Figure - available via license: Creative Commons Attribution-NonCommercial 3.0 Unported
Content may be subject to copyright.
![Molecular targets of glutamatergic drugs for mood disorders.
Notes: Sites of action and regulation for glutamate neurotransmission are shown, and drugs that target each specific site/mechanism are indicated. The specific locations depicted here are representative, though ionotropic and metabotropic glutamate receptors may be located on both presynaptic and postsynaptic cells. Numbers indicate the following targets: (1) NMDAR; (2) AMPAR; (3) Group I mGluR; (4) Group II mGluR; (5) Group III mGluR; (6) Glycine site of NMDAR; (7) Na+ Channel; (8) Ca++ Channel; (9) K+ Channel.
Abbreviations: AMPAR, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor; EAAT, excitatory amino acid transporter; Gln, glutamine; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; MTEP, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine; PHCCC, (−)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide; EMCMQM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate; Glu, glutamate; ACPC, 1-aminocyclo-propanecarboxylic acid.](profile/Laili-Soleimani/publication/256102545/figure/fig1/AS:202585832202245@1425311634633/Molecular-targets-of-glutamatergic-drugs-for-mood-disorders-Notes-Sites-of-action-and.png)
Molecular targets of glutamatergic drugs for mood disorders. Notes: Sites of action and regulation for glutamate neurotransmission are shown, and drugs that target each specific site/mechanism are indicated. The specific locations depicted here are representative, though ionotropic and metabotropic glutamate receptors may be located on both presynaptic and postsynaptic cells. Numbers indicate the following targets: (1) NMDAR; (2) AMPAR; (3) Group I mGluR; (4) Group II mGluR; (5) Group III mGluR; (6) Glycine site of NMDAR; (7) Na+ Channel; (8) Ca++ Channel; (9) K+ Channel. Abbreviations: AMPAR, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor; EAAT, excitatory amino acid transporter; Gln, glutamine; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; MTEP, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine; PHCCC, (−)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide; EMCMQM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate; Glu, glutamate; ACPC, 1-aminocyclo-propanecarboxylic acid.
Source publication
Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action...
Similar publications
Ketamine and MK-801 by blocking NMDA receptors may induce reinforcing effects as well as schizophrenia-like symptoms. Recent results showed that ketamine can also effectively reverse depressive signs in patients’ refractory to standard therapies. This evidence clearly points to the need of characterization of effects of these NMDARs antagonists on...
Depression has a major effect on the prefrontal cortex and hippocampus. Several studies have showed that decreased serotonin levels in the brain plays a key role in depression. Most antidepressant medications aim towards enhancement of serotonin concentration in synaptic clefts. However, only 50% of the patients receiving the treatment responds and...
Background:
There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes.
Method:
We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, r...
Citations
... [68][69][70] Previous evidence also points to a reduction in the brain and CSF levels of GABA neurons in patients with AD. [71][72][73] However, pharmacological activation of GABA receptors in patients with AD failed to confer beneficial effects, indicating that the GABAergic system may not serve as an ideal therapeutic target in AD. 74 In the past few decades, there have also been growing insights into the roles performed by the glutamatergic system in the pathogenesis and treatment of MDD and AD. [75][76][77] Abnormalities of the glutamatergic system such as those induced by pharmacological inactivation have been associated with depression-like symptoms including anhedonia. 78,79 Furthermore, results of neuroimaging studies have revealed significant alterations in the plasma as well as brain levels of glutamate in individuals with MDD. ...
Alzheimer disease (AD) is a devastating neuro- degenerative disorder that affects millions of individuals worldwide, with no effective cure. The main symptoms include learning and memory loss, and the inability to carry out the simplest tasks, sig- nificantly affecting patients’ quality of life. Over the past few years, tremendous progress has been made in research demonstrating a link between AD and major depressive disorder (MDD). Evidence suggests that MDD is commonly associated with AD and that it can serve as a precipitating factor for this disease. Antidepressants such as selective serotonin reuptake inhibitors, which are the first line of treatment for MDD, have shown great promise in the treatment of depression in AD, although their effectiveness remains controversial. The goal of this review is to summarize current knowledge regarding the association between AD, MDD, and antidepressant treatment. It first provides an overview of the interaction between AD and MDD at the level of genes, brain regions, neurotransmitter systems, and neuroinflammatory markers. The review then presents current evidence regarding the effective- ness of various antidepressants for AD-related pathophysiology and then finally discusses current limitations, challenges, and future directions.
