12 Niwako Ogata1 and Leticia Mattos de Souza Dantas2 1 Purdue University, West Lafayette, IN, USA 2 University of Georgia, Athens, GA, USA Glutamate (or glutamic acid) is an excitatory amino acid that works as the major neurotransmitter in the central nervous system. It triggers the long‐term potentiation (LTP) of neuronal firing and synaptic plasticity. The N‐Methyl‐D‐aspartate (NMDA) receptor, which is located not only within the synapse but also at extrasynaptic sites, is one of the three classes of glutamate‐gated ionotropic channels and is well known with the other two receptors, the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and the kainate receptors. NMDA receptors are ionotropic, ligand‐gated, glutamate‐sensitive neurotransmitter receptors. Each NMDA receptor is a tetraheteromeric complex formed through the assembly of two GluN1 and two GluN2 protein subunits. The NMDA receptor is the most permeable to Ca2+, therefore, excessive activation of the NMDA receptor leads to increased intracellular Ca2+. Although glutamate binds with one of these sites on the receptor, a molecular of glycine (an inhibitory neurotransmitter) must be attached to the glycine binding site that is located on the outside of the NMDA receptor to open the calcium channel (Carlson 2013). Several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, neuropathic pain, and glaucoma are caused by neuronal cell injury or death that is due to the overstimulation of NMDA receptors (Lipton 2006). Acute disorders of stroke, central nervous system trauma, seizures as well as hyperalgesia in pain syndromes are also led by the excitotoxicity of glutamate. Therefore, it is considered that NMDA receptor antagonists can be beneficial in a number of neurological disorders. Additionally, NMDA receptor‐mediated glutamate neurotransmission has been considered to be involved in human depression for over 20 years (Vale et al. 1971). Reports in rodents as animal models of depression and humans from postmortem tissue have shown alterations in central NMDA receptor after periods of chronic stress (Newport et al. 2015). Even though the effects of combating the excitotoxicity of glutamate and neuroprotective efforts were of interest, severe side effects from inhibiting the excitotoxicity of glutamate were challenging when in the clinical applications of NMDA receptor antagonists. This was more pronounced with competitive NMDA receptor antagonists where the antagonists simply compete with glutamate or glycine at the agonist‐binding sites to block normal functions, causing severe side effects such as drowsiness, hallucinations, and even coma (Kemp and McKernan 2002). After several investigations, researchers have shifted to using NMDA receptor antagonists that block partially to avoid unwanted side effects. These medications are called noncompetitive/uncompetitive antagonists. Examples are amantadine, memantine (uncompetitive), and ketamine. It is hypothesized that chronic treatment with conventional antidepressants results in the same functional endpoint as the administration of NMDA receptor antagonists (Skolnick 1999). However, a systematic review and meta‐analysis of ketamine and other NMDA receptor antagonists in the treatment of major depression concluded the antidepressant efficacy was only observed in ketamine. Because ketamine also has a potential for abuse and neurotoxicity as well as its potential therapeutic benefit, clinical use has started in humans but warrants caution (Newport et al. 2015). A recent paper discussed the possibility of developing a better and safer antidepressant medication than ketamine (Zanos et al. 2016). Of the three excitatory amino acid receptor subtypes, the NMDA receptor seems more specifically linked to long‐term changes in neurons that play an important role in both inflammation and nerve injury‐induced central sensitization (De Kock and Lavand’homme 2007). Therefore, NMDA receptor antagonists have been implicated in postoperative and neuropathic pain management in humans (Collins et al. 2010). A systematic review in the human literature was not conclusive on its efficacy on neuropathic pain. The authors recommended that additional randomized control trials in homogeneous groups of pain patients are necessary for further conclusions (Collins et al. 2010). In the veterinary literature, the indication of NMDA receptor antagonists (such as ketamine and amantadine) is primarily for adjunctive analgesia to minimize the sensitization of the dorsal horn neurons (Lamont 2008). For example, it was reported that dogs that received ketamine infusions before, during, and after surgery had significantly lower pain scores after surgery and were significantly more active or had improved feeding behavior during postoperative observation compared to control dogs (Wagner et al. 2002; Sarrau et al. 2007). In both studies, opioid requirements used concomitantly were not significantly different between groups (Lamont 2008). Amantadine was originally used as an antiviral drug and to treat Parkinson’s disease in human medicine. Recently in both human and veterinary medicine, it has also been used to treat