Dopamine (DA) is the major neurotransmitter within the basal ganglia, which is the involuntary motor system of the brain. Blocking DA receptors in the basal ganglia can cause extrapyramidal (parkinsonian) symptoms, acute dystonia, akathisia, tardive dyskinesia (TD), and neuroleptic malignant syndrome (NMS). Antipsychotic drugs are the most important class of medications that block DA receptors. Other DA receptor-blocking drugs, however, include antiemetic drugs, such as prochlorperazine (Compazine®), metoclopramide (Reglan®), and thiethylperazine (Torecan®), and the antidepressant drug amoxapine (Asendin®). Although these motor syndromes can all be caused by DA receptor-blocking drugs, distinguishing among these syndromes is important because their treatment is different. Of these syndromes, TD is of greatest clinical concern, especially with the long-term use of antipsychotic and antiemetic drugs, and it is the most difficult to treat. Many drug therapies have been tried for TD, but none are approved by the U.S. Food and Drug Administration (FDA). In this article, the first of two parts, I will first briefly review these motor syndromes. I will then begin a review of various drug therapies that have been used for TD, which will be concluded in next month’s article.
Antipsychotic Drug-Induced Motor Syndromes
Extrapyramidal symptoms are similar to Parkinson’s disease: resting tremor, muscle rigidity, shuffling gait, stooped posture, blunted facial expression, and drooling. This can occur at any time in treatment, is usually dose-related, is more common with high-potency first-generation (typical) antipsychotic (FGA) drugs, and can be treated with anticholinergic, antihistamine, dopamine receptor-agonist, or DA-releasing drugs.
Acute dystonia is a sudden severe prolonged muscle contraction, usually involving an isolated muscle or group of muscles. It is more likely to occur with high-potency FGA drugs, typically when first starting the drug, and is less likely to occur or recur with chronic treatment. Acute dystonias usually respond promptly with anticholinergic or antihistamine drugs.
Akathisia is characterized by a subjective and objective sense of restlessness, anxiety, and mild motor agitation. This can occur at any time, is usually dose-related, and is more common with high-potency FGA drugs. Akathisia does not usually respond to treatment with anticholinergic, antihistamine, DA-releasing, or DA receptor-agonist drugs. Beta receptor-blocker and benzodiazepine drugs are more effective.
NMS is a rare but serious and potentially fatal reaction to DA receptor-blocking drugs, which can develop at any time during the course of treatment. The motor and behavioral symptoms include muscular rigidity and dystonia, akinesia (immobility), mutism, obtundation, and agitation. Autonomic symptoms include high fever, sweating, tachycardia, and hypertension. Patients can develop increases in muscle and liver enzymes, and kidney failure may occur. This condition is considered a medical emergency, and supportive medical care is necessary.
TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. It occurs in a small proportion of patients who take antiemetic and antipsychotic drugs (typically the older FGA drugs, but also newer drugs) for long periods of time. The cause of TD is unknown, but alterations in DA function—including postsynaptic DA receptor sensitivity—within the basal ganglia have been implicated. Changes with cholinergic and noradrenergic systems within the basal ganglia may also be involved.
Atypical Antipsychotic Drugs
The second-generation antipsychotic (SGA) drugs, also referred to as atypical antipsychotic agents, were first introduced in the early 1990s. Currently available SGA drugs include clozapine (Clozaril®), risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), ziprasidone (Geodon®), aripiprazole (Abilify®), paliperidone extended-release tablets (Invega®), iloperidone (Fanapt®), asenapine (Saphris®), and lurasidone (Latuda®). Because SGA drugs share the DA-2 receptor-blocking effects of FGA drugs, they are classified as antipsychotic drugs and are all FDA approved for the treatment of schizophrenia. However, SGA drugs tend to block DA-2 receptors less potently than do FGA drugs, and they have significantly greater effects on blocking serotonin 5HT-2 receptors compared with FGA drugs. Also in contrast to FGA drugs, SGA drugs have effects on other neurotransmitters and receptors, although these pharmacological effects vary among each of the SGA drugs. Because of these unique SGA pharmacological properties, they are generally less likely to be associated with the development of extrapyramidal effects and TD. Among the SGA drugs, a few controlled studies have suggested that clozapine, olanzapine, quetiapine, and risperidone are effective in reducing the abnormal motor movements (AMMs) associated with TD.
