The angiotensin-(1-7)/MasR axis improves pneumonia caused by Pseudomonas aeruginosa: Extending the therapeutic window for antibiotic therapy.

Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.

Pharmacology of boldine: summary of the field and update on recent advances.

Over the past decade, boldine, a naturally occurring alkaloid found in several plant species including the Chilean Boldo tree, has garnered attention for its efficacy in rodent models of human disease. Some of the properties that have been attributed to boldine include antioxidant activities, neuroprotective and analgesic actions, hepatoprotective effects, anti-inflammatory actions, cardioprotective effects and anticancer potential. Compelling data now indicates that boldine blocks connexin (Cx) hemichannels (HCs) and that many if not all of its effects in rodent models of injury and disease are due to CxHC blockade. Here we provide an overview of boldine's pharmacological properties, including its efficacy in rodent models of common human injuries and diseases, and of its absorption, distribution, pharmacokinetics, and metabolism.

Use of Ketamine in Patients with Multifactorial Neuropathic Pain: A Systematic Review and Meta-Analysis.

Neuropathic pain (NP) is a heterogeneous group of conditions characterized by the experience of a number of sensory disturbances including pain, burning sensations, paroxysms of stabbing pain, dysesthesias, allodynia, and hyperalgesia. The above-mentioned sensations may occur in a specific dermatome area or other delimited region of the body. The objective of this review was to analyze the evidence for ketamine in multifactorial neuropathic pain. The research group systematically searched the databases MEDLINE (via PubMed), EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature (Cinahl), and the Web of Science. The findings of this review show that different forms of low doses of ketamine (LDK) do not present statistically significant changes for any of the scales included. In this study, the total symptom score [standardized mean difference (SMD) = -3.59, confidence interval (CI) = -4.16 to -3.02, and p < 0.00001], neuropathy impairment score (SMD = -1.42, CI = -3.68 to 0.84, and p = 0.22), and neuropathy symptom checklist (SMD = -0.09, CI = -0.15 to -0.02, and p = 0.01) were taken into account. For finality compared to the use of a placebo, the findings suggest that LDK does not exhibit significant differences in terms of pain reduction and functionality. Moreover, no specific dosages are identified to support the use of LDK in the reduction in NP.

Theophylline impact on weaning in oxygen-dependent infants followed in an outpatient Kangaroo Program.

Background: Theophylline was an orally administered xanthine used for treatment of apnea of prematurity and Bronchopulmonary Dysplasia in ambulatory follow-up of Low-Birth-Weight infants (LBWI) with oxygen-dependency in the outpatient Kangaroo Mother Care Program (KMCP). Theophylline's main metabolic product is caffeine; therefore, it was an alternative due to the frequent lack of ambulatory oral caffeine in low and middle-income countries. Objective: To assess the effectiveness of oral theophylline in decreasing days with oxygen and to describe frequency of adverse related events. Methods: Quasi-experiment before and after withdrawal of theophylline given systematically to LBWI with ambulatory oxygen in two KMCPs. Results: 729 patients were recruited; period 1: 319 infants when theophylline was given routinely and period 2: 410 infants when theophylline was no longer used. The theophylline cohort had less gestational age, less weight at birth, more days in Neonatal Intensive Care Unit, more days of oxygen-dependency at KMCP admission, and more frequencies of Intrauterine Growth Restriction and apneas. After adjusting with propensity score matching, multiple linear regression showed that nutrition was associated with days of oxygen-dependency, but theophylline treatment not. No differences were found in frequencies of readmissions up to 40 weeks, intraventricular hemorrhage or neurodevelopmental problems. Participants in period 2 had more tachycardia episodes. Conclusions: We did not find association between oral theophylline treatment and the reduction of days with ambulatory oxygen. For the current management of oxygen-dependency in LBW infants, the importance of nutrition based on exclusive breast feeding whenever possible, is the challenge.

Boosting the Beat: A Critical Showdown of Levosimendan and Milrinone in Surgical and Non-Surgical Scenarios: A Narrative Review.

