Combination Of Bupropion Research Articles

AXS-05: an investigational treatment for Alzheimer’s disease-associated agitation

ABSTRACT Introduction Agitation is common in patients with Alzheimer’s disease (AD). Although nonpharmacologic de-escalation strategies are recommend as first-line treatment, medication is often needed to treat agitation. Currently, there are no FDA-approved medications for this indication. Psychotropics used to treat agitation include antipsychotics, which are notable for their efficacy but also their potential to cause serious side effects. AXS-05, a combination of dextromethorphan and bupropion, is currently being investigated for this indication. Areas covered This review will discuss the pharmacology of AXS-05 and available clinical trial results from completed Phase I and Phase II/III studies assessing the potential for this compound to treat agitation in patients with AD. Ongoing research investigating AXS-05 for this indication will also be highlighted. Resources used for this review include PubMed, Embase, clinicaltrials.gov, and literature available on the manufacturer’s website. Expert opinion Early released clinical trial data indicate that AXS-05 may be a useful option to treat agitation in patients with AD, and that it appears to be generally well tolerated. AXS-05 may be especially helpful for patients with comorbid depression, when considering available data from separate phase III studies assessing the efficacy and safety of this compound in the treatment of depression.

Adjunctive dopaminergic enhancement of esketamine in treatment-resistant depression

Esketamine is a novel treatment for treatment resistant depression (TRD) and was approved by the FDA in early 2019. It antagonizes the NMDA receptor providing rapid improvement in symptoms with a complex mechanism of action primarily mediated through glutamatergic activation. Significant barriers exist to widespread use of esketamine including durability of response, particularly in the maintenance phase. Since it must be administered in combination with an oral antidepressant, investigating appropriate treatments to be given concomitantly may further improve outcomes and response duration. Specifically, due to dysfunction in dopaminergic pathways in many patients with MDD and TRD, addition of a prodopaminergic agent, such as bupropion, may provide additional benefit and durability of response. Historically, the addition of a dopaminergic agent to traditional treatment (e.g., SSRI, SNRI) has been shown to improve response in TRD. While we have anecdotal evidence to support adjunctive dopaminergic enhancement of esketamine response, robust data are limited. There are case reports that exhibit efficacy with the use of a MAO-I in combination with ketamine supporting at least in part a dopaminergic component. Additionally, there is mechanistic rationale for the use of dopaminergic agents with a NMDA antagonist. This includes co-localization of NMDA and dopamine receptors as well as increased glutamatergic signaling due to dopamine-induced phosphorylation of AMPAR. Recently, AXS-05, an oral combination of dextromethorphan and bupropion, has shown promise in both MDD and TRD clinical trials highlighting the potential validity of this mechanism. This paper describes how dopaminergic enhancement may increase efficacy and durability of response with esketamine, encouraging further research into this treatment option.

Practice patterns of bupropion co-prescription with antipsychotic medications

Objective: Bupropion is one of the few medications with an FDA indication for smoking cessation. This is of particular significance due to the high co-morbidity of tobacco use disorder in patients with schizophrenia spectrum and other psychotic disorders. We sought to determine whether historical suggestions of bupropion’s pro-dopaminergic activity lead prescribers to withhold bupropion in populations receiving antipsychotic medications. Methods: The prevalence in clinical practice of the combination of bupropion and 10 antipsychotic formulations was determined by a computer review of the Genoa Healthcare database for all prescribers at 10 participating community mental health centers. Actual prevalence was compared with expected prevalence using the test of proportions. A Bonferroni correction for multiple comparisons was included. Results: Clozapine, p = 0.0004, and the microsphere formulation of risperidone, p = 0.0045, were prescribed with bupropion significantly less often that chance. None of the other eight antipsychotic formulations were prescribed significantly differently than chance. Conclusions: The co-prescription of bupropion and antipsychotic medication may be affected by historical misconceptions regarding bupropion’s purportedly pro-dopamine properties. Viable options for the treatment of tobacco use disorder should not be discounted prematurely in patients with schizophrenia spectrum and other psychotic disorders. We suggest further study on the safety and efficacy of the combination of bupropion and antipsychotic medication is needed.

