Ketamine as Pharmacological Treatment for Depression

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Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond favorably to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration in treatment-resistant depressed patients. Proposed mechanism of ketamine’s antidepressant action include direct and indirect N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and conversion to the hydroxynorketamine metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR) as well as deactivation of glycogen synthase kinase-3 (GSK-3) and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to exert sustained potentiation of excitatory synapses in affective-regulating bran circuits, necessary and sufficient for antidepressant responses. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical testing, include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine – pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies provide anticipation that the future acute treatment of depression will typically occur within hours, rather than months, of treatment.

1.1.  Brain-derived neurotrophic factor (BDNF)

Brain-derived neurotrophic factor (BDNF) is a growth factor regulating functional neuronal connections and synaptic plasticity in the central nervous system (Katz & Shatz, 1996; Mamounas, Altar, Blue, Kaplan, Tessarollo & Lyons, 2000; Pattwell, Bath, Perez-Castro, Lee, Chao & Ninan, 2012; Poo, 2001). It has long been postulated that BDNF signaling via its primary receptor, tropomyosin receptor kinase B (TrkB), is deficient in major depression and that elevation of BDNF-trkB signaling contributes to antidepressant activity (Autry & Monteggia, 2012; Bocchio-Chiavetto et al., 2010; Castren & Antila, 2017; Castren, Voikar & Rantamaki, 2007; Duman, Heninger & Nestler, 1997; Karlovic, Serretti, Jevtovic, Vrkic, Seric & Peles, 2013; Manji, Moore, Rajkowska & Chen, 2000; Molendijk et al., 2011; Yoshida et al., 2012). For example, chronic administration of monoamine-acting antidepressants were reported to increase BDNF transcription and protein levels in the hippocampus in rats {Nibuya, 1995 #1434}. In addition, chronic antidepressant treatment (Shimizu et al., 2003) and electroconvulsive therapy (Bocchio-Chiavetto et al., 2010; Bocchio-Chiavetto et al., 2006) reverse a deficit in serum BDNF levels in major depressed patients. Deletion of hippocampal BDNF attenuated antidepressant efficacy of classical antidepressants in rodent models (Adachi, Barrot, Autry, Theobald & Monteggia, 2008; Monteggia et al., 2007), and the BDNF receptor TrB is required to exert antidepressant actions of typical antidepressants {Koponen, 2005 #1435}. Moreover, systemic or intra-hippocampal administration of BDNF exerts antidepressant-like effects (Hoshaw, Malberg & Lucki, 2005; Schmidt & Duman, 2010; Shirayama, Chen, Nakagawa, Russell & Duman, 2002), while over-expression of BDNF in the hippocampus leads to resilience to chronic stress (Taliaz, Loya, Gersner, Haramati, Chen & Zangen, 2011). Activation of (TrkB) is necessary for these behavioral actions (Rantamaki et al., 2007; Saarelainen et al., 2003). It should be noted though that these effects of ketamine are region-specific since there is evidence showing that enhanced BDNF-TrkB signaling in the mesolimbic dopaminergic system results in a depressive phenotype in rodents (Groves, 2007; Wook Koo et al., 2016).

BNDF signaling has been postulated to underlie ketamine’s and scopolamine’s antidepressant actions. In particular, ketamine did not exert antidepressant actions in mice with forebrain-specific Bdnf gene knockdown (Autry et al., 2011) and intra-mPFC infusion of a BDNF-neutralizing antibody abolished ketamine’s antidepressant actions (Lepack, Fuchikami, Dwyer, Banasr & Duman, 2014). In addition, mice expressing the human BDNFVal66Met (rs6265) single nucleotide polymorphism (SNP), which are characterized by deficits in BDNF processing and activity-dependent BDNF release (Chen et al., 2006), have attenuated responses to ketamine (Liu, Lee, Li, Bambico, Duman & Aghajanian, 2012) and scopolamine (Ghosal et al.). Similar dependence on BDNF-TrkB signaling has been observed for GLYX-13 (Kato, Fogaca, S., X-Y., Fukumoto & Duman, 2017) and (2R,6R)-HNK (R.S.D., unpublished data). In line with these data, patients suffering from major depression carrying the Val66Met rs6265 allele (both Val/Met and Met/Met) showed as less robust antidepressant response to ketamine compared to homozygous Val/Val individuals (~20-24% of Met carriers showed an improvement versus 40% of Val/Val carriers) (Laje et al., 2012).