Acute heart failure, advanced cardiac failure, cardiac surgery, and sepsis are conditions that require simultaneous treatment to stimulate contractility and/or reduce systemic vascular resistance, with levosimendan and milrinone being treatment options. This research's aim is to review the current indications and evidence for these medications across various scenarios. Evidence suggests that levosimendan is a non-inferior alternative to dobutamine and superior to milrinone in treating low cardiac output syndrome following cardiac surgery. In cases of septic shock, levosimendan has been linked to lower mortality rates compared to placebo, while milrinone's efficacy remains inconclusive. Furthermore, postoperative patients undergoing correction for congenital heart disease have shown reduced mechanical ventilation time and intensive care unit stays when treated with levosimendan, although differences exist between the populations assigned to each intervention. In conclusion, levosimendan, compared to milrinone, appears to offer better hemodynamic favorability in patients undergoing cardiac surgery. However, additional research is necessary to further understand its impact on hemodynamic outcomes, mortality, intensive care unit, and hospital stays in patients with cardiogenic shock of both ischemic and non-ischemic etiologies, as well as septic shock.

Introducing the concept of loss of corticosteroid credit in asthma.

The widespread use of systemic corticosteroids (SCS) in asthma is associated with significant comorbidities and mortality. A dose-response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0-<2.5 g, equivalent to four lifetime SCS courses. The purpose of creating the SCS credit concept was to increase awareness of the risks of SCS exposure and to promote better therapeutic alternatives. Consuming the lifetime SCS credit of 1.5 g/yr significantly increased morbidity and mortality.

Vitreoretinal surgical performance after acute alcohol consumption and hangover.

AIM: Routine alcohol testing of practicing physicians remains controversial since there are no uniform guidelines or legal regulations in the medical field. Our aim was to quantitatively study the acute and next-morning effects of breath alcohol concentration (BAC)-adjusted alcohol intake on overall simulated surgical performance and microtremor among senior vitreoretinal surgeons. METHODS: This prospective cohort study included 11 vitreoretinal surgeons (>10 years practice). Surgical performance was first assessed using the Eyesi surgical simulator following same-day alcohol consumption producing a BAC reading of 0.06%-0.10% (low-dose), followed by 0.11%-0.15% (high-dose). Dexterity was then evaluated after a 'night out' producing a high-dose BAC combined with a night's sleep. Changes in the total score (0-700, worst-best) and tremor (0-100, best-worst) were measured. RESULTS: Surgeon performance declined after high-dose alcohol compared with low-dose alcohol (-8.60±10.77 vs -1.21±7.71, p=0.04, respectively). The performance during hangover was similar to low-dose alcohol (-1.76±14.47 vs -1.21±7.71, p=1.00, respectively). The performance during hangover tended to be better than after high-dose alcohol (-1.76±14.47 vs -8.60±10.77, p=0.09, respectively). Tremor increased during hangover compared with low-dose alcohol (7.33±21.65 vs -10.31±10.73, p=0.03, respectively). A trend toward greater tremor during hangover occurred compared with high-dose alcohol (7.33±21.65 vs -4.12±17.17, p=0.08, respectively). CONCLUSION: Alcohol-related decline in simulated surgical dexterity among senior vitreoretinal surgeons was dose-dependent. Dexterity improved the following morning but remained comparable to after low-dose alcohol ingestion. Tremor increased during hangover compared with same-day intoxication. Further studies are needed to investigate extrapolations of these data to a real surgical environment regarding patient safety and surgeon performance.

Effects of a pro-resolving drug in COVID-19: preclinical studies to a randomized, placebo-controlled, phase Ib/IIa trial in hospitalized patients.

INTRODUCTION: Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19. METHODS: C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg-1, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO2 ≥ 93% in ambient air. RESULTS: Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1ß by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017). CONCLUSION: Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans.

Prostaglandin analogues signal detection by data mining in the FDA Adverse Event Reporting System database.

OBJECTIVE: This study aims to identify safety signals of ophthalmic prostaglandin analogues through data mining the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: A data mining search by proportional reporting ratio, reporting OR, Bayesian confidence propagation neural network, information component 0.25 and χ2 for safety signals detection was conducted to the FAERS database for the following ophthalmic medications: latanoprost, travoprost, tafluprost and bimatoprost. RESULTS: 12 preferred terms were statistically associated: diabetes mellitus, n=2; hypoacusis, n=2; malignant mediastinal neoplasm, n=1; blood immunoglobulin E increased, n=1; cataract, n=1; blepharospasm, n=1; full blood count abnormal, n=1; skin exfoliation, n=1; chest discomfort, n=1; and dry mouth, n=1. LIMITATION OF THE STUDY: The FAERS database's limitations, such as the undetermined causality of cases, under-reporting and the lack of restriction to only health professionals reporting this type of event, could modify the statistical outcomes. These limitations are particularly relevant in the context of ophthalmic drug analysis, as they can affect the accuracy and reliability of the data, potentially leading to biased or incomplete results. CONCLUSIONS: Our findings have revealed a potential relationship due to the biological plausibility among malignant mediastinal neoplasm, full blood count abnormal, blood immunoglobulin E increased, diabetes mellitus, blepharospasm, cataracts, chest discomfort and dry mouth; therefore, it is relevant to continue investigating the possible drug-event association, whether to refute the safety signal or identify a new risk.

