Profiling the combination of bupropion and dextromethorphan as a treatment option for major depressive disorder.

INTRODUCTION: Major Depressive Disorder (MDD) is a common mental health disorder marked by sadness, hopelessness, and anhedonia. Various therapies exist, but their effectiveness is limited. Dextromethorphan hydrobromide combined with bupropion hydrochloride (Auvelity®) is a recently approved alternative for treating this condition in adults. AREAS COVERED: This review summarizes the neurobiology of major depression and delves into the pharmacology, efficacy, safety, and tolerability of dextromethorphan plus bupropion in adult patients. It is based on observational studies, clinical trials, and other secondary studies obtained through systematic literature searches. EXPERT OPINION: The combination of bupropion and dextromethorphan as a new pharmacotherapy for mental health is an interesting addition to the treatment options that can be used for MDD. The combination can be used in a range of scenarios, including as a first line therapy, as a second option when a patient has failed to achieve remission with a serotonin targeting agent, and for treatment resistant depression. Further research for other indications, including addiction disorders, may provide exciting results. Although a new combination, clinicians will be very familiar with both agents, increasing their acceptability. This pharmacotherapy also may bring increased impetus for discovering other combinations that may have beneficial synergistic effects.

Evaluation of the Clinical Drug-Drug Interaction Potential of Pritelivir on Transporters and CYP450 Enzymes Using a Cocktail Approach.

Pritelivir is a novel viral helicase-primase inhibitor active against herpes simplex virus. In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential.

A bupropion modulatory site in the Gloeobacter violaceus ligand-gated ion channel.

Bupropion is an atypical antidepressant and smoking cessation drug that causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels, such as nicotinic acetylcholine and serotonin type 3A receptors, at clinically relevant concentrations. Here, we demonstrate that bupropion also inhibits a prokaryotic homolog of pentameric ligand-gated ion channels, the Gloeobacter violaceus ligand-gated ion channel (GLIC). Using the GLIC as a model, we used molecular docking to predict binding sites for bupropion. Bupropion was found to bind to several sites within the transmembrane domain, with the predominant site being localized to the interface between transmembrane segments M1 and M3 of two adjacent subunits. Residues W213, T214, and W217 in the first transmembrane segment, M1, and F267 and I271 in the third transmembrane segment, M3, most frequently reside within a 4 Å distance from bupropion. We then used single amino acid substitutions at these positions and two-electrode voltage-clamp recordings to determine their impact on bupropion inhibitory effects. The substitution T214F alters bupropion potency by shifting the half-maximal inhibitory concentration to a 13-fold higher value compared to wild-type GLIC. Residue T214 is found within a previously identified binding pocket for neurosteroids and lipids in the GLIC. This intersubunit binding pocket is structurally conserved and almost identical to a binding pocket described for neurosteroids in γ-aminobutyric acid type A receptors. Our data thus suggest that the T214 that lines a previously identified lipophilic binding pocket in GLIC and γ-aminobutyric acid type A receptors is also a modulatory site for bupropion interaction with the GLIC.

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.

The effects of bupropion alone and combined with naltrexone on blood pressure and CRP concentration: A systematic review and meta-regression analysis of randomized controlled trials.

BACKGROUND: Considering the conflicting effects of bupropion on parameters related to cardiovascular system including blood pressure and inflammation, in this meta-analysis study, we investigated the effects of this drug alone or in combination with naltrexone on systolic (SBP) and diastolic blood pressure (DBP) and C-reactive protein (CRP). METHODS: Scopus, PubMed/Medline, Web of Science and Embase databases were searched using standard keywords to identify all controlled trials investigating effects of bupropion alone and combined with naltrexone on the BP and CRP. Pooled weighted mean difference and 95% confidence intervals (CIs) were achieved by random-effects model analysis for the best estimation of outcomes. RESULTS: The pooled findings showed that that bupropion alone or in combination with naltrexone would significantly increase SBP (weighted mean difference (WMD): 1.34 mmHg, 95% CI: 0.38-2.29) and DBP (WMD: 0.93 mmHg, 95% CI 0.88-0.99) as well as decrease CRP (WMD: -0.89 mg/L, 95% CI -1.09 to -0.70). The findings of the subgroup also show the greater effect of bupropion on blood pressure (SBP and DBP) increase in a dose greater than 360 mg and a duration of intervention less equal to 26 weeks. In addition, the subgroup analysis showed that changes in SBP after receiving bupropion together with naltrexone were more compared to bupropion alone. CONCLUSIONS: The addition of combination therapies such as bupropion and naltrexone can significantly improve CRP levels. However, its effect on blood pressure requires proper management of this drug.