... Current guidelines suggest lamotrigine as a well-tolerated second-line augmentation agent for TRD [34]. The effectiveness of lamotrigine augmentation in TRD is attributed to its membrane-stabilizing actions through the inhibition of voltage-sensitive sodium channels and subsequent inhibition of cortical glutamatergic neurotransmission [35]. The effect of lamotrigine augmentation is reported to be more prominent in severely treatment-resistant patients but could also be delayed due to the time needed for dose titration [36,37]. ...
Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40−100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings.
... ADX88178, a selective and brain-penetrating mGluR4 antagonist, has demonstrated strong antidepressant effects [150]. In addition, in the TST and FST tests conducted in this instance, LuAF21934 and LSP1-2111 exhibited anxiolytic effects but no antidepressant effects [151]. Due to the unfavorable influence on the base locomotor activity, caution must take precedence. ...
Post-stroke depression (PSD) is a biopsychosocial disorder that affects individuals who have suffered a stroke at any point. PSD has a 20 to 60 percent reported prevalence among stroke survivors. Its effects are usually adverse, can lead to disability, and may increase mortality if not managed or treated early. PSD is linked to several other medical conditions, including anxiety, hyper-locomotor activity, and poor functional recovery. Despite significant awareness of its adverse impacts, understanding the pathogenesis of PSD has proved challenging. The exact pathophysiology of PSD is unknown, yet its complexity has been definitively shown, involving mechanisms such as dysfunction of monoamine, the glutamatergic systems, the gut-brain axis, and neuroinflammation. The current effectiveness of PSD treatment is about 30–40 percent of all cases. In this review, we examined different pathophysiological mechanisms and current pharmacological and non-pharmacological approaches for the treatment of PSD.
... Major depressive disorder (MDD), which is one of the most important causes of dis-ability worldwide, has the characteristics of chronicity, recurrence, and high suicide rate [1,2]. In addition, 33% of patients develop resistance to antidepressant treatment, a condition known as treatment-resistant depression (TRD) [3]. At present, the pathogenesis of depression has been explained by many mechanisms; the monoaminergic disorder of the central nervous system has always been regarded as the main pathogenesis of depression. ...
Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression.
... Indeed, decreased expression of EAATs has been observed in postmortem studies of subjects with mood disorders, whereas an increased expression (e.g., as induced by ß-lactam antibiotics) may induce antidepressant-like effects (Zarate et al. 2010). A potentiation of EEAT activity has been suggested as a potential antidepressant mechanism (Lapidus et al. 2013). Moreover, Colton and colleagues from the Ohio State University have identified a series of compounds that can induce translation of EAAT2 transcripts (Colton et al. 2010), and this may represent the first step for the preclinical investigation of this mechanism. ...
The aim of this chapter is to provide an update of the most relevant advances in the conceptualization of the modulation of glutamatergic signaling as a potential therapeutic strategy for Major Depressive Disorder (MDD), from animal models to recent phase III clinical trials. The main clinical features of MDD, its epidemiological impact in terms of disease burden, its mainstream pharmacological treatment, and current unmet needs are presented. A brief review of the implications of the glutamatergic system for MDD follows, together with its close relationship with the gabaergic system. The main molecular components of the glutamatergic system as potential drug targets for MDD are presented, namely selective NMDA receptors (NMDAR) antagonism, AMPA receptors (AMPAR) potentiation, metabotropic glutamate receptors 2 and 3 (mGluR2 and 3) antagonism, excitatory amino acid transporters (EAAT) potentiation, mammalian target of the rapamycin complex 1 (mTORC1) modulation and GABA-A receptor modulation. The current modulators of the glutamatergic signaling for the treatment of MDD are presented: intravenous ketamine (off-label use for MDD), intranasal esketamine (FDA approved for TRD), and intravenous brexanolone (FDA approved for postpartum depression). In addition, some emerging treatments related to glutamate modulating drugs for MDD are mentioned with their rationale (R-ketamine, rapastinel, lanicemine, and other compounds).
... This impaired connection causes that BG cannot optimally detect cognitive and sensory motor context to terminate the previous phoneme and initiate the next phoneme[29] in a timely manner to produce a fluent speech. Therefore, drugs like memantine by inhibiting NMDA receptors [68] and pregabalin, gabapentin, and lamotrigine by inhibiting the release of glutamate [69,70] change the normal function of glutamate in corticostriatal pathway or in the different parts of the BG motor circuit can impair balance between the direct and indirect pathways and cause motor abnormalities like stuttering. Moreover, glutamate is the main neurotransmitter in the white matter and antagonizing its effects also disturbs signal transmission through white matter fiber tracts. ...