Access to and utilisation of antimicrobials among forcibly displaced persons in Uganda, Yemen and Colombia: a pilot cross-sectional survey.

OBJECTIVES: Identifying key barriers to accessing quality-assured and affordable antimicrobials among forcibly displaced persons in Uganda, Yemen and Colombia and investigating their (1) utilisation patterns of antibiotics, (2) knowledge about antimicrobial resistance (AMR) and (3) perception of the quality of antimicrobials received. DESIGN: Pilot cross-sectional survey. SETTING: Data were collected from five health facilities in the Kiryandongo refugee settlement (Bweyale, Uganda), three camps for internally displaced persons (IDPs) in the Dar Sad district (Aden, Yemen) and a district with a high population of Venezuelan migrants (Kennedy district, Bogotá, Colombia). Data collection took place between February and May 2021. The three countries were selected due to their high number of displaced people in their respective continents. PARTICIPANTS: South Sudanese refugees in Uganda, IDPs in Yemen and Venezuelan migrants in Colombia. OUTCOME MEASURE: The most common barriers to access to quality-assured and affordable antimicrobials. RESULTS: A total of 136 participants were enrolled in this study. Obtaining antimicrobials through informal pathways, either without a doctor's prescription or through family and friends, was common in Yemen (27/50, 54.0%) and Colombia (34/50, 68.0%). In Yemen and Uganda, respondents used antibiotics to treat (58/86, 67.4%) and prevent (39/86, 45.3%) a cold. Knowledge of AMR was generally low (24/136, 17.6%). Barriers to access included financial constraints in Colombia and Uganda, prescription requirements in Yemen and Colombia, and non-availability of drugs in Uganda and Yemen. CONCLUSION: Our multicentred research identified common barriers to accessing quality antimicrobials among refugees/IDPs/migrants and common use of informal pathways. The results suggest that knowledge gaps about AMR may lead to potential misuse of antimicrobials. Due to the study's small sample size and use of non-probability sampling, the results should be interpreted with caution, and larger-scale assessments on this topic are needed. Future interventions designed for similar humanitarian settings should consider the interlinked barriers identified.

An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024?

INTRODUCTION: Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored. AREAS COVERED: Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective. EXPERT OPINION: In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

Liver Fibrosis Stages Affect Organic Cation Transporter 1/2 Activities in Hepatitis C Virus-Infected Patients.

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0-24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61-0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66-0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97-1.24), p > 0.05) and 2 (ratio 1.03 (0.94-1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.

Medicinal Orchids of Mexico: A Review.

Some species of the Orchidaceae family are used in Mexican traditional medicine. However, there are no current and critical compilations of the medicinal uses and pharmacological effects of the members of the Orchidaceae family. This review provides a current, critical, and comprehensive analysis of the traditional medicinal uses, pharmacological reports, and active compounds isolated from Mexican orchids. A total of 62 Mexican orchids with medicinal potential have been recorded, of which 14 have scientific evidence. The remaining 48 plant species have ethnomedicinal information but have not been validated with scientific studies. These orchids are distributed in 14 states of the Mexican Republic, mainly in the southern region of Mexico. The most common pharmacological activities reported are anti-inflammatory, vasorelaxant, antinociceptive, antioxidant, spasmolytic, antihypertensive, and hallucinogenic activities. It is necessary to increase the number of pharmacological, phytochemical, and toxicological studies with medicinal orchids from Mexico because there are scientific studies on only 22.5% of these species. In further studies, it will be possible to evaluate the pharmacological effects of Mexican orchids in clinical trials. In addition, the mechanisms of action by which plant extracts and their active compounds exert medicinal effects remain to be studied. Plant extracts from orchids and their active compounds show promising antinociceptive and spasmolytic effects, respectively.

Cannabidiol and Alzheimer's disease.