chronic pain. Lascelles et al. (2008) conducted a randomized, blind, placebo‐controlled study to evaluate its analgesic effects as an adjunct to an analgesic regimen in dogs with naturally occurring osteoarthritis. They reported that the addition of amantadine improved the dog’s physical activity and that it might be a useful adjunct therapy for dogs with osteoarthritic pain. In veterinary behavioral medicine, published information regarding NMDA receptor antagonists include the treatment of stereotypic behaviors, obsessive‐compulsive disorders, and putative complex partial seizures. The drugs used in these studies were dextromethorphan (Rendon et al. 2001; Dodman et al. 2004), memantine (Schneider et al. 2009b) and Huperzine‐A (Schneider et al. 2009a), which is a herbal medication. According to the literature, except for ketamine, noncompetitive or uncompetitive NMDA receptor antagonists in general are well‐tolerated drugs with no serious adverse effects reported, when used in instructed doses in humans, for example, an open trial of amantadine in depressed patients (bipolar or major depression) with Borna disease virus (BDV) infection, where 100–300 mg day−1 of amantadine were administered for a mean of 11 weeks. Major unwanted effects were observed in only one out of 25 patients that led to a drop‐out from the study. The signs reported were restlessness and blurring of vision but the rest of patients tolerated the amantadine therapy till the end of the study (Dietrich et al. 2000). Another study with memantine reported that in a randomized, pilot clinical trial for neuropathic pain following surgery, evaluating 5–20 mg day−1 of memantine for four weeks, no adverse effects were observed (Morel et al. 2016). When NMDA receptor antagonists are used for outpatient oral treatment in dogs, cats, and horses, relatively few side effects have been reported so far. Dodman et al. (2004) conducted a randomized, double‐blind, crossover‐designed study for 14 dogs with chronic allergic dermatitis for two weeks with dextromethorphan (2 mg kg−1 b.i.d.). Vomiting, retching, diarrhea, and lethargy were reported. A dog with lethargy and a dog with diarrhea withdrew from the study. All recovered once the treatment was discontinued. Schneider et al. (2009b) treated 11 dogs for compulsive disorder with memantine 0.3–1 mg kg−1 twice a day. One client reported a possible side effect from the drug on their dogs (increased frequency of urination). Since use of NMDA receptor antagonists is not yet widespread and research has been scarce, the presence or absence and the clinical significance of side effects should be interpreted prudently. For decades, most of the research on human mood disorders, especially major depression, has been based on monoaminergic systems. However, in the early 2000s, ketamine, a noncompetitive NMDA receptor antagonist, specifically received attention for its rapid and robust antidepressant effects in major depression (Zarate et al. 2006). Its action is not fully understood but recent results from studies in rodents suggested that ketamine activated the mammalian target of rapamycin pathway and subsequent synaptogenesis in the prefrontal cortex as well as glycogen synthase kinase‐r beta (GK‐3β) inactivation (Scheuing et al. 2015). Although ketamine is generally used for anesthesia, at low doses, it also works as an antidepressant. When the dose is increased, it evokes psychotomimetic actions (Miller et al. 2016) that challenge its clinical applications. In veterinary behavioral medicine, using ketamine in the treatment of behavior problems or mental health disorders has not yet been reported. Another psychiatric disorder where imbalances in glutamatergic neurotransmission might be involved is obsessive‐compulsive disorder (OCD) or compulsive disorder. The nature of glutamate perturbation in OCD remains poorly understood. Research in this area has been largely experimental with off‐label use of available medications (Pittenger 2015). Dextromethorphan (DXM) is a noncompetitive NMDA receptor antagonist, available for use in many prescription products, as well as in its most common form as over‐the‐counter (OTC) products for the treatment of cough. The typical antitussive adult human dose is 15 or 30 mg TID to QID. The antitussive effects of DXM persist for five to six hours after oral administration. When taken as directed, side effects are rarely observed (Drug Enforcement Administration 2014). Dextromethorphan is the dextro isomer of levomethorphan, a semisynthetic morphine derivative. Although structurally similar to other narcotics, DXM does not act as a mu‐receptor opioid (e.g. morphine, heroin). The antitussive activity of DXM is based on its action on σ‐opioid receptors and DXM also has analgesic and CNS depressant effects. DXM and its metabolite, dextrorphan, act as potent blockers of the NMDA receptor. At high doses used by those who abuse it, DXM causes dissociative effects, similar to the controlled substances phencyclidine (PCP) and ketamine, and inhibition of catecholamine reuptake. Approximately 5–10% of Caucasians are poor DXM metabolizers, which increases their risk