Drug-induced stuttering (DIS) is a type of neurogenic stuttering (NS). Although DIS has not been reported as frequently as other cases of NS in the literature, it is not a negligible adverse drug reaction (ADR) which can significantly affect the quality of life if not treated. This literature review aims to evaluate the epidemiological and clinical characteristics of DIS and suggests some pathophysiological mechanisms for this ADR. Relevant English-language reports in Google Scholar, PubMed, Web of Science, and Scopus were identified and assessed without time restriction. Finally, a total of 62 reports were included. Twenty-seven drugs caused 86 episodes of stuttering in 82 cases. The most episodes of DIS were related to antipsychotic drugs (57%), mostly including clozapine, followed by central nervous system agents (11.6%) and anticonvulsant drugs (9.3%). The majority of the cases were male and between the ages of 31 and 40 years. Repetitions were the most frequent core manifestations of DIS. In 55.8% of the episodes of DIS, the offending drug was withdrawn to manage stuttering, which resulted in significant improvement or complete relief of stuttering in all cases. Based on the suggested pathophysiological mechanisms for developmental stuttering and neurotransmitters dysfunctions involved in speech dysfluency, it seems that the abnormalities of several neurotransmitters, especially dopamine and glutamate, in different circuits and areas of the brain, including cortico-basal ganglia-thalamocortical loop and white matter fiber tracts, may be engaged in the pathogenesis of DIS.
... This impaired connection causes that BG cannot optimally detect cognitive and sensory motor context to terminate the previous phoneme and initiate the next phoneme[29] in a timely manner to produce a fluent speech. Therefore, drugs like memantine by inhibiting NMDA receptors [68] and pregabalin, gabapentin, and lamotrigine by inhibiting the release of glutamate [69,70] change the normal function of glutamate in corticostriatal pathway or in the different parts of the BG motor circuit can impair balance between the direct and indirect pathways and cause motor abnormalities like stuttering. Moreover, glutamate is the main neurotransmitter in the white matter and antagonizing its effects also disturbs signal transmission through white matter fiber tracts. ...
... The subtle balance of glutamate transmission is crucial for the healthy functioning of an organism. Overactivation of glutamatergic signaling, called excitotoxicity (Manev et al. 1989), is related to various pathologies, from inflammatory processes and allergies to chronic degenerative diseases, including Alzheimer's disease, depression, Parkinson's disease, amyotrophic lateral sclerosis and epilepsy (Ishikawa 2013;Lai, Zhang, and Wang 2013;Lapidus, Soleimani, and Murrough 2013). In this way, the regulation of the glutamate signal is an opportunity for the development of therapies for diseases related to depressive states, and in general for other pathologies related to aberrant glutamatergic signaling. ...
... NMDA receptors are directly related to learning, particularly to the production and maintenance of potentiated glutamatergic signaling. Blockade of NMDA receptors with selective antagonists, such as ketamine, produces a relief of depressive symptoms almost instantaneously after their administration (Lapidus, Soleimani, and Murrough 2013;Niciu et al. 2014). However, because the regulation of the NMDA receptor is at the synaptic level, its therapeutic effects are generally short-term (around a week), and at best a couple of months (Lapidus, Soleimani, and Murrough 2013;Niciu et al. 2014). ...
... Blockade of NMDA receptors with selective antagonists, such as ketamine, produces a relief of depressive symptoms almost instantaneously after their administration (Lapidus, Soleimani, and Murrough 2013;Niciu et al. 2014). However, because the regulation of the NMDA receptor is at the synaptic level, its therapeutic effects are generally short-term (around a week), and at best a couple of months (Lapidus, Soleimani, and Murrough 2013;Niciu et al. 2014). On the other hand, the long-term effects (more than 6 months (Griffiths et al. 2011)) of the action of agonists at 5-HT2A receptors could be due to a modification in the genetic transcription of glutamatergic NMDA receptors , however this hypothesis needs to be corroborated experimentally. ...