Although classical antidepressants require several weeks of administration to induce BDNF-related changes, ketamine administration was reported to rapidly (within 30 min of administration) increase total BDNF protein levels (Autry et al., 2011; Garcia et al., 2008) and BDNF in synaptoneurosomal fractions (Zanos et al., 2016) in the hippocampus of rodents. Similarly, (2R,6R)-HNK administration increases hippocampal synaptoneurosome BDNF levels at 24 hours post-injection in mice (Zanos et al., 2016). There is also considerable evidence showing increased BDNF levels following electroconvulsive shock in the hippocampus of rodents (Altar, Whitehead, Chen, Wortwein & Madsen, 2003; Angelucci, Aloe, Jimenez-Vasquez & Mathe, 2002; Balu, Hoshaw, Malberg, Rosenzweig-Lipson, Schechter & Lucki, 2008; Chen, Shin, Duman & Sanacora, 2001; Conti et al., 2007; Li, Suemaru, Cui & Araki, 2007; Newton et al., 2003; Nibuya, Morinobu & Duman, 1995; Sartorius et al., 2009; Vaidya, Siuciak, Du & Duman, 1999). Finally, sub-chronic (5 days) administration of a 5-HT2C antagonist (Opal et al., 2014), as well as partial activation of the GABAA receptor (via inhibition of GLO1) (McMurray et al., 2017), increase BDNF protein levels in the mPFC and/or hippocampus of mice. In addition, administration of ketamine, GluN2-NMDAR antagonists, mGluR2/3 antagonists and electroconvulsive shock reverse chronic stress-induced reduction in BDNF levels in the prefrontal cortex (Dong et al., 2017; Li et al., 2017) and hippocampus (Dong et al., 2017; Gersner, Toth, Isserles & Zangen, 2010; Luo et al., 2015; Vollmayr, Faust, Lewicka & Henn, 2001) of rodents, suggesting that BDNF induction could be considered as a marker of rapid antidepressant efficacy. Short-term (6-48 hours) sleep deprivation has been shown to both increase (Conti et al., 2007; Fujihara, Sei, Morita, Ueta & Morita, 2003) or decrease (Guo et al., 2016; Guzman-Marin et al., 2006) hippocampal BDNF levels in stress-naïve rats, and has been shown to restore decreased BDNF levels in the hippocampus following chronic stress (Jiang & Zhu, 2015). Moreover, although scopolamine administration has been shown to exert its antidepressant actions via a mechanism requiring activity-dependent increased BDNF release (Ghosal et al.), there are controversial results showing decreased BDNF levels following scopolamine administration (Chen et al., 2014; Heo, Shin, Kim, Kim, Baek & Baek, 2014; Konar et al., 2011; Kotani, Yamauchi, Teramoto & Ogura, 2008; Lee, Sur, Shim, Hahm & Lee, 2014; Shi et al., 2013). Ketamine and other putative rapid antidepressant drugs also increase the phosphorylation (activation) of hippocampal and/or mPFC TrkB (Autry et al., 2011; Dong et al., 2017; Ghosal et al.), suggesting a BDNF-TrkB-dependent mechanism of rapid antidepressant action.

1.1.1.      Eukaryotic elongation factor 2 (eEF2)

Increased BDNF signaling following ketamine administration has been proposed to depend on decreases in the spontaneous activation of postsynaptic NMDARs (Autry et al., 2011). Under physiological conditions, NMDAR-dependent activation of eukaryotic elongation factor 2 kinase (eEF2K), which is involved in protein synthesis and synaptic plasticity (Taha, Gildish, Gal-Ben-Ari & Rosenblum, 2013), causes an inactivation (phosphorylation) of its substrate protein, eEF2 (Thr 56), leading to the blockade of the elongation phase of protein synthesis and thus inhibition of protein translation (Chotiner, Khorasani, Nairn, O’Dell & Watson, 2003; Park et al., 2008). Ketamine is proposed to block NMDAR-mediated spontaneous activation of eEF2K, thereby causing a de-phosphorylation of eEF2 and a consequent de-suppression of protein synthesis and enhancement of BDNF translation (Autry et al., 2011). This hypothesis is supported by the finding that administration of eEF2K inhibitors induce antidepressant behavioral responses in mice using the 30-min forced-swim test (Autry et al., 2011). Administration of (2R,6R)-HNK (Zanos et al., 2016) also decreases phospho-eEF2 (Thr 56) levels in the hippocampus of mice 1 and 24 hours after administration, suggesting that this pathway could be triggered independently from NMDAR inhibition. Sub-chronic administration of 5-HT2C antagonists or GLYX-13 also appear to decrease phospho-eEF2 (Thr 56) levels in the mPFC (Opal et al., 2014) and reduce the chronic stress-induced enhancement of phospho-eEF2 (Thr 56) in the hippocampus of mice (Lu et al., 2014), respectively, further challenging NMDAR inhibition-dependency for these downstream changes. Indeed, there are multiple mechanisms other than NMDAR inhibition that could be responsible for a de-phosphorylation of eEF2 (Hizli et al., 2013; Knebel, Morrice & Cohen, 2001; Redpath, Foulstone & Proud, 1996; Wang, Li, Williams, Terada, Alessi & Proud, 2001). Finally, 8 hours of sleep deprivation cause a robust increase in phospho-eEF2 (Thr 56) levels in the PFC and hippocampus of rats (Grønli, Dagestad, Milde, Murison & Bramham, 2012). Decreased phospho-eEF2 levels alone may not be sufficient for exerting rapid-acting antidepressant actions. Opal et al. demonstrated that sub-chronic (5-day) administration of citalopram did not exert antidepressant actions in mice, even though it significantly reduced phospho-eEF2 (Thr 56) levels in the mPFC (Opal et al., 2014). Whether reduced eEF2 phosphorylation is necessary and sufficient for action of distinct rapid-acting antidepressants thus requires further investigation.

