Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions

Andrade, Chittaranjan

doi:10.4088/jcp.17f11802

Cited by 44 publications

(22 citation statements)

References 12 publications

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“…It should be noted that these interpretations are from a limited number of animals ( n = 3/time point) and further analysis is required before the potential for transporter inhibition in humans can be fully elucidated. Ketamine is metabolized by CYP2B6, which is a highly polymorphic enzyme with allelic variants that have reduced clearance of ketamine and may impact its use in a mass causality situation . The ketamine brain to plasma ratios were assessed and they varied from ~1 to 3 with all groups being ~ 2.8–3.3 at 15 minutes after the final administration, indicating that ketamine was able to rapidly partition into the brain following IM administration.…”

Section: Discussionmentioning

confidence: 99%

“…Drug–drug interactions in which markedly increased ketamine levels occur may result in unwanted central nervous system (CNS) toxicity, whereas those interactions that may reduce ketamine concentrations in target tissue might diminish or abolish effects. Ketamine and its active metabolite norketamine undergo metabolism via hepatic Cytochrome P450s primarily via CYP2B6 and CYP3A4, which may be impacted with the co‐administration of other pharmaceuticals, such as rifampicin, itraconazole, and ticolpidine, though none of the SOC agents are predicted to have effects on ketamine metabolism . In addition to metabolic clearance, ketamine is a substrate of the rat and human uptake organic cation ion transporters (OCT1, OCT2, OCT3) that mediate biliary and renal elimination of organic bases .…”

Section: Introductionmentioning

confidence: 99%

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The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Moeller

Espelien

Weber

et al. 2018

Drug Testing and Analysis

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Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid-acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well-characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography-mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non-compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co-administration with the SOC following nerve agent exposure in animal models.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Moeller

Espelien

Weber

et al. 2018

Drug Testing and Analysis

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“…The question then arises whether or not the present findings in mice could also occur following a co-administration of BZD and ketamine in patients. Few clinical studies suggest that co-administration of drugs interfering with GABAergic neurotransmission may hamper optimal ketamine response (Frye et al, 2015;Andrade, 2017). In a clinical trial carried out in TRD-BZD users, the benzodiazepine interfered with the antidepressant response produced by the first ketamine administration, but not subsequent treatments (Albott et al, 2017).…”

Section: )mentioning

confidence: 99%

Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

Pham

Lavialle-Defaix

Nguyen

et al. 2020

Preprint

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ABSTRACTAt sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABAA-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HText and Gluext. Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HText. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HText, Gluext and GABAext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABAA-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.

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“…Because ketamine is metabolized by 3A4 and 2B6 enzymes, which are expressed primarily in the liver, we must be highly cautious about potential metabolic ASEs. Eighth, although ketamine alone has been reported to alleviate TRD symptoms [77], we did not ask our patients to stop taking their prescribed antidepressants because of the potential that doing so might lead to a worsening of psychotic symptoms.…”

Section: Limitationsmentioning

confidence: 99%

Adjunct ketamine treatment effects on treatment-resistant depressive symptoms in chronic treatment-resistant schizophrenia patients are short-term and disassociated from regional homogeneity changes in key brain regions – a pilot study

Ye¹,

Lin²,

Jiang³

et al. 2019

Psychiatry and Clinical Psychopharmacology

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2019) Adjunct ketamine treatment effects on treatment-resistant depressive symptoms in chronic treatment-resistant schizophrenia patients are short-term and disassociated from regional homogeneity changes in key brain regions -a pilot study, Psychiatry and Clinical Psychopharmacology, 29:4, 907-915, ABSTRACT BACKGROUND: To investigate the effects of adjunct ketamine treatment on depressive symptoms and brain activity in chronic treatment-resistant schizophrenia (CTRS) patients with treatment-resistant depressive (TRD) symptoms. METHODS: Calgary Depression Scale for Schizophrenia (CDSS), positive and negative syndrome scale (PANSS), and regional homogeneity (ReHo) results were compared before versus after ketamine treatment in 12 CTRS patients with TRD symptoms. RESULTS: From 7 days to 14 days after the first ketamine administration, CDSS and PANSS total scores were reduced by 63.8% and 12.9%, respectively. By day 21, ReHo values had increased in the main components of the default mode network (DMN) and bilateral orbitofrontal cortex (OFC) after family-wise error correction. ReHo alterations did not correlate with TRD symptom changes. TRD symptoms relapsed by the 21-day time point, while increased ReHo was sustained. No adverse secondary effects (ASEs) necessitating medical intervention occurred. CONCLUSIONS: Adjunct ketamine alleviation of TRD symptoms lasted only a week, whereas increased ReHo in DMN regions and the OFC in CTRS patients was maintained beyond 2 weeks, indicating that adjunct ketamine is not well-suited for CTRS patients with TRD symptoms and that effects on functional activity dissociate from effects on TRD symptoms. This small-sample pilot study provides clues for further research into therapy for TRD symptoms in CTRS patients. ARTICLE HISTORY

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Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions

Cited by 44 publications

References 12 publications

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

Adjunct ketamine treatment effects on treatment-resistant depressive symptoms in chronic treatment-resistant schizophrenia patients are short-term and disassociated from regional homogeneity changes in key brain regions – a pilot study

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Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions

Cited by 44 publications

References 12 publications

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

The pharmacokinetics of ketamine following intramuscular injection to F344 rats

Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

Adjunct ketamine treatment effects on treatment-resistant depressive symptoms in chronic treatment-resistant schizophrenia patients are short-term and disassociated from regional homogeneity changes in key brain regions – a pilot study

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Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine