Targeting self-care adherence for glycaemic control in multimorbid type 2 diabetes mellitus with depression using bupropion: a protocol for cross-over randomised controlled trial.

INTRODUCTION: Diabetes and depression are among the 10 biggest health burdens globally. They often coexist and exhibit a strong bidirectional relationship. Depression leads to decreased adherence to self-care activities. This impacts glycaemic control and worsens type 2 diabetes mellitus (T2D). Both conditions have a synergistic effect and lead to greater complications, hospitalisations, healthcare expenditure and a worse quality of life. There is no consensus on managing people with comorbid T2D and depression. Bupropion is an efficacious antidepressant with many properties suitable for T2D with depression, including a favourable metabolic profile, persistent weight loss and improvement in sexual dysfunction. We will assess the efficacy and safety of add-on bupropion compared with standard care in people with T2D and mild depression. This study can give valuable insights into managing the multimorbidity of T2D and depression. This can help mitigate the health, social and economic burden of both these diseases. RESEARCH DESIGN AND METHODS: This cross-over randomised controlled trial will recruit people with T2D (for 5 years or more) with mild depression. They will be randomised to add-on bupropion and standard care. After 3 months of treatment, there will be a washout period of 1 month (without add-on bupropion while standard treatment will continue). Following this, the two arms will be swapped. Participants will be assessed for glycosylated haemoglobin, adherence to diabetes self-care activities, lipid profile, urine albumin-to-creatinine ratio, autonomic function, sexual function, quality of life and adverse events. ETHICS AND DISSEMINATION: The Institutional Ethics Committee at All India Institute of Medical Sciences, Jodhpur has approved this study (AIIMS/IEC/2022/4172, 19 September 2022). We plan to disseminate the research findings via closed group discussions at the site of study, scientific conferences, peer-reviewed published manuscripts and social media. TRIAL REGISTRATION NUMBER: CTRI/2022/10/046411.

The efficacy and acceptability of pharmacological monotherapies and e-cigarette on smoking cessation: a systemic review and network meta-analysis.

Background and aims: Several pharmacological interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, have been approved for clinical use of smoking cessation. E-cigarettes (EC) are increasingly explored by many RCTs for their potentiality in smoking cessation. In addition, some RCTs are attempting to explore new drugs for smoking cessation, such as cytisine. This network meta-analysis (NMA) aims to investigate how these drugs and e-cigarettes compare regarding their efficacy and acceptability. Materials and methods: This systematic review and NMA searched all clinical studies on smoking cessation using pharmacological monotherapies or e-cigarettes published from January 2011 to May 2022 using MEDLINE, COCHRANE Library, and PsychINFO databases. NRTs were divided into transdermal (TDN) and oronasal nicotine (ONN) by administrative routes, thus 7 network nodes were set up for direct and indirect comparison. Two different indicators measured the efficacy: prevalent and continuous smoking abstinence. The drop-out rates measured the acceptability. Results: The final 40 clinical studies included in this study comprised 77 study cohorts and 25,889 participants. Varenicline is more effective intervention to assist in smoking cessation during 16-32 weeks follow-up, and is very likely to prompt dropout. Cytisine shows more effectiveness in continuous smoking cessation but may also lead to dropout. E-cigarettes and oronasal nicotine are more effective than no treatment in encouraging prevalent abstinence, but least likely to prompt dropout. Finally, transdermal nicotine delivery is more effective than no treatment in continuous abstinence, with neither significant effect on prevalent abstinence nor dropout rate. Conclusion: This review suggested and agreed that Varenicline, Cytisine and transdermal nicotine delivery, as smoking cessation intervention, have advantages and disadvantages. However, we had to have reservations about e-cigarettes as a way to quit smoking in adolescents.

Novel predictive approaches for drug-induced convulsions in non-human primates using machine learning and heart rate variability analysis.

Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate variability (HRV) analysis in non-human primates as a biomarker for convulsions induced by GABAA receptor antagonists. The present study aimed to explore the application of this methodology to other convulsants and evaluate its specificity by testing non-convulsants that affect the autonomic nervous system. Telemetry-implanted males were administered various convulsants (4-aminopyridine, bupropion, kainic acid, and ranolazine) at different doses. Electrocardiogram data gathered during the pre-dose period were employed as training data, and the convulsive potential was evaluated using HRV and multivariate statistical process control. Our findings show that the Q-statistic-derived convulsive index for 4-aminopyridine increased at doses lower than that of the convulsive dose. Increases were also observed for kainic acid and ranolazine at convulsive doses, whereas bupropion did not change the index up to the highest dose (1/3 of the convulsive dose). When the same analysis was applied to non-convulsants (atropine, atenolol, and clonidine), an increase in the index was noted. Thus, the index elevation appeared to correlate with or even predict alterations in autonomic nerve activity indices, implying that this method might be regarded as a sensitive index to fluctuations within the autonomic nervous system. Despite potential false positives, this methodology offers valuable insights into predicting drug-induced convulsions when the pharmacological profile is used to carefully choose a compound.

Investigating disparities in smoking cessation treatment for veterans with multiple sclerosis: A national analysis.

BACKGROUND AND AIMS: Smoking is a risk factor for multiple sclerosis (MS) development, symptom burden, decreased medication efficacy, and increased disease-related mortality. Veterans with MS (VwMS) smoke at critically high rates; however, treatment rates and possible disparities are unknown. To promote equitable treatment, we aim to investigate smoking cessation prescription practices for VwMS across social determinant factors. METHODS: We extracted data from the national Veterans Health Administration electronic health records between October 1, 2017, and September 30, 2018. To derive marginal estimates of the association of MS with receipt of smoking-cessation pharmacotherapy, we used propensity score matching through the extreme gradient boosting machine learning model. VwMS who smoke were matched with veterans without MS who smoke on factors including age, race, depression, and healthcare visits. To assess the marginal association of MS with different cessation treatments, we used logistic regression and conducted stratified analyses by sex, race, and ethnicity. RESULTS: The matched sample achieved a good balance across most covariates, compared to the pre-match sample. VwMS (n = 3320) had decreased odds of receiving prescriptions for nicotine patches ([Odds Ratio]OR = 0.86, p < .01), non-patch nicotine replacement therapy (NRT; OR = 0.81, p < .001), and standard practice dual NRT (OR = 0.77, p < .01), compared to matches without MS (n = 13,280). Men with MS had lower odds of receiving prescriptions for nicotine patches (OR = 0.88, p = .05), non-patch NRT (OR = 0.77, p < .001), and dual NRT (OR = 0.72, p < .001). Similarly, Black VwMS had lower odds of receiving prescriptions for patches (OR = 0.62, p < .001), non-patch NRT (OR = 0.75, p < .05), and dual NRT (OR = 0.52, p < .01). The odds of receiving prescriptions for bupropion or varenicline did not differ between VwMS and matches without MS. CONCLUSION: VwMS received significantly less smoking cessation treatment, compared to matched controls without MS, showing a critical gap in health services as VwMS are not receiving dual NRT as the standard of care. Prescription rates were especially lower for male and Black VwMS, suggesting that under-represented demographic groups outside of the white female category, most often considered as the "traditional MS" group, could be under-treated regarding smoking cessation support. This foundational work will help inform future work to promote equitable treatment and implementation of cessation interventions for people living with MS.

Interventions for smoking cessation in hospitalised patients.