The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats.

Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted.

Effects of pre-gestational exposure to the stressors and perinatal bupropion administration on the firing activity of serotonergic neurons and anxiety-like behavior in rats.

Exposure by women to stressors before pregnancy increases their risk of contracting prenatal depression, a condition which typically may require antidepressant treatment. And even though such perinatal antidepressant treatment is generally considered to be safe. For the mother, its effects on the development and functioning of the offspring`s brain remain unknown. In this study, we aimed to investigate the effects of pregestational chronic unpredictable stress (CUS) and perinatal bupropion on the anxiety behavior and firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT) neurons. Female rats underwent CUS for three weeks before mating. Bupropion was administered to them from gestation day ten until their offspring were weaned. Behavioral (elevated plus maze or EPM test) and neurophysiological (single-unit in vivo electrophysiology) assessments were performed on offspring who reached the age of 48-56 days. We found that maternal CUS and perinatal bupropion, as separate factors on their own, did not change offspring behavior. There was, however, an interaction between their effects on the number of entries to the open arms and time spent in the intersection: maternal CUS tended to decrease these values, and perinatal bupropion tended to diminish CUS effect. Maternal CUS increased the firing activity of 5-HT neurons in males, but not females. Perinatal bupropion did not alter the firing activity of 5-HT neurons but tended to potentiate the maternal CUS-induced increase in 5-HT neuronal firing activity. The CUS-induced increase in firing activity of 5-HT neurons might be a compensatory mechanism that diminishes the negative effects of maternal stress. Perinatal bupropion does not alter the offspring`s anxiety and firing activity of 5-HT, but it does intervene in the effects of maternal stress.

Increased depression-like behaviors with altered brain dopamine metabolisms in male mice housed in large cages are alleviated by bupropion.

Psycho-environmental stress-based animal models of anxiety and depression are useful for investigating pathological mechanisms and drug development. Although several rodent-based studies have reported the beneficial effects of environmental enrichment (EE) on brain plasticity and anxiety- and depression-like behaviors, other studies have reported inverse effects. Here, we found that housing male mice in EE involving large cages and other EE materials increased anxiety- and depression-like behaviors in open field and tail suspension tests (TST). We further confirmed that housing in large cages was sufficient to induce increased depression-like behaviors in the TST and reduce the saccharine preference percentage, a sign of anhedonia, in male mice. In these experiments, the number of animals per cage was equivalent to that in standard cage housing, suggesting that low density in large cages may be a determining factor for behavioral alteration. In mice housed in large cages, sex-specific dysregulation of brain monoamine systems was observed; dopamine turnover to homovanillic acid or norepinephrine in the prefrontal cortex was elevated in males, while serotonin turnover to 5-hydroxyindoleacetic acid in the amygdala was increased in females. Finally, we demonstrated that daily intraperitoneal injections of bupropion, a dopamine and norepinephrine reuptake inhibitor, counteracted large-cage housing-induced changes in depression- and anhedonia-like behaviors in male mice. Our results suggest that housing in large cages with a low density of mice is a novel paradigm to clarify the mechanisms of environmental stress-induced emotional dysregulation and to identify drugs or food factors to alleviate the dysregulation.

Environmental enrichment affects behavioral and pharmacological response to antidepressants in CF1 mice.