Aberrant glutamatergic signaling has been closely related to several pathologies of the central nervous system. Glutamatergic activity can induce an increase in neural plasticity mediated by brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA), a nodal point in the mesolimbic dopamine system. Recent studies have related BDNF dependent plasticity in the VTA with the modulation of aversive motivation to deal with noxious environmental stimuli. The disarray of these learning mechanisms would produce an abnormal augmentation in the representation of the emotional information related to aversion, sometimes even in the absence of external environmental trigger, inducing pathologies linked to mood disorders such as depression and drug addiction. Recent studies point out that serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 2a (5-HT2a) subtype, play an important role in BDNF-related neural plasticity in the VTA. It has been observed that a single administration of a 5HT2a agonist can both revert an animal to a nondependent state from a drug-dependent state (produced by the chronic administration of a substance of abuse). The 5HT2a agonist also reverted the BDNF-induced neural plasticity in the VTA, suggesting that the administration of 5-HT2a agonists could be used as effective therapeutic agents to treat drug addiction. These findings could explain the neurobiological correlate of the therapeutic use of 5HT2a agonists, which can be found in animals, plants and fungi during traditional medicine ceremonies and rituals to treat mood related disorders.
... However, excessive AMPAR stimulation by full AMPAR agonists can lead to psychostimulant and seizure activity (Meldrum 1994). Instead, positive allosteric modulators (PAMs) -also known as ampakines or AMPAR potentiators -bind allosterically to AMPARs and slow the rate of their deactivation or desensitization (Lynch 2006), thus prolonging the duration of AMPAR-mediated responses theoretically without an overstimulation of excitatory transmission (Lapidus et al. 2013). Although the efficacy of these compounds in preclinical studies of depressive-like behavior has been demonstrated, the transition to clinical trials has not been as fruitful. ...
... However, excessive AMPAR stimulation by full AMPAR agonists can lead to psychostimulant and seizure activity (Meldrum 1994). Instead, positive allosteric modulators (PAMs) -also known as ampakinesbind allosterically to AMPARs and slow the rate of their deactivation or desensitization (Lynch 2006), thus prolonging the duration of AMPAR-mediated responses (Lapidus et al. 2013). Because ampakines do not activate directly AMPARs, the drugs are only effective with an underlying glutamatergic transmission (Arai et al. 1996). ...
Major depressive disorder (MDD) is the leading cause of disability worldwide and contributes importantly to the global burden of morbidity according to reports from the World Health Organization. Several types of antidepressant medications are used to treat moderate and severe depressive disorders although weeks or even months are required to produce clinical improvement. However, an estimated one third of the patients have inappropriate responses or no response at all to treatment. Hence, finding new, more efficient and rapid-acting antidepressant therapies is urgently needed. The discovery that ketamine produced rapid and sustained antidepressant effects has been the major breakthrough in the field of pharmacotherapy for MDD. Interestingly, studies with rodents have shown that the antidepressant-like effects of ketamine are dependent on the activation of AMPA receptors (AMPARs) because its behavioral action is blocked by AMPAR antagonists. Moreover, the removal of specific AMPAR subunits from birth results in behavioral and neurochemical characteristics relevant to depression. Taken together, these findings suggest that the stimulation of AMPARs may be a useful approach to treat MDD. Preclinical studies have reported that positive allosteric modulators (PAMs) – also known as ampakines or AMPAR potentiators – manifest antidepressant-like effects. These molecules bind allosterically to AMPARs and prolong the duration of AMPAR-mediated responses, theoretically without an overstimulation of excitatory transmission. In this chapter, we will review the most important preclinical data to date on the antidepressant-like effects of AMPA potentiators discussing their potential use as therapeutic tool in the clinic.
... Although the pathophysiology of bipolar disorder is still poorly understood, growing evidence suggests that glutamatergic abnormalities play a key role in the pathogenesis and treatment of bipolar disorder. For example, many rodent studies have demonstrated that mood stabilizers modulate glutamatergic receptors while manipulation of glutamatergic receptors causes significant changes in mood-associated behaviors (28,29). Post-mortem studies of bipolar disorder have also produced evidence of excitotoxicity in the frontal cortex (30), altered glutamatergic function on both presynaptic and post-synaptic sides, and abnormal excitatory synaptic connections (31,32). ...
In vivo ¹H magnetic resonance spectroscopy studies have found elevated brain glutamate or glutamate + glutamine levels in bipolar disorder with surprisingly high reproducibility. We propose that the elevated glutamate levels in bipolar disorder can be explained by increased pyruvate carboxylase-mediated anaplerosis in brain. Multiple independent lines of evidence supporting increased pyruvate carboxylase-mediated anaplerosis as a common mechanism underlying glutamatergic hyperactivity in bipolar disorder and the positive association between bipolar disorder and obesity are also described.