In a 1-year study of patients with preexisting TD, those randomized to receive clozapine showed significantly greater improvement in AMMs compared with haloperidol (Haldol®) (Tamminga, Thaker, Moran, Kakigi, & Gao, 1994). In addition, dyskinesia withdrawal symptoms, which occurred equally in both drug groups at the beginning of the study, were sustained in the haloperidol group but lost in the clozapine group at the end of the study. This finding suggested that the pathophysiological process underlying the development of TD had been altered by the use of clozapine, but not by haloperidol. In an 8-month study of olanzapine, patients with preexisting TD were randomized to blindly receive one or two dose reductions during the course of the study (Kinon, Jeste, Kolkack-Walker, Stauffer, & Liu-Seifert, 2004). Patients showed significant improvement in AMMs without developing withdrawal dyskinesias during dose reductions. As with clozapine, this finding suggested that the underlying pathophysiological process had been altered by olanzapine.
In a 1-year randomized rater-blinded study comparing quetiapine and haloperidol, patients with preexisting TD showed significantly greater improvement in AMMs with quetiapine (Emsley et al., 2004). In a 12-week double-blind, placebo-controlled study, risperidone was significantly better on improving AMMs in patients with preexisting TD (Bai, Yu, & Lin, 2003). A 24-week randomized rater-blinded comparison of risperidone and olanzapine found no difference between these drugs on improving AMMs (Chan et al., 2010).
Because of the central role of DA systems in the development of TD, one strategy has been to try drugs that deplete DA within the basal ganglia. Such drugs include reserpine (Resa®; FDA approved for hypertension and psychotic disorders), tetrabenazine (Xenazine®; FDA approved for Huntington’s chorea), and metyrosine (alpha-methyl-para-tyrosine; Demser®; FDA approved for pheochromocytoma). Each of these drugs has been demonstrated in controlled studies to be effective at reducing AMMs in patients with TD (Huang, Wang, Hasegawa, & Alverno, 1981; Ondo, Hanna, & Jankovic, 1999). However, potentially severe adverse effects, including depression, parkinsonian effects, akathisia, and orthostatic hypotension, limit their clinical utility. For this reason, they are rarely used for treating TD.
Amantadine (Symmetrel®), a closely related chemical analogue of the Alzheimer’s disease drug memantine (Namenda®), is an FDA-approved treatment for influenza (type A), Parkinson’s disease, and drug-induced extrapyramidal effects. It increases DA activity by facilitating the presynaptic release of DA and possibly blocking the presynaptic reuptake of DA. Similar to memantine, it may also block activity at glutamate receptors. One double-blind, placebo-controlled study found it effective in TD (Pappa, Tsouli, Apostolou, Mavreas, & Konitsiotis, 2010). Possible adverse effects include dizziness, headache, nausea, loss of appetite, irritability, insomnia, speech dysarthria, ataxia, and impaired concentration. Rarely, seizures and psychosis can occur.
Bromocriptine (Parlodel®) is a postsynaptic DA receptor agonist that is FDA approved for the treatment of hyperprolactinemia and Parkinson’s disease and is sometimes used to treat extrapyramidal effects of antipsychotic drugs. A double-blind, placebo-controlled study found no benefit for TD (Lieberman, Alvir, Mukherjee, & Kane, 1989).
Selegiline (Deprenyl®) is a selective inhibitor of monoamine oxidase type B, which increases DA, and it also has potential neuroprotective properties. It is FDA approved for the treatment of Parkinson’s disease. The transdermal patch formulation (Emsam®) is FDA approved for the treatment of depression. A double-blind, placebo-controlled trial found no benefit for TD (Goff et al., 1993).
