Off-label use of ketamine for treatment-resistant depression in clinical practice: European perspective

López‐Díaz, Álvaro; Murillo-Izquierdo, M; Moreno-Mellado, Elisa

doi:10.1192/bjp.2019.102

Cited by 14 publications

(9 citation statements)

References 3 publications

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“…Furthermore, beneficial effects of ( R , S )-ketamine were also exhibited in patients with treatment-resistant post-traumatic stress disorder (PTSD) [ 29 , 30 ]. Despite the lack of long-term data on efficacy and limited data on safety, off-label use of ( R , S )-ketamine is increasing in the United States of America (USA) and Europe [ 31 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

2021

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The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of (R,S)-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain–gut–microbiota axis and brain–spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson’s disease, osteoporosis, inflammatory bowel diseases, and stroke.

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Section: Introductionmentioning

confidence: 99%

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

2021

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“…Racemic ketamine and its S‐enantiomer, show fast‐acting and effective antidepressant effects in patients with major depression 3 . While racemic ketamine is being used off‐label to treat depression, 3–5 intranasal esketamine, has been approved in 2019 as an antidepressant by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) 6 . It is used in combination with an oral antidepressant in treatment of adults with treatment‐resistant depression (TRD) and major depressive disorder (MDD) including acute suicidal ideation 6 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Langmia

Just

Yamoune

et al. 2022

Brit J Clinical Pharma

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Ketamine and its enantiomer S‐ketamine (esketamine) are known to produce rapid‐onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short‐term use in anaesthesia and analgesia, the experience with ketamine as long‐term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene‐drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug–drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug–drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long‐term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.

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“…In the UK it remains a "novel" treatment (Royal College of Psychiatrists, 2017) and it is uncertain if availability will expand beyond the two NHS healthcare providers treating depression with ketamine as an "off-label" treatment; or whether availability via private clinics will increase. Ketamine is a potential option to treat individuals with complex TRD when no further evidence-based therapies are available; nonetheless, more evidence on long-term efficacy and safety is required before inclusion in treatment algorithms of clinical practice guidelines (López-Díaz et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Ketamine Infusion (KI) in Treatment Resistant Depression (TRD): Retrospective Clinical Data Analysis

Griffiths¹,

O’Neill-Kerr²,

Vai³

et al. 2019

OJD

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Objective: The aim of this paper is to present the clinical data analysis results from a service delivering ketamine infusion, repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy for people with treatment resistant depression (TRD). Methods: The study was a retrospective investigation of routinely collected data on patients receiving ketamine infusion between 2017 and 2019. Measures used were the clinician-rated Clinical Global Impression (CGI) and self-reported Beck Depression Inventory (BDI) and Quick Inventory of Depressive Symptomatology (QIDS-SR). The outcome data of 28 patients with TRD were analysed. A minimum course of treatment was defined as three ketamine infusions. Results: Response combined with partial response, response, and remission rates respectively were 42.3%, 23.1% and 4.2% for the BDI; 18.2%, 9.1% and 0% for the QIDS-SR; 50%, 18.2% and 4.6% for the CGI. There was a statistically significant improvement on the BDI with a medium effect size (0.63). There was not a significant improvement in the CGI or QIDS-SR. Conclusions: The results show a mixed picture the impact ketamine on symptoms of depression in TRD over the course of multiple infusions. The results need to be viewed in the context of clinical outcome data collection: outcome scores are taken prior to treatment and so are at a point when ketamine is not having an active effect. The findings can inform the availability of ketamine infusion as a treatment option for TRD where treatment adhering to national guidelines has not succeeded. A qualitative investigation of the experience of people receiving ketamine would provide further insights.

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Off-label use of ketamine for treatment-resistant depression in clinical practice: European perspective

Cited by 14 publications

References 3 publications

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Ketamine Infusion (KI) in Treatment Resistant Depression (TRD): Retrospective Clinical Data Analysis

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