BACKGROUND: In 2020, 32.6% of the world's population used tobacco. Smoking contributes to many illnesses that require hospitalisation. A hospital admission may prompt a quit attempt. Initiating smoking cessation treatment, such as pharmacotherapy and/or counselling, in hospitals may be an effective preventive health strategy. Pharmacotherapies work to reduce withdrawal/craving and counselling provides behavioural skills for quitting smoking. This review updates the evidence on interventions for smoking cessation in hospitalised patients, to understand the most effective smoking cessation treatment methods for hospitalised smokers. OBJECTIVES: To assess the effects of any type of smoking cessation programme for patients admitted to an acute care hospital. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 7 September 2022. SELECTION CRITERIA: We included randomised and quasi-randomised studies of behavioural, pharmacological or multicomponent interventions to help patients admitted to hospital quit. Interventions had to start in the hospital (including at discharge), and people had to have smoked within the last month. We excluded studies in psychiatric, substance and rehabilitation centres, as well as studies that did not measure abstinence at six months or longer. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was abstinence from smoking assessed at least six months after discharge or the start of the intervention. We used the most rigorous definition of abstinence, preferring biochemically-validated rates where reported. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 82 studies (74 RCTs) that included 42,273 participants in the review (71 studies, 37,237 participants included in the meta-analyses); 36 studies are new to this update. We rated 10 studies as being at low risk of bias overall (low risk in all domains assessed), 48 at high risk of bias overall (high risk in at least one domain), and the remaining 24 at unclear risk. Cessation counselling versus no counselling, grouped by intensity of intervention Hospitalised patients who received smoking cessation counselling that began in the hospital and continued for more than a month after discharge had higher quit rates than patients who received no counselling in the hospital or following hospitalisation (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.24 to 1.49; 28 studies, 8234 participants; high-certainty evidence). In absolute terms, this might account for an additional 76 quitters in every 1000 participants (95% CI 51 to 103). The evidence was uncertain (very low-certainty) about the effects of counselling interventions of less intensity or shorter duration (in-hospital only counselling ≤ 15 minutes: RR 1.52, 95% CI 0.80 to 2.89; 2 studies, 1417 participants; and in-hospital contact plus follow-up counselling support for ≤ 1 month: RR 1.04, 95% CI 0.90 to 1.20; 7 studies, 4627 participants) versus no counselling. There was moderate-certainty evidence, limited by imprecision, that smoking cessation counselling for at least 15 minutes in the hospital without post-discharge support led to higher quit rates than no counselling in the hospital (RR 1.27, 95% CI 1.02 to 1.58; 12 studies, 4432 participants). Pharmacotherapy versus placebo or no pharmacotherapy Nicotine replacement therapy helped more patients to quit than placebo or no pharmacotherapy (RR 1.33, 95% CI 1.05 to 1.67; 8 studies, 3838 participants; high-certainty evidence). In absolute terms, this might equate to an additional 62 quitters per 1000 participants (95% CI 9 to 126). There was moderate-certainty evidence, limited by imprecision (as CI encompassed the possibility of no difference), that varenicline helped more hospitalised patients to quit than placebo or no pharmacotherapy (RR 1.29, 95% CI 0.96 to 1.75; 4 studies, 829 participants). Evidence for bupropion was low-certainty; the point estimate indicated a modest benefit at best, but CIs were wide and incorporated clinically significant harm and clinically significant benefit (RR 1.11, 95% CI 0.86 to 1.43, 4 studies, 872 participants). Hospital-only intervention versus intervention that continues after hospital discharge Patients offered both smoking cessation counselling and pharmacotherapy after discharge had higher quit rates than patients offered counselling in hospital but not offered post-discharge support (RR 1.23, 95% CI 1.09 to 1.38; 7 studies, 5610 participants; high-certainty evidence). In absolute terms, this might equate to an additional 34 quitters per 1000 participants (95% CI 13 to 55). Post-discharge interventions offering real-time counselling without pharmacotherapy (RR 1.23, 95% CI 0.95 to 1.60, 8 studies, 2299 participants; low certainty-evidence) and those offering unscheduled counselling without pharmacotherapy (RR 0.97, 95% CI 0.83 to 1.14; 2 studies, 1598 participants; very low-certainty evidence) may have little to no effect on quit rates compared to control. Telephone quitlines versus control To provide post-discharge support, hospitals may refer patients to community-based telephone quitlines. Both comparisons relating to these interventions had wide CIs encompassing both possible harm and possible benefit, and were judged to be of very low certainty due to imprecision, inconsistency, and risk of bias (post-discharge telephone counselling versus quitline referral: RR 1.23, 95% CI 1.00 to 1.51; 3 studies, 3260 participants; quitline referral versus control: RR 1.17, 95% CI 0.70 to 1.96; 2 studies, 1870 participants). AUTHORS' CONCLUSIONS: Offering hospitalised patients smoking cessation counselling beginning in hospital and continuing for over one month after discharge increases quit rates, compared to no hospital intervention. Counselling provided only in hospital, without post-discharge support, may have a modest impact on quit rates, but evidence is less certain. When all patients receive counselling in the hospital, high-certainty evidence indicates that providing both counselling and pharmacotherapy after discharge increases quit rates compared to no post-discharge intervention. Starting nicotine replacement or varenicline in hospitalised patients helps more patients to quit smoking than a placebo or no medication, though evidence for varenicline is only moderate-certainty due to imprecision. There is less evidence of benefit for bupropion in this setting. Some of our evidence was limited by imprecision (bupropion versus placebo and varenicline versus placebo), risk of bias, and inconsistency related to heterogeneity. Future research is needed to identify effective strategies to implement, disseminate, and sustain interventions, and to ensure cessation counselling and pharmacotherapy initiated in the hospital is sustained after discharge.