1.1.2.      Mechanistic target of rapamycin (mTOR)

Enhanced BDNF release and activation of TrkB trigger downstream pathways via an activation of the phosphatidylinositol 3-kinase (PI3K), which in turn translocates Akt (protein kinase B) to the plasma membrane (Reichardt, 2006). TrkB activation can also induce activation of the downstream MEK-MAPK/Erk signaling pathway. Both pathways promote protein synthesis through activation of the mechanistic target of rapamycin complex 1 (mTORC1) (Yoshii & Constantine-Paton, 2010). Among the mTOR-regulated proteins are several that regulate neurogenesis and dendrite spine growth via phosphorylation of the synaptic p70S6 kinase and suppression of 4E binding proteins (4EBP) (Duman, Li, Liu, Duric & Aghajanian, 2012; Hay & Sonenberg, 2004; Hoeffer & Klann, 2010).

mTORC1 signaling has been implicated in rapid antidepressant actions. In particular, administration of ketamine (Carrier & Kabbaj, 2013; Li et al., 2010; Miller et al., 2014; Paul et al., 2014; Yang, Hu, Zhou, Zhang & Yang, 2013; Zhang, Yamaki, Wei, Zheng & Cai, 2017; Zhou, Wang, Yang, Li, Zhou & Yang, 2014), mGluR2/3 antagonists (Dwyer, Lepack & Duman, 2013), GluN2B-NMDAR antagonists (Li et al., 2010), GLYX-13 (Liu et al., 2017; Lu et al., 2014), scopolamine (Voleti et al., 2013), 7-chlorokynurenic acid (Zhu et al., 2013) and 5-HT2C antagonists (Opal et al., 2014) induces a fast-onset increase in levels of phospho-mTOR (Ser 2448), phospho-p70S6 kinase (Thr 389), and phospho-4EBP1 (Thr 37/46) in the hippocampus and/or mPFC of rodents. Enhanced mTORC1 signaling following administration of ketamine is transient (Li et al., 2010), indicating that acute activation of mTORC1 and thus protein translation may transiently induce synaptic plasticity responsible for the prolonged effects of ketamine. mTORC1 activation was shown to be necessary for the behavioral antidepressant responses of ketamine, scopolamine, GLYX-13 and mGluR2/3 antagonists. Specifically, pre-treatment with the selective mTORC1 inhibitor rapamycin blocks ketamine-induced synaptic molecular changes (Li et al., 2010), as well as the antidepressant actions of ketamine, scopolamine, Ro 25-6981, GLYX-13 and mGluR2/3 inhibition in rodents (Dwyer, Lepack & Duman, 2012; Holubova, Kleteckova, Skurlova, Ricny, Stuchlik & Vales, 2016; Li et al., 2010; Liu et al., 2017; Voleti et al., 2013). Importantly, AMPAR inhibition prior to ketamine administration not only blocks its antidepressant actions, but also blocks ketamine-induced actions on mTORC1 signaling (Li et al., 2010). There is evidence that chronic SSRI administration does not induce mTORC1 activation (Li et al., 2010) (but see (Opal et al., 2014)), suggesting that mTORC1 is a point of convergence that is uniquely activated by rapid-acting antidepressants.