It has been described that environmental enrichment (EE) exerts beneficial effects on cognitive and emotional performances, dendritic branching, synaptic density, neurogenesis and modulation of neurotrophic systems and neurotransmitters in rodents. However, the influence of EE on pharmacological and behavioral responses in animal models of psychiatric disorders has not been fully established. In this context, the aim of this study was to evaluate the influence of exposure to EE on mice behavior in the open field test (OFT) and forced swimming tests (FST), as well as the response to antidepressant drugs (fluoxetine 30 mg/kg and bupropion 30 mg/kg, p.o.). CF1 mice were exposed to an enriched housing condition at different developmental stages: from mating to postnatal day (PND) 55 (lifelong enrichment), from mating to PND21 (perinatal enrichment) and from PND21 to PND55 (post-weaning enrichment). At PND58 the male offspring were evaluated in the OFT and FST. BDNF gene expression in the hippocampus was determined through qPCR. Mice exposed to perinatal enrichment remained longer in the peripheral zone of the OFT and performed fewer grooming than mice housed under standard condition, and these effects were independent of drug treatment. Post-weaning and lifelong enrichment increased grooming behavior. Bupropion reduced grooming in all groups except in perinatal enriched. In turn, fluoxetine decreased grooming only in post-weaning enriched group. None of the enriched housing conditions altered the immobility time in the FST, which indicates that EE had no antidepressant-like effect. However, all enriched housing conditions abolished the anti-immobility effect of bupropion. None of the EE protocols affected BDNF hippocampal expression. The main conclusion is that mice behavior in the OFT is sensitive to alterations in the housing environment and depends on the developmental stage of exposure. Bupropion and fluoxetine yielded divergent responses depending on the housing condition, which suggests that EE modulates monoaminergic neurotransmission pathways.

Effects of the dopamine depleting agent tetrabenazine in tests evaluating different components of depressive-like behavior in mice: sex-dependent response to antidepressant drugs with SERT and DAT blocker profiles.

BACKGROUND: Depression is a disorder twice as common in women than in men. There are sex differences in the symptomatology and treatment response to this disorder. Impairments in behavioral activation (i.e. anergia, fatigue) are often seen in people with depression and are highly resistant to treatment. The role of mesolimbic dopamine (DA) in regulating behavioral activation has been extensively studied in male rodents, but little is known in female rodents. OBJECTIVE: The present studies assessed potential sex differences in rodent paradigms used to study different components of depressive-like behavior, and in the treatment response to antidepressants with different mechanisms of action. METHODS: Male and female CD1 mice received Tetrabenazine (TBZ), a VMAT-2 blocker that depletes DA and induces depressive symptoms in humans. Mice were tested on the Forced Swim Test, (FST), the Dark-Light box (DL), the elevated plus maze (EPM), Social Interaction (SI) test, and sucrose preference and consumption using the two bottles test. In addition, bupropion (a DA reuptake inhibitor) or fluoxetine (a serotonin reuptake inhibitor) were used to reverse TBZ-induced anergia. RESULTS: In the FST, bupropion reversed TBZ effects in both sexes but fluoxetine was only effective in female mice. DA depletion did not affect other aspects of depression such as anxiety, sociability or sucrose consumption, and there was no interaction with bupropion on these parameters. In TBZ treated-females SERT-blockers may be effective at reversing anergia in aversive contexts (FST), and potentiating avoidance of anxiogenic stimuli. CONCLUSIONS: Pro-dopaminergic antidepressants seem more efficacious at improving anergia in both sexes than SERT-blockers.

Anti-inflammatory activity of bupropion through immunomodulation of the macrophages.

Depression might manifest itself with a chronic inflammation in different tissues and organs independent of the central nervous system. Psoriasis, Crohn's disease, and fibromyalgia are among these disorders accompanying the depression. The treatment options for these conditions are a combination of the anti-depressants and anti-inflammatory agents. Bupropion has been widely utilized as an anti-depressant. It has been preferred among the patients with Crohn's disease and psoriasis due to its anti-inflammatory role, as well. In this study, we aimed to decipher its target in the immune system. Macrophages were activated in the presence of LPS and increasing concentrations of the bupropion. TNF-α, IL-6, GM-CSF, and IL-12p40 cytokines' production levels were measured by ELISA to compare it to the control groups. These cytokines have been associated with the aggressive inflammation in different tissues. Moreover, p38 and PI3K proteins' phosphorylated levels were measured to examine whether bupropion acts through these pathways or not. Our results suggest that bupropion had anti-inflammatory action on the activated macrophages and its mechanism of action was partially dependent on p38 but independent of PI3K pathways.