Antidepressant nonadherence and sexual dysfunction among young adult males: the cross-sectional YAMAN study.

PURPOSE: Selective serotonin reuptake inhibitors are associated with high rates of nonadherence and sexual dysfunction, yet the correlation between these findings in young adult men is poorly characterized. We aimed to evaluate if young adult men are less willing to adhere to antidepressant treatment due to intolerable side effects, such as sexual dysfunction. METHODS: Deidentified, compensated survey that assessed baseline demographics, PHQ-8 and GAD-7 scores, attitudes towards antidepressant medication side effects, and perceptions of antidepressant medications including selective serotonin reuptake inhibitors, bupropion, and mirtazapine. RESULTS: From 665 delivered surveys, 505 respondents completed their survey (response rate: 76%), of which 486 were included for final analysis. After seeing common side effect profiles, our sample's willingness to take sexual function-sparing agents, such as bupropion or mirtazapine, was significantly greater than selective serotonin reuptake inhibitors (p < 0.001), with no significant difference between bupropion and mirtazapine (p = 0.263). The negative influence of erectile dysfunction and anorgasmia scored significantly higher than other common antidepressant side effects like weight gain, nausea, and dry mouth (range: p < 0.001, p = 0.043). With the exception of insomnia, participants indicated that experiencing sexual dysfunction while taking an antidepressant medication would lead to nonadherence at a significantly higher frequency than any other side effect assessed (range: p < 0.001, p = 0.005). CONCLUSION: The risk of experiencing sexual side effects when taking antidepressants could lead young adult men to become nonadherent to these medications. Strategies to augment the effectiveness of antidepressants, such as shared decision-making and the use of sexual function-sparing agents, are critical.

Sleep-related adverse events of smoking cessation drugs: A network meta-analysis of randomized controlled trials.

Smoking cessation medications have the potential to affect the functioning of the nervous system, leading to sleep disturbances. Our study aimed to compare the sleep-related side effects (such as insomnia, abnormal dreams, nightmares, and somnolence) induced by different smoking cessation medications in non-psychiatric smokers. We conducted a thorough search of five electronic databases (Cochrane, EMBASE, PubMed, PsycInfo, and Web of Science) for randomized controlled trials. This study was registered with the PROSPERO (registration number CRD42022347976). A total of 79 full-text articles, encompassing 36,731 participants, were included in our analysis. Individuals using bupropion, bupropion in combination with a nicotinic acetylcholine receptor agonist (NRA), and bupropion in conjunction with nicotine replacement therapy (NRT) exhibited a higher likelihood of experiencing insomnia compared to those using NRT alone. Bupropion plus NRA had the highest ranking on the surface under the cumulative ranking curve (SUCRA) for insomnia risk, while placebo had the lowest ranking. Additionally, NRA plus NRT ranked first for abnormal dream outcomes, NRA alone for nightmares, and nortriptyline for somnolence, based on the SUCRA results. Healthcare providers should exercise caution when prescribing smoking cessation drugs, particularly in consideration of their potential sleep-related side effects.

Effectiveness of Antidepressants in Combination with Psychotherapy.