Cost-Effectiveness Analysis of Varenicline Versus Currently Funded Smoking Cessation Strategies in Brazil

ObjectivesTo assess the cost-effectiveness of varenicline in comparison to currently funded smoking cessation strategies in Brazil. MethodsWe modeled the lifetime direct costs and health-related quality of life of a hypothetical cohort of smokers with a single attempt to quit smoking using one of the following: (1) cognitive behavioral therapy (CBT) without any pharmacological intervention, (2) varenicline, (3) bupropion, (4) nicotine replacement therapy (NRT) with transdermal patch, (5) bupropion in combination with NRT transdermal patch, and (6) combined NRT (oral plus transdermal). All drug alternatives were considered with concomitant CBT. The analysis relied on a Markov model based on the Benefits of Smoking Cessation and Outcomes study and used different age and sex categories in the consideration of relative risks and incidence rates of the diseases included in the model. The analysis was conducted from the healthcare system perspective, and a 3% discounting rate for costs and outcomes was applied. Model parameter values were sourced from published literature. Probabilistic and deterministic sensitivity analyses assessed robustness. ResultsAmong the smoking cessation alternatives available in Brazil, varenicline and combined NRT were estimated to have higher effectiveness; varenicline, however, was dominated due to its higher average cost. In the base-case analysis, combined NRT had an incremental gain of 0.25 quality-adjusted life-years (QALYs) in comparison to the second-best option (bupropion in combination with NRT transdermal patch) and an incremental cost-effectiveness ratio of R$2173.47/QALY ($595.45/QALY). ConclusionsCombination of oral and transdermal NRT (coupled with CBT) was the most effective smoking cessation option and was 100% cost-effective within a conservative willingness-to-pay threshold.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Current Intervention Treatments for Food Addiction: A Systematic Review.

Research on the concept of food addiction (FA) has steadily grown and, based on a widely used self-report, FA is estimated to affect between 16–20% of the adult population. However, there are few interventions available for people with self-reported FA, and their efficacy is unclear. The primary aim of the review was to examine the efficacy of different interventions, including behavioural/lifestyle, medication and surgical approaches, for reducing symptoms and/or changing diagnosis of FA among adolescents and adults. A secondary aim was to examine the influence of sex as a moderator of intervention effects. A systematic search was performed from 2008–2020 to identify studies that used the YFAS to assess the effectiveness of interventions on FA. Nine studies were identified (n = 7 adults, n = 2 adolescents) including a total of 812 participants (range 22–256) with an average of 69% females per study. The types of interventions included medications (n = 3), lifestyle modification (n = 3), surgical (n = 2) and behavioural (n = 1), with FA being assessed as a secondary outcome in all studies. Five studies in adults reported a significant reduction in FA symptoms or diagnosis from pre to post-intervention, two when compared to a control group and three in the intervention group only. Efficacious interventions included: medication (combination of naltrexone and bupropion, as well as pexacerfont), bariatric surgery and lifestyle modification. No significant changes in FA were reported in adolescent studies. Given few studies were identified by the review, there is insufficient evidence to provide clear recommendations for practice; however, some interventions show potential for reducing self-reported FA outcomes in adults. Future research should explore the longer-term efficacy of interventions and the effectiveness of treatments with sufficient sample sizes.

Bupropion plus naltrexone shows some benefit in stimulant use disorder

A combination of oral bupropion and injectable naltrexone generated a weighted average response rate of 13.6% in a placebo‐controlled trial involving 403 adults with methamphetamine use disorder. The low response rate for the drug combination was higher than the placebo response, however. Study results were published in the Jan. 14, 2021 issue of the New England Journal of Medicine.

Naltrexone + Bupropion Combination for the Treatment of Binge-eating Disorder with Obesity: A Randomized, Controlled Pilot Study

PurposeBinge-eating disorder (BED), the most prevalent eating disorder, is associated strongly with obesity and functional impairments. Few evidence-based treatments for BED exist; a pharmacotherapy effective in reducing both binge eating and weight needs to be identified. This placebo-controlled double-blind pilot RCT evaluated the acute effects of naltrexone + bupropion (NB) on BED with obesity and examined the longer-term effects through 6-month follow-up after the discontinuation of medication. MethodsTwenty-two adult patients with BED were randomized to receive 12 weeks of double-blind treatment with fixed-dose NB (naltrexone + bupropion XL 50/300 mg) or placebo. Independent (blinded) researcher–clinicians evaluated patients at major outcome time points (baseline, posttreatment, and 6-month follow-up after the treatment period); patients were also evaluated for the tracking of course/tolerability throughout treatments and at 3-month follow-up. Primary outcomes were changes from baseline in binge-eating frequency and percentage weight. Secondary outcomes were changes in eating-disorder psychopathology and depression. FindingsA total of 22 patients were enrolled (86.4% women; mean age, 50.4 years), with 77.3% of patients completing treatments; completion rates (NB, 83.3%; placebo, 70.0%) and adverse events did not differ significantly between NB and placebo. Analyses revealed significant reductions from baseline in binge-eating, eating-disorder psychopathology, depression, and weight during treatment, but these changes with NB did not differ significantly from those with placebo. The percentage of patients who attained 3% weight loss was significantly greater with NB than with placebo (45.5% vs 0%); weight-loss and binge-eating reductions were significantly correlated in the group that received NB. At 6-month follow-up, outcomes remained improved relative to baseline, with no significant differences between NB and placebo. ImplicationsThe findings from this pilot RCT suggest that NB was well-tolerated in these patients with BED and comorbid obesity. Most outcomes were not statistically different between NB and placebo. A larger-scale, adequately powered RCT is needed for determining the efficacy of NB in the treatment of BED. ClinicalTrials.gov identifier: NCT02317744.

