Intranasal bilosomes in thermosensitive hydrogel: advancing desvenlafaxine succinate delivery for depression management.

Depression, the second biggest cause of disability worldwide, is widespread. Many antidepressant medications, including Desvenlafaxine Succinate (D.V.S.), function by elevating neurotransmitter levels at the synapse through the inhibition of reabsorption by neurons. However, the effectiveness of these treatments is often limited by their inability to reach the brain using conventional administration methods. Bilosome-stabilized nanovesicles containing bile salts have drawn much interest because of their adaptability and versatility in various applications. This study aimed to address this issue by formulating intranasal bilosomes incorporated into a mucoadhesive in situ gel to deliver D.V.S. directly to the brain for depression treatment. The desvenlafaxine-loaded bilosomes were developed using a thin film hydration method based on the l-optimal design. They were intended to provide a more convenient route of administration for antidepressants, enhancing bioavailability and brain targeting through intranasal delivery. The study assessed the optimized bilosomes for particle size (311.21 ± 0.42 nm), Zeta potential (-37.35 ± 0.43)and encapsulation efficiency (99.53 ± 0.41%) and further evaluated them in ex vivo and in vivo pharmacokinetics studies. Pharmacokinetic data reveal enhanced brain uptake compared to a free drug. A statistically optimized bilosome formulation was determined. The intranasal administration of mucoadhesive in situ gel containing desvenlafaxine succinate-loaded bilosomes facilitated direct nose-to-brain drug delivery, improving brain bioavailability.

Clinical and Adverse Outcomes Associated With Concomitant Use of CYP2D6-Metabolized Opioids With Antidepressants in Older Nursing Home Residents : A Target Trial Emulation Study.

BACKGROUND: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents. OBJECTIVE: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs). DESIGN: Retrospective cohort study using a target trial emulation framework. SETTING: 100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021. PARTICIPANTS: Long-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use. INTERVENTION: Initiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more. MEASUREMENTS: Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting. RESULTS: Among 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose. LIMITATION: Findings are generalizable to NH populations only. CONCLUSION: Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents. PRIMARY FUNDING SOURCE: National Institute on Aging.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

INTRODUCTION: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. METHODS: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. RESULTS: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. DISCUSSION: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

Pharmacogenomic Characterization of Childbearing-Aged Individuals With Mood Disorders in a Tertiary Care Perinatal Mental Health Clinic.

Objective: The effectiveness of antidepressant treatment for mood disorders is often limited by either a poor response or the emergence of adverse effects. These complications often necessitate multiple drug trials. This clinical challenge intensifies during pregnancy, when medications must be selected to improve the likelihood of response and optimize reproductive outcomes. We determined the distribution of common pharmacogenetic variants, metabolizer phenotypes, past medication responses, and side effects in childbearing-aged individuals seeking treatment in a tertiary care perinatal mental health clinic.Methods: Sixty treatment-seeking women (based on sex at birth) with DSM-5- defined bipolar disorder (n = 28) or major depressive disorder (n = 32) provided DNA samples and completed psychiatric diagnostic and severity assessments between April 2014 and December 2017. Samples were genotyped for single-nucleotide variants in drug metabolizing enzyme genes of commonly prescribed antidepressants (cytochrome P450 [CYP] 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5), and the frequency of normative metabolizer status was compared to reference populations data from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The Antidepressant Treatment History Form was used to record historic medication trials and side effects.Results: A significantly greater proportion of extensive metabolizers for CYP2B6 was observed in the study population when compared to CPIC population frequency databases in Caucasians (0.64 vs 0.43 [95% CI: 0.49-0.76]; P value = .006) and African Americans (0.71 vs 0.33 [95% CI: 0.29-0.96]; P value = .045). No significant association was found between metabolizer phenotype and the likelihood of a medication side effect.Conclusion: Pharmacogenomic testing may have value for personalized prescribing in individuals capable of or considering pregnancy.

Population Pharmacokinetics of Sertraline in Psychiatric and Substance Use Disorders.

This study aimed to characterize the population pharmacokinetics of sertraline in Mexican patients with psychiatric and substance use disorders. Fifty-nine patients (13 to 76 years old) treated with doses of sertraline between 12.5 and 100 mg/day were included. Plasma sertraline concentrations were determined in blood samples and five of the main substances of abuse were determined by rapid tests in urine samples. Demographic, clinical, and pharmacogenetic factors were also evaluated. Population pharmacokinetic analysis was performed using NONMEM software with first-order conditional estimation method. A one-compartment model with proportional residual error adequately described the sertraline concentrations versus time. CYP2D6*2 polymorphism and CYP2C19 phenotypes significantly influenced sertraline clearance, which had a population mean value of 66 L/h in the final model. The absorption constant and volume of distribution were fixed at 0.855 1/h and 20.2 L/kg, respectively. The model explained 11.3% of the interindividual variability in sertraline clearance. The presence of the CYP2D6*2 polymorphism caused a 23.1% decrease in sertraline clearance, whereas patients with intermediate and poor phenotype of CYP2C19 showed 19.06% and 48.26% decreases in sertraline clearance, respectively. The model was internally validated by bootstrap and visual predictive check. Finally, stochastic simulations were performed to propose dosing regimens to achieve therapeutic levels that contribute to improving treatment response.