BACKGROUND: Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no specific advice on which antidepressant is best for a given medical history. AIMS OF THE STUDY: For patients with major depression who are in psychotherapy, this study provides an empirically derived guideline for prescribing antidepressant medications that fit patients' medical history. METHODS: This retrospective, observational, cohort study analyzed a large insurance database of 3,678,082 patients. Data was obtained from healthcare providers in the U.S. between January 1, 2001, and December 31, 2018. These patients had 10,221,145 episodes of antidepressant treatments. This study reports the remission rates for the 14 most commonly prescribed single antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine) and a category named "Other" (other antidepressants/combination of antidepressants). The study used robust LASSO regressions to identify factors that affected remission rate and clinicians' selection of antidepressants. The selection bias in observational data was removed through stratification. We organized the data into 16,770 subgroups, of at least 100 cases, using the combination of the largest factors that affected remission and selection bias. This paper reports on 2,467 subgroups of patients who had received psychotherapy. RESULTS: We found large, and statistically significant, differences in remission rates within subgroups of patients. Remission rates for sertraline ranged from 4.5% to 77.86%, for fluoxetine from 2.86% to 77.78%, for venlafaxine from 5.07% to 76.44%, for bupropion from 0.5% to 64.63%, for desvenlafaxine from 1.59% to 75%, for duloxetine from 3.77% to 75%, for paroxetine from 6.48% to 68.79%, for escitalopram from 1.85% to 65%, and for citalopram from 4.67% to 76.23%. Clearly these medications are ideal for patients in some subgroups but not others. If patients are matched to the subgroups, clinicians can prescribe the medication that works best in the subgroup. Some medications (amitriptyline, doxepin, nortriptyline, and trazodone) always had remission rates below 11% and therefore were not suitable as single antidepressant therapy for any of the subgroups. DISCUSSIONS: This study provides an opportunity for clinicians to identify an optimal antidepressant for their patients, before they engage in repeated trials of antidepressants. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: To facilitate the matching of patients to the most effective antidepressants, this study provides access to a free, non-commercial, decision aid at http://MeAgainMeds.com. IMPLICATIONS FOR HEALTH POLICIES:  Policymakers should evaluate how study findings can be made available through fragmented electronic health records at point-of-care. Alternatively, policymakers can put in place an AI system that recommends antidepressants to patients online, at home, and encourages them to bring the recommendation to their clinicians at their next visit. IMPLICATIONS FOR FURTHER RESEARCH:  Future research could investigate (i) the effectiveness of our recommendations in changing clinical practice, (ii) increasing remission of depression symptoms, and (iii) reducing cost of care. These studies need to be prospective but pragmatic. It is unlikely random clinical trials can address the large number of factors that affect remission.

5-EPIFAT trial protocol: a multi-center, randomized, placebo-controlled trial of the efficacy of pharmacotherapy for fatigue using methylphenidate, bupropion, ginseng, and amantadine in advanced cancer patients on active treatment.

BACKGROUND: Cancer-related fatigue (CRF) is still undertreated in most patients, as evidence for pharmacological treatments is limited and conflicting. Also, the efficacy of the pharmacological agents relative to each other is still unclear. Therefore, medications that may potentially contribute to improving CRF will be investigated in this head-to-head trial. Our main objective is to compare the efficacy of methylphenidate vs. bupropion vs. ginseng vs. amantadine vs. placebo in patients with advanced cancer. METHODS: The 5-EPIFAT study is a 5-arm, randomized, multi-blind, placebo-controlled, multicenter trial that will use a parallel-group design with an equal allocation ratio comparing the efficacy and safety of four medications (Methylphenidate vs. Bupropion vs. Ginseng vs. Amantadine) versus placebo for management of CRF. We will recruit 255 adult patients with advanced cancer who experience fatigue intensity ≥ 4 based on a 0-10 scale. The study period includes a 4-week intervention and a 4-week follow-up with repeated measurements over time. The primary outcome is the cancer-related fatigue level over time, which will be measured by the functional assessment of chronic illness therapy-fatigue (FACIT-F) scale. To evaluate safety, the secondary outcome is the symptomatic adverse events, which will be assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events in cancer clinical trials (PRO-CTCAE). Also, a subgroup analysis based on a decision tree-based machine learning algorithm will be employed for the clinical prediction of different agents in homogeneous subgroups. DISCUSSION: The findings of the 5-EPIFAT trial could be helpful to guide clinical decision-making, personalization treatment approach, design of future trials, as well as the development of CRF management guidelines. TRIAL REGISTRATION: IRCT.ir IRCT20150302021307N6. Registered on 13 May 2023.

Suicide ideation and male-female differences in major depressive disorder.