Effects of bupropion on sign- and goal-tracking in male Sprague Dawley rats.

Relapse into addiction is often triggered by cues that have a Pavlovian association with drugs and drug-taking. Sign-tracking involves approach of and interaction with Pavlovian conditioned signals for appetitive events (as opposed to goal-tracking, which involves approach of the site of the appetitive events themselves) and may be important in understanding cue-driven relapse. Bupropion is an atypical antidepressant and smoking cessation aid with effects on dopamine and norepinephrine that may have some utility in reducing sign-tracking. Male Sprague-Dawley rats were trained in a task where sign- and goal-tracking were possible and then administered doses of bupropion during a test phase. Bupropion decreased measures of sign-tracking and increased goal-tracking. This suggests that bupropion might be a useful adjunct medication for many kinds of behavioral disorders in which cue-driven behavior is problematic.

Influences of resting-state intrinsic functional brain connectivity on the antidepressant treatment response in late-life depression.

BACKGROUND: Late-life depression (LLD) is characterized by differences in resting state functional connectivity within and between intrinsic functional networks. This study examined whether clinical improvement to antidepressant medications is associated with pre-randomization functional connectivity in intrinsic brain networks. METHODS: Participants were 95 elders aged 60 years or older with major depressive disorder. After clinical assessments and baseline MRI, participants were randomized to escitalopram or placebo with a two-to-one allocation for 8 weeks. Non-remitting participants subsequently entered an 8-week trial of open-label bupropion. The main clinical outcome was depression severity measured by MADRS. Resting state functional connectivity was measured between a priori key seeds in the default mode (DMN), cognitive control, and limbic networks. RESULTS: In primary analyses of blinded data, lower post-treatment MADRS score was associated with higher resting connectivity between: (a) posterior cingulate cortex (PCC) and left medial prefrontal cortex; (b) PCC and subgenual anterior cingulate cortex (ACC); (c) right medial PFC and subgenual ACC; (d) right orbitofrontal cortex and left hippocampus. Lower post-treatment MADRS was further associated with lower connectivity between: (e) the right orbitofrontal cortex and left amygdala; and (f) left dorsolateral PFC and left dorsal ACC. Secondary analyses associated mood improvement on escitalopram with anterior DMN hub connectivity. Exploratory analyses of the bupropion open-label trial associated improvement with subgenual ACC, frontal, and amygdala connectivity. CONCLUSIONS: Response to antidepressants in LLD is related to connectivity in the DMN, cognitive control and limbic networks. Future work should focus on clinical markers of network connectivity informing prognosis. REGISTRATION: ClinicalTrials.gov NCT02332291.

Conditioned anti-immobility by ketamine: A comparison to escitalopram and bupropion.

This study was designed to explore the clinical belief that "set and setting" play an important role in favorable responses to psychedelic agents such as ketamine (KET). In fact, there is evidence in animals that the antidepressant effect of this drug may involve drug-environment interactions in which a context paired with its effects acquires the ability to influence behavior. Therefore, it was investigated in male Sprague-Dawley rats whether exposure to a context paired with the effects of KET, or with the effects of the common antidepressant medications bupropion (BUP) and escitalopram (ESC), could produce an antidepressant-like conditioned response. In Experiment 1, subjects received saline in a vehicle-paired context (denoted as CS-), and 0, 10, or 20 mg/kg KET, 10 mg/kg ESC, or 10 mg/kg BUP in a drug-paired context (denoted as CS +), on 10 alternating days (5 pairings with each context). The rats were then exposed drug free to the CS- and CS + prior to the assessment of immobility in the forced-swimming test. Experiment 2 assessed approach/avoidance responses induced by the CS- and CS + in a place-conditioning test. It was found that exposure to the KET CS + significantly reduced immobility without affecting general locomotor activity in comparison to the SAL CS + and the BUP CS +, but not the ESC CS+. Moreover, no group differences were observed in the place-conditioning test, indicating that the anti-immobility effect of the KET CS + was likely not influenced by a conditioned incentive or aversive state. Together, these data suggest that a KET-paired context can elicit a conditioned antidepressant-like response, which may be a mechanism involved in its sustained antidepressant clinical action. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A 1:1 ratio of cannabidiol: tetrahydrocannabinol attenuates methamphetamine conditioned place preference in mice: A prospective study of antidopaminergic mechanism.