Alzheimer's disease (AD) stands as the most prevalent form of neuropsychiatric disorder among the elderly population, impacting a minimum of 50 million individuals worldwide. Current pharmacological treatments rely on the prescribing cholinesterase inhibitors and memantine. However,recently anecdotal findings based on low-quality real-world data had prompted physicians, patients, and their relatives to consider the use of cannabinoids, especially Cannabidiol (CBD), for alleviating of AD symptoms. CBD the primary non-psychotomimetic compound found in the Cannabis sp. plant, exhibits promising therapeutic potential across various clinical contexts. Pre-clinical and in vitro studies indicate that CBD could mitigate cognitive decline and amyloid-beta-induced neurodegeneration by modulating oxidative stress and neuroinflammation. In addition, CBD demonstrates significant effects in promoting neuroplasticity, particularly in brain regions such as the hippocampus. However, the available clinical evidence presents conflicting results, and no randomized placebo-controlled trials have been published to date. In conclusion, although pre-clinical and in vitro studies offer encouraging insights into the potential benefits of CBD in AD models, new and well-designed clinical trials are imperative to ascertain the clinical relevance of CBD use in the management of AD symptoms, especially in comparison to conventional treatments.

Effectiveness of pharmacological interventions for managing ADHD symptoms in individuals with autism spectrum disorder: A systematic review and meta-analysis.

OBJECTIVES: This systematic review sought to provide evidence for the effectiveness of common pharmacological interventions used for treating attention deficit hyperactivity disorder (ADHD) symptoms in the autism spectrum disorder (ASD) population, considering studies attempting to find safe and effective drugs. METHODS: We searched for randomized controlled trials describing the effectiveness and/or safety profile of pharmacological interventions for treating ASD and ADHD or ASD with ADHD symptoms using three bibliographic databases: PubMed, Cochrane Library, and Embase. We have chosen ADHD symptoms measured by any clinical scale as the primary outcome. As additional outcomes, we have used other symptoms of aberrant behavior measured by the aberrant behavior checklist, satisfaction with treatment, and peer satisfaction. RESULTS: Twenty-two publications met the inclusion criteria for the systematic review and eight for the meta-analysis. In our investigation, we found a few articles using clonidine, modafinil, and bupropion as interventions when compared to methylphenidate (MPH). Our meta-analysis showed that MPH had positive changes compared to placebo in symptoms such as hyperactivity, irritability, or inattention. However, no effect was found in stereotyped symptoms, and our data's quantitative analysis revealed a large effect of MPH-induced adverse effects on the dropout rate. On the other hand, atomoxetine initiation had positive effects when compared to placebo on symptoms of hyperactivity and inattention. We have found no effect of atomoxetine on stereotypes or irritability. Furthermore, atomoxetine did not influence side effects that caused dropouts from studies. CONCLUSION: Our results indicated that atomoxetine has a modest effect on hyperactivity and inattention symptoms, with a relatively benign profile of side effects. MPH appears to be effective in handling hyperactivity, inattention, and irritability symptoms. However, our results on atomoxetine revealed increased dropouts due to adverse effects when compared to MPH or placebo. Evidence for other substances such as guanfacine, clonidine, bupropion, or modafinil is either preliminary or nonexistent.

Management of hereditary hemorrhagic telangiectasia-like symptoms induced by trastuzumab emtansine in a breast cancer patient: case report.

Trastuzumab emtansine (T-DM1) is a targeted therapy combining trastuzumab and emtansine for human epidermal growth factor receptor 2(HER2)-positive breast cancer, with common side effects including fatigue, nausea, pain, headache, low platelet count, and elevated liver enzymes. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by vascular malformations and telangiectasias in various organs. We present a case of a female patient with advanced breast cancer who developed HHT-like symptoms while on T-DM1 treatment. A 59-year-old woman treated with radiotherapy and T-DM1 every 21 days developed recurring nosebleeds and mucocutaneous and liver telangiectasias indistinguishable from HHT three months after receiving the first dose of T-DM1. Other organ vascular malformations were ruled out through screening protocols. The patient had no previous HHT symptoms or family history. Nasal care measures like lubrication and antifibrinolytics (tranexamic acid) were provided. In addition, propranolol was also prescribed due to its antiangiogenic and antitumoral properties, leading to significantly decreased epistaxis and telangiectasias. Microtubule disruptions caused by T-DM1, along with other angiogenic mechanisms may contribute to the development of telangiectasias resembling HHT. The use of propranolol, an initial approach for HHT, proved to be effective in this case. It is crucial for oncologists and HHT specialists to be aware of this rare adverse event associated with T-DM1 and to implement appropriate management strategies.

Pharmacokinetic Profile and Comparative Bioavailability of an Oral Fixed-Dose Combination of Metformin and Acetylsalicylic Acid (Aspirin).

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2 × 2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0 -t), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC0 ∞) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study.

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.