OBJECTIVE: This study aimed to explore male-female differences in suicide ideation (SI) and suicide risk factors in major depressive disorder (MDD). METHODS: We analysed 482 adults (sample 1) and 438 elderly outpatients (sample 2) with MDD. Sample 1 was treated with different antidepressant combinations (escitalopram; bupropion plus escitalopram; venlafaxine plus mirtazapine) and assessed by means of the Concise Health Risk Tracking (SI), Quick Inventory of Depressive Symptomatology, Altman Mania Rating Scale and Psychiatric Diagnostic Screening Questionnaire. Sample 2 was treated with venlafaxine and assessed using the Hamilton scale for depression, Anxiety Sensitivity Index and Penn State Worry Questionnaire for anxiety, Beck Scale for Suicide Ideation and Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: In sample 1, females had greater depression severity (O.R 0.961 99%CI: 0.929 - 0.995), males reported more alcohol abuse (O.R 1.299 99%CI: 1.118 - 1.509) and active SI (O.R 1.109 99%CI: 1.005 - 1.255). In sample 2 men showed more severe SI (O.R 1.067; 99%CI: 1.014 - 1.122) and weight loss (OR = 5.89 99%CI: 1.01 - 34.19), women more gastrointestinal symptoms. CONCLUSIONS: In these selected samples, although women had more severe depression, men had more suicide risk factors. Such differences might contribute to men's increased suicide risk.

In major depressive disorder sex differences affect the clinical expression of depressive episodes. In comparison to men, women endorse higher levels of overall depression in adult MDD and more somatic anxiety and gastrointestinal symptoms in late-life MDD.After controlling for confounding variables, males have more severe SI and a larger number of suicide risk factors (eg. alcohol abuse; weight loss). The association between male sex and SI is detectable in both adults and elderly patients with MDD.Further studies are necessary to elucidate how sex differences in suicide ideation and suicide risk factors are related to men's increased suicide risk.

Efficacy and safety of aripiprazole or bupropion augmentation and switching in patients with treatment-resistant depression or major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical Presentations of Bupropion Prescription Drug Misuse: A Systematic Review.

BACKGROUND: Among prescribers, bupropion is considered a substance of low misuse potential, with some studies showing lesser misuse potential than caffeine. However, several case reports exist of recreational bupropion misuse and diversion. Our goal is to understand at-risk populations, clinical courses, interventions, and outcomes after acute ingestion of bupropion via oral, intravenous route, and insufflation. METHODS: The systematic review was registered with PROSPERO on August 5, 2023. We conducted a systematic literature search on July 30, 2023, utilizing 8 databases with the help of the Medical Subject Headings (MeSH) term "Bupropion" in the context of misuse and abuse. Ultimately, we found 17 articles with qualitative synthesis relevant to our study objective and meeting our inclusion/exclusion criteria. RESULTS: Bupropion insufflation and intravenous injection occur almost exclusively in patients with a substance use disorder history, with a preponderance of patients with stimulant use disorder or multiple substance use disorders. Additionally, many were dual-diagnosis patients with a history of attention deficit hyperactivity disorder and stimulant use disorder, treated with bupropion. Patients describe the effects of bupropion insufflation/IV injection as a milder "cocaine-like" high that is brief, with less severe withdrawal effects of anxiety and agitation. The most common side effect at presentation was tachycardia, followed by seizures responsive to IV benzodiazepines. IV injection seems particularly insulting to the vascular system, with cellulitis, tissue necrosis, and digital ischemia as documented adverse effects. CONCLUSIONS: This systematic review highlights the bupropion misuse potential in certain patient populations and serves to increase awareness among clinicians. Additional patient screening, monitoring and follow-up, surveillance, and further research are needed to investigate and prevent bupropion misuse in at-risk patient populations entirely.

Uncoupling of Cytochrome P450 2B6 and stimulation of reactive oxygen species production in pharmacogenomic alleles affected by interethnic variability.