A 1:1 ratio of cannabidiol to tetrahydrocannabinol (CT) was suggested to be safer for therapeutic purposes in many illnesses. However, CT effects on methamphetamine (METH) conditioned place preference (CPP) remained largely unexplored. This study aimed to examine the effects of CT on METH CPP mice evaluated by animal behaviors accompanied by local field potential (LFP) signals analysis. Male ICR mice were implanted with the LFP electrode in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Animals were next subjected to induce METH CPP by peritoneal injection with 1 mg/kg METH and 0.9 % NaCl on an alternate day for ten sessions and confined to the corresponding compartment for 30 min meanwhile control mice were given normal saline all day for both compartments. On testing day, either 10 mg/kg CT or 20 mg/kg bupropion (BP), a dopamine reuptake inhibitor, and VTA GABAergic suppressor were orally administered before CPP testing. The results revealed that CPP scores elevation was observed in the METH+vehicle and METH+BP mice, but this was reversed by CT treatment. Although both METH+vehicle and METH+BP enhanced the VTA delta power, NAc gamma I power, NAc delta-gamma coupling, and VTA-NAc gamma I coherence, changes in opposite trends of all mentioned parameters were seen by CT application. These improvements were postulated to involve the antidopaminergic effects of CT via modulations of neural signaling in the VTA and NAc. Altogether, the evidence-based study may suggest the use of CT as alternative drug for METH-seeking and craving therapy.

Bupropion XL unapproved use in the prisons: Two cases focused on the bupropion pharmacology.

BACKGRUND: Bupropion (BUP) is a norepinephrine-dopamine reuptake inhibitor frequently used in prisons. Although its positive effects on depression treatment are often presented, there are many questions about its approved use in prisons and similar facilities. In this context, this article aims to present two case reports of BUP XL unapproved use and a review of the mechanism of action, formulations, and the clinical profile of BUP. METHODS: Two case reports. The patients' data for the case reports were obtained from their medical records. A PubMed search was conducted using the terms BUP, inmates, and efficacy to identify randomized and non-randomized controlled trials and case reports to evaluate the possible effects of BUP in prison settings. Only approved medications were included. RESULTS: The positive effects of BUP XL on major depressive disorder treatment are well-reported, but few reports are on the pharmacokinetics of BUP XL in prisons. The exact mechanism of its effect on the central nervous system is predominantly connected with its unique pharmacokinetics. CONCLUSIONS: This paper shows that BUP XL will continue to play an essential role in treating a major depressive disorder in adults in prisons and other related disorders, although a different treatment strategy should be preferred in patients with high addictive potential. Because of a similar mechanism of action, the most appropriate alternatives for BUP XL could be mirtazapine, agomelatine, aripiprazole, and quetiapine, although clinical trials are needed to confirm these alternatives.

Neural signaling of methamphetamine craving and seeking intensified by bupropion in the ventral tegmental area-cortico-accumbens circuitry in mice.

Previously, bupropion (BUP), a norepinephrine (NE)/dopamine (DA) transporter blocker and nicotinic acetylcholine receptors (nAChRs) antagonist, was found to intensify methamphetamine (METH) craving behaviours in mice. Intense craving causes relapse in drug dependence. This study characterized local field potential (LFP) patterns in the brain regions associated with METH-conditioned place preference (CPP) enhanced by BUP. Male Swiss albino ICR mice were implanted with LFP electrodes to the ventral tegmental area (VTA), medial prefrontal cortex (mPFC) and the nucleus accumbens core (NAcc). Animals received sessions to learn the association between injection effects (1 mg/kg METH and normal saline) with contextual environments (METH- and saline-paired compartments) during the conditioning phase. A total of 20 mg/kg BUP was given to animals before LFP, and behaviour recording in the CPP apparatus during the post-conditioning phase. The results showed that increased CPP scores and % number of entries to the METH-paired zone, as well as changes in VTA, mPFC and NAcc spectral powers and coherence among these areas, were associated with METH-CPP. Treatment with BUP increased VTA delta and gamma I, decreased mPFC alpha, increased NAcc gamma I and decreased gamma II powers. Coherence analyses revealed that BUP decreased gamma II VTA-mPFC and increased beta and gamma I VTA-NAcc connectivity. Altogether, BUP produced additional effects to that of METH-CPP alone. These findings demonstrated changes in neural circuit activities associated with METH-CPP intensified by BUP. Moreover, modulation of NE/DA systems and/or nAChRs actions in the VTA-cortico-accumbens loop might underlie METH craving and dependence.