for overdose and death (Chyka et al. 2007). In the veterinary field, it is used as an antitussive and few side effects have been reported when given clinically relevant doses. In the veterinary behavior field, IV administration of DXM is used for cribbing horses (Rendon et al. 2001) and oral DXM is used for dogs with repetitive behavior problems (Dodman et al. 2004). DXM has been available as an OTC antitussive medication for over 50 years and has been considered to have a high margin of safety with a clinical relevant dose. Since DXM binds to serotonergic receptors, the human literature states that it might not be safe to administer DXM with antidepressants due to the risk of inducing a life‐threatening serotonergic syndrome (Chyka et al. 2007). Vomiting, retching, diarrhea, and lethargy were reported in dogs with oral DXM (2 mg kg−1 b.i.d.) (Dodman et al. 2004). A dog with lethargy and a dog with diarrhea withdrew from the study reported above. All patients recovered once the treatment was discontinued. According to the pharmacokinetics study of dextromethorphan after intravenous and oral administration in six healthy beagles (KuKanich and Papich 2004), the drug had a short half‐life, and had poor bioavailability, such as 11% in oral administration. The authors concluded that its potential use with chronic oral administration is limited. Therefore, its effectiveness and long‐term safety need to be further studied (Moriello 2005; Saridomichelakis and Olivry 2016). Recently pharmacology studies in mice showed antidepressant‐like effects of DXM through forced swim and tail suspension tests (Nguyen and Matsumoto 2015). According to the study, it is speculated that DXM may modulate the glutamatergic function through an NMDA blockade that indirectly activates AMPA receptors. It is considered that AMPA receptors may contribute to the efficacy of antidepressant medications, including that of ketamine (Sanacora et al. 2008). Dodman et al. (2004) conducted a randomized, double‐blind, crossover designed study to test the efficacy of oral DXM (2 mg kg−1 b.i.d. for two weeks) on 14 dogs with repetitive behavior problems (e.g. self‐licking, self‐chewing, and self‐biting associated with chronic allergic dermatitis). Based on a dermatology score and the owners’ daily observations, it was concluded that DXM induced a mild to moderate improvement in clinical signs (i.e. reduced the percentage of time that allergic dogs spent in repetitive behaviors). Saridomichelakis and Olivry (2016) recommended further studies to fully appreciate the effectiveness and long‐term safety of DXM in atopic dermatitis. Maurer and Dodman (2007) published one case report of the treatment for compulsive disorder in a dog using dextromethorphan as an alternative medication to memantine due to its cost. Details are given in the memantine section of this chapter. Rendon et al. (2001) reported DXM effects on cribbing horses. Jugular injection of DXM (1 mg kg−1) was administered to nine cribbing horses and eight horses responded with mean of 48% decrease in frequency compared to baseline, and its effect lasted 35–60 minutes following injection in almost half of the horses. Although no major side effects were reported, one horse in the study showed higher rate of cribbing rate after the injection. Amantadine is a weak, noncompetitive NMDA receptor antagonist. It has been used treat Parkinson’s disease, drug‐induced extrapyramidal reactions, and virus infections. Although its mechanism of action for each condition is not clearly understood, it appears to exert its antiviral effect by preventing penetration of the virus into the host cell, and it is also known to prevent virus assembly during virus replication (Endo Pharmaceuticals Inc. 2009). Amantadine is considered to have direct or indirect effects on dopamine neurons and oftentimes is prescribed with L‐Dopa for the management of L‐Dopa‐induced dyskinesia in Parkinson’s disease (Oertel and Schulz 2016). Analgesic effects in orally administered amantadine in humans had inconsistent results (Taira 1998; Kleinböhl et al. 2006). Lascelles et al. (2008) published a randomized, blind, and placebo‐controlled study on the use of oral amantadine in addition to meloxicam (a nonsteroidal anti‐inflammatory drug) on refractory osteoarthritis pain in 31 client‐owned dogs. In the study, physical activity in dogs was improved per client‐specific outcome measures with the addition of amantadine (3–5 mg kg−1 orally every 24 hours) to meloxicam treatment (0.1 mg kg−1 administered orally every 24 hours after a 0.2 mg kg−1 oral loading dose) within three weeks of the treatment. No abnormalities were reported on the patients’ laboratory work or adverse effects during the study.
N‐Methyl‐D‐Aspartate (NMDA) Receptor Antagonists
Action
Overview of Indications
Contraindications/Side Effects, and Adverse Events
Clinical Guidelines
Specific Medications
I. Dextromethorphan
Clinical Pharmacology
Contraindications and Side Effects
Other Information
Effects Documented in Nonhuman Animals
Dogs
Horses
II. Amantadine
Clinical Pharmacology
Use in Humans
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