Tardive dyskinesia (TD) is a serious complication associated with the long-term use of dopamine receptor-blocking drugs, especially antipsychotic drugs but also anti-emetic drugs. No drugs are approved by the U.S. Food and Drug Administration (FDA) for treatment of TD. In last month’s article (Howland, 2011), I described TD and the other motor syndromes and reviewed the therapeutic use of atypical antipsychotic, dopamine-depleting, and dopamine-modulating drugs for TD. This month, I complete a brief review of other drug therapies for TD.
Essential Fatty Acids
Essential fatty acids are important components of neuronal membranes influencing neuronal function. Lower levels are found in patients with TD (Vaddadi, Hakansson, Clifford, & Waddington, 2006). However, controlled studies of essential fatty acids, such as the omega-3 fatty acid eicosapentaenoic acid, have demonstrated no benefit for the treatment of TD (Emsley et al., 2006).
Branched-Chain Amino Acids
Some studies have found high levels of the large neutral amino acid phenylalanine in patients with TD (Richardson et al., 2003; Richardson, Small, Read, Chao, & Clelland, 2004). Ingestion of branched-chain amino acids (BCAAs) decreases the concentration of aromatic amino acids (phenylalanine, tyrosine, tryptophan). A double-blind, placebo-controlled (DBPC) study demonstrated a significant benefit for BCAAs in men with TD (Richardson et al., 2003). Possible adverse effects of BCAAs include nausea, flushing, intrahepatic cholestasis, increased ammonia levels, thrombocytopenia, and thrombophlebitis.
BCAA products, commercially available as an FDA-designated “medical food,” have been used in patients with cirrhosis and hepatic encephalopathy. A medical food is defined as:
a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.
Medical foods are exempt from FDA labeling requirements for health claims and nutrient content, and they are not reviewed or approved by the FDA. They must comply with good manufacturing practice regulations and labeling practices for protection against food allergens.
The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA receptor systems are the target of a wide range of drugs, including anti-anxiety, sedative-hypnotic, general anesthetic, and anticonvulsant agents. GABA also modulates the activity of dopamine and other neurotransmitters.
The main GABA receptor complexes are referred to as GABA-A, GABA-B, and GABA-C. The GABA-A receptor complex is the most clinically important. Benzodiazepine receptor agonist drugs (BzRAs) work by binding to GABA-A receptors in the brain. The two BzRA drug classes are referred to as benzodiazepine and nonbenzodiazepine drugs. The benzodiazepine drugs bind nonspecifically to the GABA-A receptor complex and are related by their similar central chemical structure, but they have different chemical side chains that result in pharmacokinetic differences. Among the multiple FDA-approved benzodiazepine drugs, some evidence from controlled studies indicates that clonazepam (Klonopin®) and diazepam (Valium®) are effective in reducing abnormal motor movements in patients with TD (Thaker et al., 1990).
Baclofen (Lioresal®), an agonist at presynaptic GABA-B receptors, is FDA approved for treating spasticity. A DBPC study found no benefit for the treatment of TD (Glazer, Moore, Bowers, Bunney, & Roffman, 1985).
The term nootropic was first used to describe the cognitive effects of the compound piracetam, and nootropic agents most specifically describe the larger class of drugs that are chemically related to piracetam (Malykh & Sadaie, 2010). Piracetam and piracetam-like drugs are cyclic derivatives of GABA. The precise mechanism of action of these drugs is unclear, but they have anticonvulsant and antioxidant properties, may enhance the function of cholinergic receptor systems, and might modulate glutamate receptor systems. Piracetam is manufactured outside of the United States under various trade names (Nootropil®, Nootrop®, Nootropyl®). The drug is designated by the FDA as an orphan drug for the treatment of myoclonus, a type of epilepsy characterized by brief involuntary muscle twitching. Drugs are designated as orphan for the treatment of rare diseases or conditions. Piracetam is not otherwise regulated by the FDA and can be obtained in the United States without a prescription. A DBPC study demonstrated significant benefit for piracetam in TD (Libov, Miodownik, Bersudsky, Dwolatzky, & Lerner, 2007). Possible adverse effects of piracetam include anxiety, insomnia, irritability, headache, agitation, tremor, and nausea. Elevations of liver enzymes have been reported rarely. Because the drug is cleared through the kidneys, patients with impaired renal function have a higher risk of adverse effects. Abrupt discontinuation can be associated with seizures.
Levetiracetam (Keppra®), FDA approved as adjunctive therapy for various seizure types, is the S-enantiomer of the racemate drug etiracetam, which is structurally similar to piracetam. A DBPC study demonstrated significant benefit for levetiracetam in TD (Woods, Saksa, Baker, Cohen, & Tek, 2008). Common adverse effects of levetiracetam are dizziness, somnolence, weakness, and irritability. Behavioral changes, hallucinations, and psychosis have been reported.
Valproic acid (VPA; Depakene®, Stavzor®), divalproex sodium (Depakote®), and valproate sodium intravenous injection (Depacon®) are different formulations of the same chemical compound, which is FDA approved for epilepsy, bipolar disorder, and migraines. The precise mechanism of action of VPA is unknown, but it increases GABA concentrations in the brain. Two DBPC studies found no benefit for TD (Fisk & York, 1987; Nasrallah, Dunner, & McCalley-Whitters, 1985).