Buspirone (Buspar®) is an azapirone drug that is a partial agonist at the serotonin 5HT-1A receptor. It has DA-modulating effects and was originally developed as a potential antipsychotic drug. It is FDA approved for the treatment of generalized anxiety disorder. Buspirone has been suggested as a potential treatment for TD (Ross, 1987), but only one open-label study has been reported to show some benefit (Moss, Neppe, & Drevets, 1993). Possible adverse effects include headache, nausea, dizziness, and insomnia.
Naloxone (Narcan®) is an opioid receptor antagonist drug that has DA-modulating effects. In a double-blind, placebo-controlled study, naloxone produced improvement in involuntary movements, cognition (memory and problem solving), and clinical ratings in patients with TD (Lindenmayer et al., 1988). A second double-blind, placebo-controlled study investigated naloxone in 13 patients with TD (Blum, Nisipeanu, & Roberts, 1987). Three patients showed significant improvement, although it is notable that these three patients had TD for a relatively short duration (less than 3 years) compared with the other patients (who had TD for up to 20 years).
Within the basal ganglia, DA and acetylcholine pathways have a reciprocal and counter-regulatory effect on each other. Anticholinergic drugs, which block acetylcholine receptors, are used to treat Parkinson’s disease and the extrapyramidal effects associated with antipsychotic drugs, but they are not effective for TD and may increase the severity of AMMs. Drugs that enhance cholinergic activity, including acetylcholine precursors and acetylcholinesterase inhibitor (AChI) drugs block the effects of cholinesterase enzymes that metabolize the neurotransmitter acetylcholine, and they are used clinically to boost cholinergic function. There is no evidence from controlled studies that the AChI drugs donepezil (Aricept®) and galantamine (Reminyl®, Razadyne®) or other cholinergic drugs are effective in TD (Caroff et al., 2007; Ogunmefun, Hasnain, Alam, Osuala, & Regenold, 2009; Tammenmaa, Sailas, McGrath, Soares-Weiser, & Wahlbeck, 2004).
Nurses should be familiar with TD and other motor syndromes, as well as the potential benefits and adverse effects of drug therapies used for TD. SGA drugs should be considered as a first-choice treatment for clinically significant TD, because they will also be potentially effective as a primary treatment for the underlying disorder (e.g., schizophrenia, bipolar disorder, Tourette syndrome). DA-depleting drugs are effective for TD, but their practical use is severely limited because of tolerability and safety concerns. Various DA-modulating drugs have been tried, and clinical evidence of efficacy suggests that amantadine and naloxone are worthwhile to try. Although efficacy evidence for buspirone in TD is limited, it is safe, well tolerated, and commonly used in practice for other clinical reasons. As such, trying it for TD would be reasonable. In next month’s article, I will review other drug therapies for TD.