Smoking and Nicotine Effects on Surgery: Is Nicotine Replacement Therapy (NRT) a Safe Option?

Smoking and Nicotine Effects on Surgery: Is Nicotine Replacement Therapy (NRT) a Safe Option?

Antidepressants for smoking cessation.

Antidepressants for smoking cessation.

In patients who smoke cigarettes, is varenicline with bupropion combination therapy more effective than varenicline monotherapy for smoking cessation?

In patients who smoke cigarettes, is varenicline with bupropion combination therapy more effective than varenicline monotherapy for smoking cessation?

Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats

Opiate addiction has risen substantially during the past decade. New treatments to combat opiate addiction are sorely needed. The current study was conducted to determine the acute individual and interactive effects of bupropion and dextromethorphan in a rat model of opiate self-administration using the short-acting synthetic opioid remifentanil. Both of these drugs have been found to reduce self-administration of nicotine. Bupropion and dextromethorphan and their combination had differential effects depending on whether the rats showed higher or lower baseline remifentanil self-administration. The rats with higher initial remifentanil self-administration showed a significant decrease in remifentanil self-administration with bupropion or dextromethorphan treatment, compared to the vehicle control condition. This decrease in self-remifentanil administration was most pronounced when combination of the higher doses of bupropion and dextromethorphan were administered. In contrast, the rats with lower baseline remifentanil self-administration showed the opposite effect of drug treatment with an increase in remifentanil self-administration with bupropion treatment compared to the vehicle control condition. Dextromethorphan had no significant effect inthis group. This study shows that combination bupropion and dextromethorphan affects remifentanil self-administration in a complex fashion with differential effects on low and high baseline responders. In subjects with high baseline remifentanil self-administration, bupropion and dextromethorphan treatment significantly reduced self-administration, whereas in subjects with low baseline remifentanil self-administration, bupropion increased remifentanil self-administration and dextromethorphan had no discernible effect. This finding suggests that combination bupropion-dextromethorphan should be tested in humans, with a focus on treating people with high-level opiate use.

The Opioid System and Food Intake: Use of Opiate Antagonists in Treatment of Binge Eating Disorder and Abnormal Eating Behavior

Eating disorders (EDs) and substance use disorders (SUDs) commonly co-occur, especially in conjunction with affective syndromes, yet little is known about opiate abuse and ED symptoms in patients on naltrexone-bupropion therapy. Moreover, evidence suggests that the opioid system can also be regarded as one of the major systems regulating the anticipatory processes preceding binge eating episodes. The lack of evidence in the effectiveness of psychotherapy treatment in addition to psychotropic mediations compounds the difficulties in stabilizing individuals with EDs. This article aims to exhaustively review literature relating to the use of opioid antagonists in the management of binge eating disorder (BED) and other abnormal eating habits and how this can be augmented by the use of psychological approaches to come up with the most effective therapy or combination of therapies to manage these conditions. Although this approach is promising, it has not been evaluated. A review of the literature pertaining to the use of naltrexone in patients with EDs was performed through PubMed, PsycINFO and MEDLINE. We selected 63 relevant articles published between 1981 and 2018 and those written in English. Search terms included “Opioid antagonists”, “naltrexone”, “bupropion” and “Psychotherapy” each combined with “Binge Eating Disorder”, “Bulimia Nervosa”, “Anorexia Nervosa”, “Eating Disorder”, “EDNOS” and “Obesity”. While working with these articles, we also identified several problems related to use of these methods in real clinical practice. Seventy-seven articles were reviewed, and 63 were selected for inclusion. Data obtained from these sources confirmed that the blockade of opioid receptors diminishes food intake. More recent findings also indicate that the combination of bupropion and naltrexone can induce weight loss. Augmentation of this by introducing psychotherapy may lead to better outcomes. Cognitive behavioral therapy (CBT) was the most frequently recommended psychotherapy intervention, showing efficacy for EDs and chemical addictions as documented by most of the studies, but with uncertain efficacy when utilized as augmentation strategy. There are limited data supporting the use of psychotherapy in augmentation of standard therapy in ED; however, there is evidence to support that psychotherapy is safe in this population and has been effective in cases of patients with opiate addiction with and without psychiatric comorbidities as well as BED. More research is needed to establish treatment guidelines. Combining pharmacotherapeutic and psychotherapeutic interventions leads to the achievement of a better outcome in managing patients with EDs. Involving families or the use of support groups increases chances of adherence to the prescribed interventions resulting in higher rates of remission. However, it is clear that all of these interventions must occur in the context of a comprehensive treatment program. We believe that patient-specific psychotherapy may not only facilitate the treatment process, but also cause significant alterations in eating pattern. This approach for BED may lead to more significant treatment outcomes, but this possibility must be tested in larger samples.