Basmisanil, an α5-GABAAR negative allosteric modulator, produces rapid and sustained antidepressant-like responses in male mice.

There is a critical need for safer and better-tolerated alternatives to address the current limitations of antidepressant treatments for major depressive disorder. Recently, drugs targeting the GABA system via α5-containing GABAA receptors (α5-GABAAR) as negative allosteric modulators (α5-NAMs) have shown promise in alleviating stress-related behaviors in preclinical studies, suggesting that α5-NAMs may have translational relevance as novel antidepressant medications. Here, we evaluated the efficacy of Basmisanil, an α5-NAM that has been evaluated in Phase 2 clinical studies as a cognitive enhancer, in a battery of behavioral tests relevant to coping strategies, motivation, and aversion in male mice, along with plasma and brain pharmacokinetic measurements. Our findings reveal that Basmisanil induces dose-dependent rapid antidepressant-like responses in the forced swim test and sucrose splash test without promoting locomotor stimulating effects. Furthermore, Basmisanil elicits sustained behavioral responses in the female urine sniffing test and sucrose splash test, observed 24 h and 48 h post-treatment, respectively. Bioanalysis of plasma and brain samples confirms effective blood-brain barrier penetration by Basmisanil and extrapolation to previously published data suggest that effects were observed at doses (10 and 30 mg/kg i.p.) corresponding to relatively modest levels of α5-GABAAR occupancy (40-65 %). These results suggest that Basmisanil exhibits a combination of rapid and sustained antidepressant-like effects highlighting the potential of α5-NAMs as a novel therapeutic strategy for depression.

Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study.

BACKGROUND: Intranasal esketamine is an approved drug for treatment­resistant depression (TRD); however, it is costly and may result in specific adverse effects. In this single case study, we explored if oral esketamine can be a suitable alternative. METHODS: In collaboration with a 39­year­old female with TRD, we compared plasma concentration curves of intranasal (84 mg) and oral (1, 2 and 4 mg/kg) esketamine. Because oral esketamine has a relatively low bioavailability, it results in a different ratio between esketamine and its primary metabolite noresketamine. To increase the bioavailability of oral esketamine, we co­administered a single dose of the cytochrome P­450 (CYP) 3A4 inhibitor cobicistat (150 mg). RESULTS: For all doses administered, oral esketamine resulted in lower esketamine but higher noresketamine peak plasma concentrations compared with intranasal treatment. Using oral esketamine it was not possible to generate a similar esketamine plasma concentration curve as with the intranasal treatment, except when combined with cobicistat (esketamine 2 mg/kg plus cobicistat 150 mg). CONCLUSIONS: Our findings demonstrate that cobicistat effectively increases the bioavailability of oral esketamine. Further research is required in a larger population, especially to investigate the clinical benefit of cobicistat as a booster drug for oral esketamine.

Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats.

Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants, amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4 % and 33.3 %, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7 % and 49.4 %, respectively. It indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with amitriptyline or fluoxetine in ongoing clinical practice.

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide.

The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a ß-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

A Combination of Magnoflorine and Spinosin Improves the Antidepressant effects on CUMS Mouse Model.

BACKGROUND: Depression is a common neuropsychiatric disease. As a famous traditional Chinese medicine with significant anti-depressive and sleep-promoting effects, Ziziphi Spinosae Semen (ZSS) has attracted the attention of many researchers. Although it is well known that Magnoflorine (MAG) and Spinosin (SPI) were the main active components isolated from ZSS, there is a lack of research on the combined treatment of depression with these two ingredients. METHODS: The shaking bottle method was used to simulate the human environment for detecting the changes in oil-water partition coefficient before and after the drug combination. Cell viability was evaluated by the MTT assay. To establish a mouse model of depression and insomnia by CUMS method, and then to explore the effect of combined administration of MAG and SPI on depression in CUMS model by observing behavior and analyzing pharmacokinetics. RESULTS: The change in LogP values affected the lipid solubility of MAG and increased the water solubility of SPI, allowing them to penetrate more easily through the blood-brain barrier into the brain. Compared with the model group, MAG-SPI with a concentration of 60 µM significantly increased cell survival rate. In both the TST and FST experiments, the mice showed a decrease in immobilization time. Pharmacokinetic results showed that the pharmacokinetic parameters, Cmax and AUC of MAG and SPI, were increased in the case of combination, which resulted in enhancement of their relative bioavailability and improvement of in vivo effects. CONCLUSIONS: The present study demonstrated that a combination of MAG and SPI had a synergistic antidepressant effect in CUMS mouse model.