- Bai, Y.M., Yu, S.C. & Lin, C.C. (2003). Risperidone for severe tardive dyskinesia: A 12-week randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry, 64, 1342–1348. doi:10.4088/JCP.v64n1110 [CrossRef]
- Blum, I., Nisipeanu, P.F. & Roberts, E. (1987). Naloxone in tardive dyskinesia. Psychopharmacology, 93, 538. doi:10.1007/BF00207250 [CrossRef]
- Caroff, S.N., Walker, P., Campbell, C., Lorry, A., Petro, C., Lynch, K. & Gallop, R. (2007). Treatment of tardive dyskinesia with galantamine: A randomized controlled crossover trial. Journal of Clinical Psychiatry, 68, 410–415. doi:10.4088/JCP.v68n0309 [CrossRef]
- Chan, H.Y., Chiang, S.C., Chang, C.J., Gau, S.S., Chen, J.J., Chen, C.H. & Lai, M.S.,… (2010). A randomized controlled trial of risperidone and olanzapine for schizophrenic patients with neuroleptic-induced tardive dyskinesia. Journal of Clinical Psychiatry, 71, 1226–1233. doi:10.4088/JCP.09m05155yel [CrossRef]
- Emsley, R., Turner, H.J., Schronen, J., Botha, K., Smit, R. & Oosthuizen, P.P. (2004). A single-blind randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia. Journal of Clinical Psychiatry, 65, 696–701. doi:10.4088/JCP.v65n0516 [CrossRef]
- Goff, D.C., Renshaw, P.F., Sarid-Segal, O., Dreyfuss, D.A., Amico, E.T. & Ciraulo, D.A. (1993). A placebo-controlled trial of selegiline (L-deprenyl) in the treatment of tardive dyskinesia. Biological Psychiatry, 33, 700–706. doi:10.1016/0006-3223(93)90119-X [CrossRef]
- Huang, C.C., Wang, R.I., Hasegawa, A. & Alverno, L. (1981). Reserpine and alpha-methyldopa in the treatment of tardive dyskinesia. Psychopharmacology, 73, 359–362. doi:10.1007/BF00426466 [CrossRef]
- Kinon, B.J., Jeste, D.V., Kolkack-Walker, S., Stauffer, V. & Liu-Seifert, H. (2004). Olanzapine treatment for tardive dyskinesia in schizophrenia patients: A prospective clinical trial with patients randomized to blinded dose reduction. Progress in Neuropsychopharmacology and Biological Psychiatry, 28, 985–986. doi:10.1016/j.pnpbp.2004.05.016 [CrossRef]
- Lieberman, J.A., Alvir, J., Mukherjee, S. & Kane, J.M. (1989). Treatment of tardive dyskinesia with bromocriptine: A test of the receptor modification strategy. Archives of General Psychiatry, 46, 908–913.
- Lindenmayer, J.P., Gardner, E., Goldberg, E., Opler, L.A., Kay, S.R., van Praag, H.M. & Zukin, S.,… (1988). High-dose naloxone in tardive dyskinesia. Psychiatry Research, 26, 19–28. doi:10.1016/0165-1781(88)90083-2 [CrossRef]
- Moss, L.E., Neppe, V.M. & Drevets, W.C. (1993). Buspirone in the treatment of tardive dyskinesia. Journal of Clinical Psychopharmacology, 13, 204–209. doi:10.1097/00004714-199306000-00009 [CrossRef]
- Ogunmefun, A., Hasnain, M., Alam, A., Osuala, T. & Regenold, W.T. (2009). Effect of donepezil on tardive dyskinesia. Journal of Clinical Psychopharmacology, 29, 102–104. doi:10.1097/JCP.0b013e3181934475 [CrossRef]
- Ondo, W.G., Hanna, P.A. & Jankovic, J. (1999). Tetrabenazine treatment for tardive dyskinesia: Assessment by randomized videotape protocol. American Journal of Psychiatry, 156, 1279–1281.
- Pappa, S., Tsouli, S., Apostolou, G., Mavreas, V. & Konitsiotis, S. (2010). Effects of amantadine on tardive dyskinesia: A randomized double-blind placebo-controlled study. Clinical Neuropharmacology, 33, 271–275. doi:10.1097/WNF.0b013e3181ffde32 [CrossRef]
- Ross, C.A. (1987). Buspirone in the treatment of tardive dyskinesia. Medical Hypotheses, 22, 321–328. doi:10.1016/0306-9877(87)90197-6 [CrossRef]
- Tammenmaa, I.A., Sailas, E., McGrath, J.J., Soares-Weiser, K. & Wahlbeck, K. (2004). Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: A meta-analysis of randomized controlled trials. Progress in Neuropsychopharmacology and Biological Psychiatry, 28, 1099–1107. doi:10.1016/j.pnpbp.2004.05.045 [CrossRef]
- Tamminga, C.A., Thaker, G.K., Moran, M., Kakigi, T. & Gao, X.M. (1994). Clozapine in tardive dyskinesia: Observations from human and animal model studies. Journal of Clinical Psychiatry, 55(Suppl. B), 102–106.