Dextromethorphan/Bupropion: First Approval.

An oral, fixed-dose combination of dextromethorphan hydrobromide [an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist] and the antidepressant bupropion hydrochloride (an aminoketone and CYP2D6 inhibitor that increases dextromethorphan bioavailability) [AUVELITYTM; dextromethorphan/bupropion], is being developed by Axsome Therapeutics, Inc. for the treatment of major depressive disorder (MDD), Alzheimer's disease agitation and smoking cessation. Dextromethorphan/bupropion was approved in the USA in August 2022 for the treatment of MDD in adults. This article summarizes the milestones in the development of dextromethorphan/bupropion leading to this first approval for the treatment of adults with MDD.

Is there a therapeutic potential in combining bupropion and naltrexone in schizophrenia?

INTRODUCTION: A sustained-release tablet composed of a combination of the dopamine and norepinephrine reuptake inhibitor bupropion (BUP) and the µ-opioid receptor antagonist naltrexone (NAT) is marketed under the brand name Contrave by Orexigen Therapeutics for appetite control. Minimal literature is available regarding the use of combination bupropion and naltrexone (BUPNAT) in individuals with schizophrenia. AREAS COVERED: In this review, we propose a theoretical model where BUPNAT may have a therapeutic effect in the treatment of schizophrenia. We explore the pathways targeted by the constituent drugs BUP and NAT and summarize the literature on their efficacy and possible adverse effects. We then look at the potential use of BUPNAT in schizophrenia. EXPERT OPINION: Research has hinted that BUP's dopaminergic properties affect the same striatal pathways involved in schizophrenia. NAT, via opioid receptor antagonism, indirectly increases striatal dopamine release by disinhibiting nicotinic acetylcholine receptors. As such, we hypothesize that BUPNAT can have a therapeutic effect in schizophrenia, particularly on negative symptoms. We also suggest that it may ameliorate comorbidities frequently seen in this group of patients, including obesity, smoking, and substance use. Further research and clinical data are needed to elucidate the potential clinical benefits of BUPNAT in the treatment of schizophrenia.

Selective deuteration of bupropion slows epimerization and reduces metabolism.

Strategically replacing hydrogen with deuterium at sites of metabolism in small molecule drugs can significantly alter clearance and potentially enhance clinical safety. Bupropion is an antidepressant and smoking cessation medication with the potential to cause seizures. We hypothesized that incorporating deuterium at specific sites in bupropion may greatly reduce epimerization, potentially slow metabolism, and reduce the formation of toxic metabolites, namely hydroxybupropion which has been associated with bupropion's toxicity. Four deuterated analogues were synthesized incorporating deuterium at sites of metabolism and epimerization with the aim of altering the metabolic profile of bupropion. Spectroscopic binding and metabolism studies with bupropion and R-or S-d4 and R-or S-d10 analogs were performed with recombinant CYP2B6, human liver microsomes, and human hepatocytes. Results demonstrate that deuterated bupropion analogues exhibited 20-25% decrease in racemization and displayed a significant decrease in the formation of CYP2B6-mediated R,R - or S,S-hydroxybupropion with recombinant protein and human liver microsomes. In primary human hepatocytes, metabolism of deuterated analogs to R,R - and S,S-hydroxybupropion and threo- and erythro-hydrobupropion was significantly less than R/S-d0 bupropion. Selective deuterium substitution at metabolic soft spots in bupropion has the potential to provide a drug with a simplified pharmacokinetic profile, reduced toxicity and improved tolerability in patients.