Ketamine induces rapid onset of antidepressant action: neurophysiological biomarkers as predictors of effect

Abstract

Biomarkers in MedicineVol. 3, No. 1 EditorialFree AccessKetamine induces rapid onset of antidepressant action: neurophysiological biomarkers as predictors of effectJoão Quevedo, Clarissa M Comim and Elaine C GavioliJoão Quevedo† Author for correspondenceLaboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806–88000 Criciúma, SC, Brazil. Search for more papers by this authorEmail the corresponding author at quevedo@unesc.net, Clarissa M ComimUniversidade do Extremo Sul Catarinense, Criciúma, SC, BrazilSearch for more papers by this author and Elaine C GavioliUniversidade do Extremo Sul Catarinense, Criciúma, SC, BrazilSearch for more papers by this authorPublished Online:10 Feb 2009https://doi.org/10.2217/17520363.3.1.5AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Several recent studies have investigated the optimal treatment for major depression, despite the fact that adequate management of this psychopathology remains a challenge. The primary reasons for these pitfalls include: ▪ The incidence of undesirable side effects produced by currently available antidepressants;▪ The apparent delay in achieving measurable therapeutic benefit;▪ A high percentage of treatment-resistant patients [1,2].While progress has been made to reduce side effects, currently available antidepressants do not show convincing evidence for a shorter delay of onset of therapeutic actions nor for improved efficacy in the treatment of major depression [3]. Thus, there is clearly a need to develop fast-acting and potent treatments for major depression.Major depression & NMDA receptorA growing body of evidence has pointed to the ionotropic glutamate N-methyl-D-aspartate (NMDA) receptor as an important player in the etiology of psychopathologies, including anxiety and major depression [4,5]. In fact, drugs that block NMDA receptor signaling have shown antidepressant properties in both preclinical and clinical studies [6]. In this way, chemical compounds acting on NMDA receptors could be interesting as pharmacological targets for the treatment of mood disorders.Several preclinical studies have demonstrated that NMDA antagonists, such as MK-801, AP7, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, neramexane and others, display anxiolytic- and antidepressant-like effects in rodents subjected to distinct animal models of anxiety and depression [7–12]. Of those NMDA receptor antagonists preclinically tested, ketamine displayed an outstanding profile of antidepressant-like action, which will be discussed further in the text.Ketamine as a novel antidepressant drugKetamine, as well as phencyclidine, MK-801 and memantine, are noncompetitive antagonists of the NMDA receptor for glutamate, which works in a use- and voltage-dependent manner. Ketamine binds the ionic channel of the NMDA receptor, thus blocking the entrance of Ca2+ to the neuron [13,14]. However, distinct from other NMDA receptor antagonists, ketamine also interacts with voltage-sensitive Ca2+ channels, as well as opioid, monoaminergic and muscarinic receptors [15].A growing body of evidence suggests that ketamine induces anxiolytic- and antidepressant-like effects in rodent models of depression [7,16,17]. In the tail suspension test, ketamine also produced anti-immobility effects in mice [18]. Yilmaz et al. demonstrated that a single injection of an anaesthetic dose of ketamine (160 mg/kg) reduced the immobility time in the rat forced swimming test assessed 3, 7 or 10 days after injection [16]. Other literature findings show that treatment with ketamine reversed the shock-induced increase of immobility time in the mouse forced swimming test [18]. Maeng et al. demonstrated that a single injection of ketamine reversed learned helplessness behavior in mice, and reduced immobility time in the mouse forced swimming test assessed 30 min and 2 weeks after drug administration [19]. In addition, these authors demonstrated that α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors mediate the antidepressant-like effects of ketamine [19]. Taken together, these findings support robust and sustained effects of ketamine on behavioral tests used for screening antidepressant drugs.Recently, our research group demonstrated that ketamine at a 10 and 15 mg/kg dose reduced immobility time of rats in the forced swimming test; this effect was similar to imipramine – a tricyclic antidepressant [20]. We also demonstrated that chronic treatment with ketamine induced an antidepressant-like effect at doses that were acutely inactive [21]. Very recently, we demonstrated that physiological alterations (e.g., increase of corticosterone and ACTH levels, and increase of adrenal gland weight) induced by 40 days of chronic stressful situations were reversed by acute (1 day) and repeated (7 day) ketamine administration in rats [22]. We also observed that the repeated, but not