Gabapentin (Neurontin®) is structurally related to GABA but does not bind to GABA-A or GABA-B receptors. It is FDA approved for the treatment of epilepsy and post-herpetic neuralgia. An open-label study with up to 1-year follow up suggested some benefit for the treatment of TD, but no controlled studies have been conducted (Hardoy et al., 2003). Common adverse effects are sedation, dizziness, ataxia, and weight gain.
More than a dozen beta-adrenergic receptor antagonist drugs (beta-blockers) are currently FDA approved. Propranolol (Inderal®) is the beta-blocker used most often in psychiatry. Blocking postsynaptic beta-receptors in the nervous system attenuates the effects of increased adrenergic activity throughout the body. For this reason, propranolol has been used for treating medication-induced tremors and akathisia. Several small trials and multiple case reports have suggested some benefit for TD, but the supporting evidence is weak (Aia, Revuelta, Cloud, & Factor, 2011). Common adverse effects of beta-blockers are fatigue, dizziness, bradycardia, hypotension, and decreased exercise tolerance. Impotence can occur in men. Depression and bronchospasm are possible but not common. With chronic use, abruptly stopping beta-blockers can cause rebound restlessness, sweating, tremors, tachycardia, headache, hypertension, and angina.
Clonidine (Catapres®) is a presynaptic alpha-2 receptor agonist drug. Stimulation of presynaptic alpha-2 receptors reduces the firing rate of adrenergic neurons in the brain and reduces plasma concentrations of norepinephrine. Based on this effect, clonidine has been used for treating conditions associated with increased adrenergic activity. In Tourette syndrome and other tic disorders, it can suppress motor/vocal tics. A DBPC crossover study demonstrated significant benefit for clonidine in TD (Browne et al., 1986). Common adverse effects of clonidine are dry mouth, dry eyes, fatigue, sedation, dizziness, constipation, and hypotension. Depression and bradycardia are less common. After chronic use, abruptly stopping clonidine can cause rebound anxiety, restlessness, sweating, tremors, abdominal pain, heart palpitations, headache, and hypertension.
Calcium channel-blocking (CCB) drugs, including diltiazem (Cardizem®), nifedipine (Procardia®), nimodipine (Nimotop®), and verapamil (Calan®), are FDA approved for various cardiovascular indications. Calcium channels may be directly or indirectly involved in modulating dopamine neuronal function, and CCB drugs have been suggested as a treatment for TD. An analysis of eight published nonrandomized studies and five small randomized studies concluded that the outcome data from these studies could not be used to support or refute the efficacy of CCB drugs for the treatment of TD (Soares-Weiser & Rathbone, 2004).
The hypothesis that free radicals may be involved in the pathophysiological process that underlies the development of TD has stimulated interest in investigating drugs that have antioxidant properties. A recent DBPC study of an extract of ginkgo biloba demonstrated significant benefit in TD (Zhang et al., 2010). Common side effects are nausea, vomiting, diarrhea, headache, irritability, and dizziness. Bruising and bleeding may occur, with rare reports of serious intracranial bleeding (e.g., subdural hematoma). Potential drug interactions include anticoagulant and anti-platelet drugs. Ginkgo may also affect liver metabolic enzymes.
Vitamin E has been investigated in multiple studies of TD. Although it has minimal acute benefit on reducing abnormal motor movements, it may have more significant benefit at protecting against the deterioration of TD symptoms over time (Soares-Weiser, Maayan, & McGrath, 2011). Vitamin E supplementation has been associated with an increased risk of bleeding and mortality.
Melatonin, a hormone synthesized from serotonin and secreted by the pineal gland, regulates sleep-wake cycles. It has potent antioxidant effects and attenuates dopamine activity in certain brain regions. A DBPC study found it significantly effective for TD (Shamir et al., 2001). Potential adverse effects are headache, confusion, and sedation or fatigue.
Vitamin B6 (pyridoxine) also has potent antioxidant properties. Two DBPC crossover studies by the same research group demonstrated significant benefit for TD (Lerner et al., 2007). Potential adverse effects include decreased folic acid levels, paresthesias, and somnolence.
A number of drugs reviewed here appear to have some benefit for the treatment of TD, including BCAAs, piracetam, clonazepam, levetiracetam, propranolol, and clonidine, and they would be clinically reasonable to try. The use of BCAAs and piracetam is hampered by finding an appropriate source. Gabapentin has a good safety profile and would be appropriate to consider, although no DBPC trials support its use. The efficacy of ginkgo biloba should be balanced against its safety concerns. Essential fatty acids have not been shown to be beneficial. Antioxidant therapies, including vitamin E, melatonin, and vitamin B6, could conceivably be used together with other drug therapies (e.g., those reviewed here and in last month’s article). Nurses should be familiar with the potential benefits and adverse effects of various drug therapies used for TD.
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- U.S. Food and Drug Administration. (2009). Medical foods: Overview. Retrieved from http://www.fda.gov/Food/FoodSafety/Product-SpecificInformation/MedicalFoods/default.htm
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