Metabolic bioactivation of antidepressants: advance and underlying hepatotoxicity.

Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors. Although the precise mechanism by which toxicity is induced may be difficult to determine, identifying reactive metabolites that cause toxicity can offer valuable insights for decreasing the bioactivation potential of candidates during the drug discovery process. A comprehensive understanding of drug metabolic pathways can mitigate adverse drug-drug interactions that may be caused by elevated formation of reactive metabolites. This review provides a comprehensive overview of the current state of knowledge on antidepressant bioactivation, the metabolizing enzymes responsible for the formation of reactive metabolites, and their potential implication in hepatotoxicity. This information can be a valuable resource for medicinal chemists, toxicologists, and clinicians engaged in the fields of antidepressant development, toxicity, and depression treatment.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Changes in Serum Concentration of Antidepressants After Bariatric Surgery and Recommendations for Postbariatric Surgery Antidepressant Therapy.

BACKGROUND: Bariatric surgery affects the absorption of medications including antidepressants, but data regarding these effects are limited. OBJECTIVES: Our objectives were to review publicly available data regarding changes in antidepressant serum concentration following bariatric surgery in order to develop medication dosing recommendations in this patient population. METHODS: A comprehensive literature review was performed utilizing key search terms in Pubmed. Additional data were retrieved from the Food and Drug Administration and DrugBank Online resources. RESULTS: A total of twelve published articles were included in addition to the publicly available data from the Food and Drug Administration and DrugBank. The serum concentration of antidepressants following bariatric surgery demonstrated considerable variability between and within drug classes due to unique pharmacokinetic features, drug preparation, and formulation. Recommendations were developed from published data regarding changes in serum concentration and drug-specific pharmacokinetic data. CONCLUSIONS: To our knowledge, this is the first study to propose medication dose-adjustment recommendations for patients on antidepressants undergoing bariatric surgery. We were limited by the relatively small amount of data available and recommend monitoring patients and use of clinical judgment along with this guidance.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy.

Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient's individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug's absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient's response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment.

Recent Advances in Analytical Techniques for Antidepressants Determination in Complex Biological Matrices: A Review.

Depression is one of the most prevalent but severe of mental disorders, affecting thousands of individuals across the globe. Depression, in its most extreme form, may result in self-harm and an increased likelihood of suicide. Antidepressant drugs are first-line medications to treat mental disorders. Unfortunately, these medications are also prescribed for other in- and off-label conditions, such as deficit/hyperactivity disorders, attention disorders, migraine, smoking cessation, eating disorders, fibromyalgia, pain, and insomnia. This results in an increase in the use of antidepressant medications, leading to clinical and forensic overdose cases that could be either accidental or deliberate. The findings revealed that people who used antidepressants had a 33% greater chance of dying sooner than expected, compared to those who did not take the medications. Analytical techniques for precisely identifying and detecting antidepressants and their metabolic products in a variety of biological matrices are greatly needed to be developed and made available. Hence, this study attempts to discuss various analytical techniques used to identify and determine antidepressants in various biological matrices, which include urine, blood, oral fluid (saliva), and tissues, which are commonly encountered in clinical and forensic science laboratories.

Influence of Genetic Polymorphisms on the Pharmacokinetics of Trazodone Hydrochloride: A Scoping Review and Future Perspective.

BACKGROUND: Trazodone hydrochloride is an antidepressant used in clinical practice. As a substrate of cytochrome P450 enzymes that is vulnerable to P-glycoprotein transport, several factors can alter its plasma concentration, and hence, dose adjustment may be required. The aim of this scoping review was to identify genetic polymorphisms that influence the pharmacokinetics of trazodone hydrochloride. METHODS: A literature search was performed using PubMed, PubMed Central, BVS/BIREME, EBSCOhost, Web of Science, Embase, Cochrane Library, and Medline databases for studies published until August 2021. The search strategy was based on the following keywords: Trazodone OR "m-chlorophenyl piperazine" AND "Pharmacogenetics" OR "Genetics" OR "Cytochrome P-450 Enzyme System" OR "Polymorphism, Single Nucleotide" OR "Polymorphism, Genetic." RESULTS: The search retrieved 684 candidate articles; 307 duplicates were eliminated. In total, 377 articles were eligible for the first screen. However, only 4 met the eligibility criteria, and 12 polymorphisms in 5 different genes (CYP2D6, CYP1A2, CYP3A4, CYP3A5, and ABCB1). Notably, only C3435T ABCB1 influenced the pharmacokinetics of trazodone hydrochloride. Individuals with the T/T genotype had lower area under the curve, half-life, and maximum concentration values with a higher clearance rate. CONCLUSIONS: Polymorphisms in CYP450 do not seem to directly influence the pharmacokinetics of trazodone hydrochloride or its metabolites. By contrast, genetic polymorphisms in ABCB1 seem to have an important effect on the pharmacokinetics of trazodone hydrochloride by enhancing drug metabolism and elimination.

CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity.

Esketamine, the S-stereoisomer of (R,S)-ketamine was recently approved by drug agencies (FDA, EMA), as an antidepressant drug with a new mechanism of action. (R,S)-ketamine is a N-methyl-d-aspartate receptor (NMDA-R) antagonist putatively acting on GABAergic inhibitory synapses to increase excitatory synaptic glutamatergic neurotransmission. Unlike monoamine-based antidepressants, (R,S)-ketamine exhibits rapid and persistent antidepressant activity at subanesthetic doses in preclinical rodent models and in treatment-resistant depressed patients. Its major brain metabolite, (2R,6R)-hydroxynorketamine (HNK) is formed following (R,S)-ketamine metabolism by various cytochrome P450 enzymes (CYP) mainly activated in the liver depending on routes of administration [e.g., intravenous (largely used for a better bioavailability), intranasal spray, intracerebral, subcutaneous, intramuscular or oral]. Experimental or clinical studies suggest that (2R,6R)-HNK could be an antidepressant drug candidate. However, questions still remain regarding its molecular and cellular targets in the brain and its role in (R,S)-ketamine's fast-acting antidepressant effects. The purpose of the present review is: 1) to review (R,S)-ketamine pharmacokinetic properties in humans and rodents and its metabolism by CYP enzymes to form norketamine and HNK metabolites; 2) to provide a summary of preclinical strategies challenging the role of these metabolites by modifying (R,S)-ketamine metabolism, e.g., by administering a pre-treatment CYP inducers or inhibitors; 3) to analyze the influence of sex and age on CYP expression and (R,S)-ketamine metabolism. Importantly, this review describes (R,S)-ketamine pharmacodynamics and pharmacokinetics to alert clinicians about possible drug-drug interactions during a concomitant administration of (R,S)-ketamine and CYP inducers/inhibitors that could enhance or blunt, respectively, (R,S)-ketamine's therapeutic antidepressant efficacy in patients.

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans.

BACKGROUND: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of (2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of (2R,6R)-HNK following the direct administration of (2R,6R)-HNK. AIM: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of (2R,6R)-HNK. METHODS: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and (2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. RESULTS: In humans, plasma levels of ketamine and norketamine were higher in males than females, while (2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of (2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct (2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of (2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. CONCLUSION: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

Pharmacokinetic Modeling of Ketamine Enantiomers and Their Metabolites After Administration of Prolonged-Release Ketamine With Emphasis on 2,6-Hydroxynorketamines.

Modeling of metabolite kinetics after oral administration of ketamine is of special interest because of the higher concentrations of active metabolites because of the hepatic first-pass effect. This holds especially in view of the potential analgesic and antidepressant effects of 2R,6R- and 2S,6S-hydroxynorketamine at low doses of ketamine. Therefore, a 9-compartment model was developed to analyze the pharmacokinetics of ketamine enantiomers and their metabolites after racemic ketamine administered intravenously (5 mg) and as 4 doses (10, 20, 40, and 80 mg) of a prolonged-release formulation (PR-ketamine). Using a population approach, the serum concentration-time data of the enantiomers of ketamine, norketamine, dehydronorketamine, and 2,6-hydroxynorketamine obtained in 15 healthy volunteers could be adequately fitted. The estimated model parameters were used to simulate serum concentration-time profiles; after multiple dosing of PR-ketamine (2 daily doses of 20 mg), the steady-state concentrations of R- and S-ketamine were 1.4 and 1.3 ng/mL, respectively. The steady-state concentration of 2R,6R-hydroxynorketamine exceeded those of R-norketamine (4-fold), R-dehydonorketamine (8-fold), and R-ketamine (46-fold), whereas that of 2S,6S-hydroxynorketamine exceeded that of S-ketamine by 14-fold. The model may be useful for identifying dosing regimens aiming at optimal plasma concentrations of 2,6-hydroxynorketamines.