acute, administration of ketamine reverted anhedonic behavior in stressed rats. Taken together, ketamine induces a rapid onset of action, and a robust and sustained antidepressant-like effect in rodents assessed in distinct assays and experimental conditions.Interestingly enough, some clinical studies suggested that the acute administration of ketamine rapidly ameliorates depressive symptoms in patients suffering from major depression [23–26]. These effects are long lasting and display a rapid onset of action, thus strongly suggesting that ketamine could be an innovative antidepressant drug with a distinct mechanism of action compared with available drugs.Biomarkers as predictors of ketamine antidepressant actionAvailable antidepressant drugs require 3–4 weeks of daily administration in order to experience some effect, if any. Nowadays, small advances have been obtained in improving the efficacy of antidepressants and reducing the onset of action [27]. Interesting data are pointing to ketamine as an antidepressant drug displaying a distinct profile of action. In fact, recent preclinical and clinical studies employing ketamine have been performed in order to identify biomarkers that could predict a rapid antidepressant response.Neurotrophins, and particularly brain-derived neurotrophic factor (BDNF), have been shown to function as a key regulator of neurite outgrowth, synaptic plasticity and the selection of functional neuronal connections in the CNS, which make neurotrophins potential mediators of the plastic changes induced by antidepressants [28]. In fact, some authors have shown that chronic administration of classic antidepressants increases mRNA-encoding BDNF and BDNF-immunoreactive fibers in the hippocampus of rodents [28]. Interestingly, few studies reporting hippocampal BDNF protein levels in rats treated with antidepressants are still available, and these studies mostly indicate that chronic antidepressant treatment does not affect BDNF levels [29–31].Recently, some data point to the rat hippocampal BDNF levels as a possible biomarker from the rapid onset of antidepressant action of ketamine. In fact, Garcia et al. demonstrated that an acute injection of ketamine, but not imipramine – a tricyclic antidepressant drug – increased BDNF protein levels in the rat hippocampus [20]. However, the chronic administration (14 days) of both drugs (ketamine and imipramine) did not modify hippocampal BDNF levels in rats [22]. These contrasting effects (acute vs chronic administration) could be due to adaptive mechanisms induced by the chronic administration of ketamine or induction of tolerance to the effects of this drug on BDNF protein levels. A time course of rat hippocampal BDNF protein level is mandatory to gain further information regarding the onset and length of these effects induced by ketamine. In addition, circulating levels of BDNF in depressed humans treated with ketamine could further support the view of BDNF as a physiological biomarker to the rapid onset of antidepressant action of ketamine.Very recently, Salvadore et al. proposed the activation of anterior cingulate cortex induced by rapidly presenting fearful faces to patients infused with a single injection of ketamine as a neurophysiologycal biomarker that identifies a subgroup of patients who will respond favorably to ketamine’s antidepressant effects. This pilot study gives substantial evidence that the activation of anterior cingulated cortex could predict the response of major depressive patients who will respond favorably to ketamine within hours [32].A recent study showed that genetic factors could be on the base of a rapid response to antidepressant effects of ketamine. Phelps et al. demonstrated that subjects with a self-reported family history of alcohol dependence showed a significantly greater improvement in depressive symptoms compared with subjects who had no family history of alcohol dependence [33]. Thus, the genetic profile of subjects with a family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.In conclusion, particular target-based therapies such as ketamine, displaying a new profile of action, are useful pharmacological tools that should be further investigated in order to find biomarkers to better understand the underlying neurobiological mechanisms of these effects. These studies could provide new information regarding the psychopathology and pharmacological treatment of patients suffering from major depression.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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Psychiatry65(2),181–184 (2008).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByKetamine as a rapid antidepressant: the debate and implications2 January 2018 | BJPsych Advances, Vol. 22, No. 4 Vol. 3, No. 1 Follow us on social media for the latest updates Metrics History Published online 10 February 2009 Published in print February 2009 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download