10 Sharon L. Crowell‐Davis1, Mami Irimajiri2, and Leticia Mattos de Souza Dantas1 1 University of Georgia, Athens, GA, USA 2 Kitasato University, Aomori, Japan Anticonvulsants or antiepileptic medications are used primarily for the treatment of epilepsy. However, it has been recognized in human medicine that antiepileptic drugs may be effective for psychiatric conditions such as bipolar depression and anxiety disorders (Stahl 2008). Some of these drugs have also been proven to be effective in the treatment of painful conditions, such as neuropathic pain (Backonja et al. 1998). Anticonvulsants have a variety of mechanisms and actions on neurotransmitter receptors, so it is not surprising that these medications can be useful in mental health care (Piedad et al. 2012). Some anticonvulsants can change and modulate neuronal membrane polarity, neurotransmitter activity, and neuronal firing, affecting signal transduction (Stahl 2008; Piedad et al. 2012). Anticonvulsants act principally by reducing glutaminergic excitation, gamma‐aminobutyric acid (GABA)‐A stimulation for GABA‐ergic activation, and blocking voltage‐gated Na+ or Ca+ channel (Table 10.1). Table 10.1 Activity profiles on selected anticonvulsants. Source: Piedad et al. (2012). a L type = voltage gated calcium channel subtypes with varying levels of threshold activation. b α2δ subunit = a constituent subunit within different channel subtypes. Table 10.2 Dose range for gabapentin in cats and dogs. a Situational medication refers to using the medication for particular stressful events, such as visits to the veterinary office. The low dose is a recommended starting point. The dose can be titrated up, as needed. Psychiatric or mental health disorders are often treated effectively with antidepressants and/or anxiolytics. However, these medications can interact with anticonvulsant drugs. Phenobarbital is commonly used for dogs with seizures. It increases neuronal responsiveness to GABA and decreases Ca inflow in neurons. Phenobarbital may affect behavior in some animals because it can reduce anxiety. This effect is reported in mice, rats, monkeys, and baboons (Patel and Migler 1982; Kilfroil et al. 1989; Griffiths et al. 1991; Bertoglio and Carobrez 2002). However, phenobarbital and other GABA‐A‐stimulating drugs such as benzodiazepines can increase agitation and anxiety in dogs (Siracusa 2016). Gabapentin and pregabalin selectively bind to and have high affinity to the α2 delta site of voltage‐sensitive calcium channels (VSCCs) (Stahl 2008). They seem to have little or no effect as mood stabilizers in humans but are used for various pain conditions from neuropathic pain to fibromyalgia, and for various anxiety disorders (Stahl 2008). Carbamazepine binds to the alpha subunit of VSCCs and could act on the calcium and potassium ion channels. This mechanism of action may enhance the inhibitory actions for GABA. Carbamazepine is used to treat manic phases of bipolar disorder in humans, and it is also found to be effective in controlling aggressive behavior in bipolar depression or dementia in humans (Tariot et al. 1998; Stahl 2008). Carbamazepine has been used to treat aggression and agitation in psychotic and bipolar affective disorders in humans. Carbamazepine has also been used to control aggression in dogs and cats (Schwartz 1994; Galliccio and Notali 2010). Anticonvulsant drugs were primarily developed for the treatment of epilepsy, a neurological condition that affects approximately 50 million people worldwide (Mackey 2010). They reduce seizure frequency by suppressing neuronal excitability via various molecular targets in the synapse, including voltage‐gated ion channels, voltage‐gated sodium channels, GABAA (γ‐aminobutyric acid type A) receptors, and glutamate receptors (Piedad et al. 2012). In the veterinary literature, indications for anticonvulsants (besides treating disorders that cause seizures) include stereotypic behavior and obsessive‐compulsive disorders, including tail‐chasing, fly‐snapping, or excessive self‐licking in dogs and cats (Bain 2012). Some of these conditions have been proven to be caused by seizure activity as opposed to anxiety, so the actual reason for efficacy of treatment can vary. The ultimate choice of anticonvulsants for an individual patient with recently diagnosed or untreated epilepsy in humans usually includes consideration of the strength of the evidence for each medicine, along with other variables such as the medication’s safety and tolerability profile, its pharmacokinetic properties, formulations, and expense (Glauser et al. 2006). The treatment of epilepsy in pregnancy is particularly challenging in that the fetal and maternal risks associated with maternal seizures need to be balanced against the potential teratogenic effects of antiepileptic drugs (AEDs). No systematic information is available on the pharmacokinetics of the newer AEDs (e.g. gabapentin, pregabalin, tiagabine, topiramate, or zonisamide) during pregnancy (Tomson and Buttino 2007). In an open prospective clinical study, plasma clearance of phenytoin, phenobarbitone, and carbamazepine was assessed in 14 epileptic patients during and after pregnancy. Plasma clearance showed a marked increase during pregnancy, reached a maximum just before or after delivery, and then decreased to early pregnancy values (Dam et al. 1979). In veterinary clinical behavioral medicine, when stereotypic/compulsive behaviors such as tail‐chasing, self‐licking or self‐injurious behaviors are observed, these clinical signs have traditionally been diagnosed as compulsive or obsessive‐compulsive disorders. However, some of these cases are multifactorial and other medical problems such as psychomotor seizure activity and pain can coexist, and polypharmacy might be the most effective approach. Carbamazepine is one of the oldest anticonvulsant drugs available. In spite of this, its mechanism of action has still not definitively been established. It apparently decreases postsynaptic response and blocks post‐tetanic activation. It is metabolized in the liver by CYP3A4. It has one active metabolite, carbamazepine‐10,11‐epoxide. Its half‐life in humans is highly variable, ranging from 25 to 65 hours. Excretion is 72% in the urine and 28% in the feces (PDR Staff (2017). Carbamazepine is still extensively used for treatment of epilepsy in children. Oral bioavailability of carbamazepine in children is about 75–85%, and it is approximately 75–85% bound to plasma proteins. Pharmacokinetics of carbamazepine in children is dependent on age and body weight and is highly variable due to the influence of the dosing regimen and any co‐medication. The importance of human leukocyte antigen (HLA) typing for prediction of adverse drug reactions to carbamazepine in children was confirmed (Djordjevic et al. 2017). For safe and effective use of carbamazepine in this population, physicians are asked to adjust the dosing regimen according to existing patterns of genetic and environmental influences (Djordjevic et al. 2017). This medication can be effective in the manic phase of bipolar disorder treatment (Stahl 2008). It is also effective for the treatment of neuropathic pain (Stahl 2008). Carbamazepine has suppressant effects on the bone marrow, requiring blood cell counts to be monitored. It can cause fetal toxicity, such as neural tube deficit (Stahl 2008). In one report, a dog with unpredictable aggression to people was examined and an MRI found an arachnoid cyst in the retrocerebellar location. The dog was treated with dexamethasone but showed avoidance behaviors to the owner, so carbamazepine (10 mg kg−1 Q12h) was prescribed. Until the dog was euthanized, aggression toward the owner was under control while increasing the carbamazepine dosage as needed (Galliccio and Notali 2010). In 126 epileptic dogs with spontaneously recurring generalized tonic–clonic (grand mal) seizures, epidemiological aspects and the efficacy of chronic oral treatment with common antiepileptic drugs were studied. Furthermore, the pharmacokinetics of antiepileptic drugs in dogs was compared with the values known for humans. Comparison of the pharmacokinetics of antiepileptic drugs showed that some drugs were suited for maintenance therapy in dogs (primidone, phenobarbital, ethosuximide, trimethadione) whereas others appeared not to be ideally suited because of their short half‐lives (phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, nitrazepam) (Loscher et al. 1985). Currently, this is not a common medication for use in veterinary medicine. Schwartz (1994) reported successful treatment of two cats with owner‐directed aggression using carbamazepine at 25 mg q12h. Gabapentin is a GABA analogue. It binds with high affinity to α2‐delta subunits of voltage‐activated Ca2+ channels. Its half‐life in humans is five to seven hours. It is eliminated, unchanged, in the urine (PDR Staff (2017). Gabapentin can be an effective adjunctive treatment for patients with refractory partial epilepsy. It is usually well tolerated and it appears to have a favorable efficacy‐to‐toxicity ratio in human study (UK Gabapentin Study Group 1990). Gabapentin also provides analgesic activity for patients with neuropathic pain and has the advantage of a low side effect profile and drug toxicity (Rosner et al. 1996). One study showed that gabapentin is effective for pain in post‐herpetic neuralgia syndrome without side effects (Rowbotham et al. 1998). It can also be effective for pain from peripheral neuropathy in diabetes mellitus (Backonja et al. 1998). Allergy to gabapentin or any of the inactive ingredients in the medication. Severe liver or kidney disease.
Anticonvulsants and Mood Stabilizers
Action
Anticonvulsant
Voltage‐gated ion channel blockade
Carbamazepine
Inhibit Na↑
Gabapentin
Inhibit Ca2↑ (L‐type)a
Inhibit α2δ subunitb
Pregabalin
Inhibit Ca2↑
Inhibit α2δ subunit
Cats
Dogs
Daily medication
3–10 mg kg−1 q8h
2–20 mg kg−1 q8h
Situational medicationa
5–20 mg kg−1
10–20 mg kg−1
Overview of Indications
Clinical Guidelines
Specific Medications
I. Carbamazepine
Clinical Pharmacology
Side Effects
Effects in Non‐human Animals
Dogs
Cats
II. Gabapentin
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
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