsychotic major depressive disorder received sustained-release bupropion, sertraline, or extended-release venlafaxine after a lack of response to or an inability to tolerate the selective serotonin-reuptake inhibitor (SSRI) citalopram. Approximately one in four patients had a remission of symptoms after switching to another antidepressant. All these medications provided a reasonable second-step choice for depressed outpatients who did not have a remission with or could not tolerate the SSRI. Adult outpatients with a nonpsychotic major depressive disorder received bupropion, sertraline, or venlafaxine after a lack of response to or an inability to tolerate citalopram. Approximately one in four patients had a remission of symptoms after switching to another antidepressant. Major depressive disorder is associated with substantial morbidity, mortality, family burden, and health care costs. 1 Since no single treatment is uniformly effective, 2 – 4 subsequent interventions are often needed. Second-step treatments include augmenting the first agent with a second or discontinuing the first agent and beginning a second (switching). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial used an equipoise, stratified, randomized design to evaluate the relative efficacy and tolerability of various antidepressant treatments for outpatients with nonpsychotic major depressive disorder who had a lack of remission or could not tolerate the selective serotonin-reuptake inhibitor (SSRI) citalopram (Celexa, Forest Pharmaceuticals) . . .

To report the first and largest systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression (TRD) or major depressive disorder(MDD). We conducted a systematic literature retrieval via PubMed, Embase, Web of Science, and Cochrane until April 2023 for RCT, which evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching for patients with TRD or MDD. Outcomes measured were changes in the Montgomery-Asberg Depression Rating Scale (MADRS), response and remission rate, and serious adverse events. Five RCTs, including 4480 patients, were included for meta-analysis. Among them, two RCTs were rated as \"high risk\" in three aspects (allocation concealment, blinding of participants and personnel and blinding of outcome assessment) because of the non-blind method, and the quality evaluation of the remaining works of literature was \"low risk\". Augmentation treatment with Aripiprazole (A-ARI) was associated with a significant higher response rate compared with augmentation treatment with bupropion (A-BUP) (RR: 1.15; 95% CI: 1.05, 1.25; P = 0.0007; I2 = 23%). Besides, A-ARI had a significant higher remission rate compared with switching to bupropion (S-BUP) (RR: 1.22; 95% CI: 1.00, 1.49; P = 0.05; I2 = 59%) and A-BUP had a significant higher remission rate compared with S-BUP (RR: 1.20; 95% CI: 1.06, 1.36; P = 0.0004; I2 = 0%). In addition, there was no significant difference in remission rate(RR: 1.05; 95% CI: 0.94, 1.17; P = 0.42; I2 = 33%), improvement of MADRS(WMD: -2.07; 95% CI: -5.84, 1.70; P = 0.28; I2 = 70%) between A-ARI and A-BUP. No significant difference was observed in adverse events and serious adverse events among the three treatment strategies. A-ARI may be a better comprehensive antidepressant treatment strategy than A-BUP or S-BUP for patients with TRD or MDD. More large-scale, multi-center, double-blind RCTs are needed to further evaluated the efficacy and safety of aripiprazole or bupropion augmentation and switching treatment strategies.

Aim To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity. Methods Thirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity. Results The volunteers carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/ AUC_bup than those CYP2B6*1/*6 and CYP2B6*6/*6 variants (15.66 ± 1.65 vs. 9.25 ± 1.92, P  = 0.008 and 15.66 ± 1.65 vs. 8.21 ± 1.74, P  = 0.006, respectively). POR rs2868177 (6593 A > G) AA homozygotes showed a significantly lower mean AUC_hyd/ AUC_bup than that of POR rs2868177 AG heterozygotes or GG homozygotes (8.13 ± 1.37 vs. 12.15 ± 2.97, P  = 0.005 and 8.13 ± 1.37 vs. 17.59 ± 3.25, P  = 0.001, respectively). Moreover, POR rs2868177 AG heterozygotes and GG homozygotes showed a significantly increased mean AUC_hyd/AUC_bup than AA homozygotes in the CYP2B6*1/*1 and CYP2B6*6 carriers (16.40 ± 2.01 vs. 12.40 ± 1.45, P  = 0.006 and 10.65 ± 1.47 vs. 6.54 ± 1.25, P  = 0.004, respectively). Meanwhile, a strong correlation between the genetic variations ( POR rs2868177 and CYP2B6*6 ) and AUC_hyd/ AUC_bup was found ( P  = 0.009 and P  = 0.001, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR *28 genotypes ( P  > 0.05) . Conclusion POR rs2868177 and CYP2B6*6 variants contribute to the interindividual variability in human CYP2B6 activity, which may affect the disposition and interaction of other CYP2B6 substrate drugs.