Cytochrome P450 mediated substrate metabolism is generally characterized by the formation of reactive intermediates. In vitro and in vivo reaction uncoupling, results in the accumulation and dissociation of reactive intermediates, leading to increased ROS formation. The susceptibility towards uncoupling and altered metabolic activity is partly modulated by pharmacogenomic alleles resulting in amino acid substitutions. A large variability in the prevalence of these alleles has been demonstrated in CYP2B6, with some being predominantly unique to African populations. The aim of this study is to characterize the uncoupling potential of recombinant CYP2B6*1, CYP2B6*6 and CYP2B6*34 metabolism of specific substrates. Therefore, functional effects of these alterations on enzyme activity were determined by quantification of bupropion, efavirenz and ketamine biotransformation using HPLC-MS/MS. Determination of H2O2 levels was performed by the AmplexRed/horseradish peroxidase assay. Our studies of the amino acid substitutions Q172H, K262R and R487S revealed an exclusive use of the peroxide shunt for the metabolism of bupropion and ketamine by CYP2B6*K262R. Ketamine was also identified as a trigger for the peroxide shunt in CYP2B6*1 and all variants. Concurrently, ketamine acted as an uncoupler for all enzymes. We further showed that the expressed CYP2B6*34 allele results in the highest H2O2 formation. We therefore conclude that the reaction uncoupling and peroxide shunt are directly linked and can be substrate specifically induced with K262R carriers being most likely to use the peroxide shunt and R487S carrier being most prone to reaction uncoupling. This elucidates the functional diversity of pharmacogenomics in drug metabolism and safety.

Comparison of the Efficacy of Anti-Obesity Medications in Real-World Practice.

Purpose: Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting. Patients and Methods: The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit. Results: A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area. Conclusion: All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.

Insomnia and parasomnia induced by validated smoking cessation pharmacotherapies and electronic cigarettes: a network meta-analysis.

We aim to assess the relationship between validated smoking cessation pharmacotherapies and electronic cigarettes (e-cigarettes) and insomnia and parasomnia using a systematic review and a network meta-analysis. A systematic search was performed until August 2022 in the following databases: PUBMED, COCHRANE, CLINICALTRIAL. Randomized controlled studies against placebo or validated therapeutic smoking cessation methods and e-cigarettes in adult smokers without unstable or psychiatric comorbidity were included. The primary outcome was the presence of "insomnia" and "parasomnia." A total of 1261 studies were selected. Thirty-seven studies were included in the quantitative analysis (34 for insomnia and 23 for parasomnia). The reported interventions were varenicline (23 studies), nicotine replacement therapy (NRT, 10 studies), bupropion (15 studies). No studies on e-cigarettes were included. Bayesian analyses found that insomnia and parasomnia are more frequent with smoking cessation therapies than placebo except for bupropion. Insomnia was less frequent with nicotine substitutes but more frequent with bupropion than the over pharmacotherapies. Parasomnia are less frequent with bupropion but more frequent with varenicline than the over pharmacotherapies. Validated smoking cessation pharmacotherapies can induce sleep disturbances with different degrees of frequency. Our network meta-analysis shows a more favorable profile of nicotine substitutes for insomnia and bupropion for parasomnia. It seems essential to systematize the assessment of sleep disturbances in the initiation of smoking cessation treatment. This could help professionals to personalize the choice of treatment according to sleep parameters of each patient. Considering co-addictions, broadening the populations studied and standardizing the measurement are additional avenues for future research.

Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample.

Despite the large public health toll of smoking, genetic studies of smoking cessation have been limited with few discoveries of risk or protective loci. We investigated common and rare variant associations with success in quitting smoking using a cohort from 8 randomized controlled trials involving 2231 participants and a total of 10,020 common and 24,147 rare variants. We identified 14 novel markers including 6 mapping to genes previously related to psychiatric and substance use disorders, 4 of which were protective (CYP2B6 (rs1175607105), HTR3B (rs1413172952; rs1204720503), rs80210037 on chr15), and 2 of which were associated with reduced cessation (PARP15 (rs2173763), SCL18A2 (rs363222)). The others mapped to areas associated with cancer including FOXP1 (rs1288980) and ZEB1 (rs7349). Network analysis identified significant canonical pathways for the serotonin receptor signaling pathway, nicotine and bupropion metabolism, and several related to tumor suppression. Two novel markers (rs6749438; rs6718083) on chr2 are flanked by genes associated with regulation of bodyweight. The identification of novel loci in this study can provide new targets of pharmacotherapy and inform efforts to develop personalized treatments based on genetic profiles.

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.