Briefly Noted

Naltrexone alone is already approved for treating alcohol use disorder, but a new study has opened the door to looking at the combination of naltrexone and bupropion to reduce binge drinking. The study, an open‐label, single‐arm, 12‐week study, recruited 12 people who had at least five (in the case of the men) or three (in the case of the women) binge‐drinking episodes a month. All subjects received both bupropion extended‐release 300 mg/day and naltrexone 50 mg/day and were monitored for three months. Their average number of drinks per binge‐drinking day went from 7.8 to 6.4, and the average percentage of binge‐drinking days per month went from 19' to 5'. Insomnia, headache and nausea/diarrhea were the most common side effects, with the medications well‐tolerated; six subjects stayed on the medication after the trial. The study, “A Preliminary, Open‐Label Study of Naltrexone and Bupropion Combination Therapy for Treating Binge Drinking in Human Subjects,” by Thomas J. Walter and colleagues, was published online Nov. 20 in Alcohol and Alcoholism.

Combined administration of varenicline and bupropion produces additive effects on accumbal dopamine and abolishes the alcohol deprivation effect in rats.

Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug-induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5mg/kg) and bupropion (2.5, 5, or 10mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle-treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.

Sex differences in the effect of bupropion and naltrexone combination on alcohol drinking in mice

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE−/−) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE−/− males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.

The effect of bupropion augmentation of minocycline in the treatment of depression

The aim of the current study was to analyse the augmentation of minocycline with bupropion in treating depression. 'Saline' (10 ml/kg), 'minocycline per se' (25 mg/kg), 'minocycline per se' (50 mg/kg), 'bupropion per se' (5 mg/kg), 'bupropion per se' (10 mg/kg) and 'bupropion + minocycline' (5 mg/kg + 25 mg/kg each) were administered to mice via the intraperitoneal route. In the forced swim and tail suspension test, the immobility period was analysed after 30 min of the treatment. Monoamines like dopamine, norepinephrine and serotonin levels were analysed in brain areas such as the whole brain, hippocampus and cerebral cortex using an HPLC-fluorescence detector. Euthanasia of mice was performed 1 h after treatment. Comparison between the control group and combination therapy and other standard drug groups showed a significant decrease in immobility in both antidepressant animal models. The combination of bupropion and minocycline showed greater benefits with respect to a reduction in the immobility time period and enhancement of dopamine, serotonin, and norepinephrine levels in the cerebral cortex, hippocampus and the whole brain when compared to the monotherapy treated groups. Hence, the side effects may be reduced drastically through this combination by a reduction in the bupropion/minocycline dosage.

Optimized regimens of combined medications for the treatment of major depressive disorder: a double-blind, randomized-controlled trial.