In addition to the direct activation through the BDNF/TrkB pathway, it is hypothesized that mTORC1 activation could also occur via alternate pathways. One alternate is upstream phosphorylation-dependent deactivation of glycogen synthase kinase-3 (GSK-3). GSK-3, which has two isoforms, α and β, with similar but not identical functions, has been extensively linked with the antidepressant actions of lithium (Beurel, Grieco & Jope, 2015; Can, Schulze & Gould, 2014) and has been implicated in the rapid antidepressant actions of ketamine (Beurel, Song & Jope, 2011). Ketamine administration increases the levels of phosphorylated GSK-3β (Ser 9) in the PFC and/or hippocampus in rodents (Beurel, Song & Jope, 2011; Liu, Fuchikami, Dwyer, Lepack, Duman & Aghajanian, 2013; Zhou et al., 2014). Mice carrying a knock-in mutation of both α and β isoforms of GSK-3 that prevents their kinase activity do not show antidepressant behavioral responses to ketamine (Beurel, Song & Jope, 2011), and lack ketamine-induced upregulation of cell surface GluA1 in the hippocampus (Beurel, Grieco, Amadei, Downey & Jope, 2016). Moreover, when lithium (a non-selective GSK-3 inhibitor) is co-administered with ketamine at sub-effective doses, it induces an activation of the mTORC1 signaling pathway, phosphorylation of GSK-3, synaptogenesis and greater antidepressant effects (Liu, Fuchikami, Dwyer, Lepack, Duman & Aghajanian, 2013), indicating that a convergent mechanism between mTORC1 signaling and GSK-3 might be involved in ketamine’s rapid antidepressant actions. Similar to ketamine, a single electroconvulsive shock enhances phosphorylation of GSK-3β (Ser 9) in the PFC and/or hippocampus of rodents (Basar, Eren-Kocak, Ozdemir & Ertugrul, 2013; Kang et al., 2004; Roh et al., 2003).

2.     Conclusion

Elucidation of the neurobiological underpinnings of ketamine’s rapid and persistent antidepressant actions has been a major recent research focus in psychopharmacology, with the expectation that knowledge gained from such studies will lead to the development of novel pharmacotherapies for the effective, rapid treatment of depression. Here we discussed clinical and pre-clinical findings demonstrating rapid onset antidepressant actions of ketamine and other promising candidate drugs. We have reviewed convergent mechanisms of actions underlying the induction of rapid antidepressant efficacy including NMDAR modulation, synaptic plasticity strengthening, and synaptogenesis, as well as the common downstream effector pathways such as AMPAR activation, enhanced BDNF-TrkB signaling, de-phosphorylation of eEF2, and activation of mTORC1. Pre-clinical and/or clinical findings suggest that other compounds, including scopolamine, (2R,6R)-HNK, GLYX-13, 4-chlorokynurenine, GluN2B-NMDAR antagonists, mGluR2/3 antagonists, and GABAA receptor negative allosteric modulators also possess fast-onset antidepressant efficacy (see Tables 1 and 2).

It is important to better understand the convergent mechanisms underlying rapid antidepressant efficacy in preclinical models in order to maximize their antidepressant potency and ameliorate any undesirable side effects these drugs may currently display. Although NMDAR inhibition was long assumed to underlie ketamine’s antidepressant actions, recent evidence indicates that additional downstream mechanisms are likely to be involved. Indeed, it was recently shown that the (2S,6S;2R,6R)-HNK metabolite of ketamine is essential for its antidepressant actions and that the antidepressant actions of (2R,6R)-HNK possess robust antidepressant efficacy with low potency at the NMDAR (Morris et al., 2017a; Suzuki, Nosyreva, Hunt, Kavalali & Monteggia, 2017; Zanos et al., 2016; Zanos et al., 2017a; Zanos et al., 2017b).

A well-acknowledge point of convergence between distinct mechanistic hypotheses is the required activation of the AMPAR for the emergence of rapid antidepressant actions. AMPAR activation promotes activation of downstream signaling pathways, including BDNF/TrkB signaling and activation of mTORC1, thereby promoting protein synthesis, neosynaptogenesis, and restoration of synaptic function in reward and mood-related circuits, where its impairment contributes to the symptoms of depression (Hare, Ghosal & Duman, 2017; Wohleb, Gerhard, Thomas & Duman, 2017). The ultimate result of these processes is a sustained potentiation of excitatory synapses in cortico-mesolimbic brain circuits involved in the maintenance of mood and appropriate reactivity to stress (Thompson, Kallarackal, Kvarta, Van Dyke, LeGates & Cai, 2015).

Rapid-acting antidepressants hold a promising future for the effective treatment of depression. Although ketamine is increasingly being used as a treatment (Wilkinson, Toprak, Turner, Levine, Katz & Sanacora, 2017), there is not a single rapid-acting antidepressant medication that is approved for the long-term treatment of major depression to date. (S)-ketamine and GLYX-13 are currently in phase III clinical trials for the treatment of depression. However, a significant amount of research remains to be performed to delineate the exact mechanisms responsible for the emergence of rapid antidepressant efficacy and to define the most efficacious dose regimens for achieving the desired clinical effects, with fewer side effects. The identification of additional putative rapid-acting antidepressants in pre-clinical tests that lack ketamine-like side effects, including ketamine’s metabolite (2R,6R)-HNK, which does not possess NMDAR inhibition-mediated side effects in rodents, opens new paths for the treatment of depression. An important aspect for consideration and an area of future research is the tolerability and efficacy of these treatments following long-term administration. It is important to identify antidepressant medications that can be routinely administered in depressed patients and provide rapid and sustained relief of their lowered mood symptoms.

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