IntroductionThis study investigated if optimized dose regimens of escitalopram and bupropion combination from treatment initiation can be superior to either drug alone in speed of onset, remission rate, and maintenance of therapeutic efficacy.MethodsPatients from a single site (N=85) within a larger double-blind 12-week trial (N=245) showed a lower dropout rate (14% vs 40%) and used higher doses; therefore, this cohort was analyzed separately. Uniquely at this single site, after 12 weeks, non-remitters on a single drug received the other one in addition and combination non-remitters underwent a switch of escitalopram for duloxetine for a 6-week period. Escitalopram could be given up to 40 mg/day and bupropion up to 450 mg/day. A 6-month prolongation was then implemented in remitters, maintaining the double-blind design throughout. Remission was defined as ≤7 on the 17-item Hamilton Rating Scale for Depression, as in the initial publication.ResultsAt week 2, combination treatment was superior in remission rate (5/28) compared with both bupropion (0/26) and escitalopram monotherapies (0/31; P=0.03 and P=0.02, respectively). The week 12 remission rate of combination treatment showed a higher rate (15/28) relative to bupropion monotherapy (7/26; P=0.04), but not statistically different from escitalopram monotherapy (11/31; P=0.13). The 6-week augmentation produced remission in 7/21 monotherapy non-remitters and 0/6 in the switch group (P=0.13). Remission was sustained in 28/31 patients enrolled in the 6-month maintenance.ConclusionThese results suggest that combination of escitalopram and bupropion from treatment initiation is superior to either monotherapy in speed of onset. The addition of a second drug in non-remitters can lead to additional remissions, as shown with other combinations of medications. Treatment prolongation using optimized regimens leads to low relapse rates.

Molybdenum bupropion combined neurotoxicity in rats

Heavy metal toxicity is a common foodborne problem in Egypt, especially in combination. Molybdenum toxicity has been studied as a model of the heavy metal toxicity. Molybdenum could promote toxicity via oxidative-inflammatory mechanisms. Bupropion is a well-known antidepressant that has anti-oxidant mechanisms. It exerts a cytoprotective action against molybdenum induced metal toxicity. The aim of the study is to evaluate the effects of combined bupropion and molybdenum in a toxic animal model. The results showed that the combination of bupropion and high doses of molybdenum was extremely toxic with an evident animal fatality. Bupropion showed a clear anti-oxidant/anti-inflammatory profile detected by the ELISA assay of malondialdehyde (MDA), reduced glutathione, and interleukin −6 (IL-6), and real-time gene expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and tumor necrosis factor-α (TNF-α). The immunohistochemistry of nuclear factor Kappa Beta (NF-κB) showed that bupropion reduced the inflammatory response induced by the molybdenum neurotoxicity. Despite the improved laboratory profile, the animals were extremely intoxicated with recorded fatalities raising the question about other pathways and mechanisms explaining the drug metal interaction. Furthermore, Bupropion even in normal doses was toxic to the animals. Choroid plexus hyperplasia was reported in the histological examination of the animal brain loaded with bupropion, and choroid plexus papilloma was recorded in the combined drug metal group. More wide-scale studies are needed to verify the safety of the current antidepressant medications for the long-term therapy. It is important to focus on drug metal interaction as a possible cause of neuropathology.

An RCT with the combination of varenicline and bupropion for smoking cessation: clinical implications for front line use.

Despite the availability of several efficacious smoking cessation treatments, fewer than 25% of smokers who quit remain abstinent 1year post-treatment. This study aimed to determine if varenicline and bupropion combination treatment would result in higher abstinence rates than varenicline alone. A double-blind, randomized, parallel-group smoking cessation clinical trial in which participants were exposed to 12weeks of treatment and followed for 12months. Hospital-based out-patient clinic in Texas, USA specializing in cancer prevention. A total of 385 community smokers (58.44% male) who smoked 1 pack of cigarettes/day [mean=19.66 cigarettes/day, standard deviation (SD)=9.45]; had average carbon monoxide (CO) of 26.43parts per million (SD=13.74); and were moderately dependent (Fagerström Test for Cigarette Dependence =4.79; SD=2.07). Smokers were randomized in a 3:1 (active: Placebo) ratio to 12weeks of treatment as follows: placebo (n=56), varenicline (Var; n=166), and varenicline + bupropion (Combo; n=163). A priori primary outcome: prolonged abstinence at 12months. 7-day point prevalence abstinence and continuous abstinence; all abstinence measures at end of treatment and 6-month follow-ups. Intention-to-treat analysis: the Combo group (n=163) failed to demonstrate superiority to the Var group (n=166) for prolonged abstinence at 12months [odds ratio (OR)=0.91, 95% confidence interval (CI)=0.50-1.64], supported by Bayes factor=0.06. Both the Var (OR=6.66, 95% CI=1.61-59.27) and Combo groups (OR=6.06, 95% CI=1.45-54.09) demonstrated superiority to the Placebo group (n=56; score=8.38, P<0.016). The addition of bupropion to varenicline treatment does not appear to increase smoking abstinence rates above that of varenicline alone. The findings support previous research showing a consistently favorable effect of both varenicline and the combination of varenicline and bupropion on smoking cessation compared with placebo.