Treatment of Acute Neuroleptic-Induced Movement Disorders Margaret E. Tonda, Pharm.D., and Sally K. Guthrie, Pharm.D. Acute extrapyramidal syndromes (EPS), including dystonia, parkinsonism, and akathisia, are associated with the use of virtually all neuroleptic agents. They may be alleviated by reducing the neuroleptic dosage, switching to a lower- potency drug, or administering an adjunctive agent such as an anticholinergic, amantadine, benzodiazepine, or P-blocker. Akathisia may be only partly dispelled by anticholinergics; alternatives are P-blockers, benzodiazepines, and clonidine. In patients receiving long-term neuroleptic therapy, both the prophylactic use and the duration of treatment with concomitant anti-EPS drugs are controversial. Administration of prophylactic anti-EPS drugs should be based on the likelihood that the patient will develop EPS, as well as the risk of adverse reactions resulting from extended use of the agents in a specific patient. The decision to continue anti-EPS therapy should be reevaluated frequently, especially in elderly patients. (Pharmacotherapy 1994;14( 51543-560) OUTLINE range of extrapyramidal syndromes (EPS) was Pharmacology observed. Although neuroleptics belong to several Pathophysiology and Clinical Manifestations of Drug- different chemical classes including phenothiazines, Induced EPS thioxanthenes, butyrophenones, dihydroindolones, Pseudoparkinsonism dibenzoxazepines, and diphenylbutylpiperidones, Acute Dystonic Reactions they are all dopamine antagonists and induce EPS Akathisia to various degrees.', ' Other drugs that cause Treatment central dopamine receptor blockade, such as Anticholinergic Agents metoclopramide (an antiemetic) and amoxapine Dopaminergic Agents (an antidepressant), can also produce extra- Benzodiazepines pyramidal movement disorder^.^^ P-Adrenergic Blockers in Akathisia Antipsychotic-induced EPS fall into four Other Agents categories: parkinsonism-like movements, acute Prophylaxis dystonia, akathisia, and tardive dyskinesia. This Conclusion article focuses only on the acute movement disorders; several excellent reviews have been Antipsychotic or neuroleptic agents have been written on tardive dyskinesia.1.5.6 used in clinical practice for the past 30 years. They revolutionized the management of psychoses, Pharmacology but they are associated with significant side effects. Almost immediately after their introduction, a The production of voluntary movement results from complex interactions among the motor From the Department of Pharmacy Services (Dr. Tonda) cortex, basal ganglia, and spinal cord. The and the Department of Psychiatry (Dr. Guthrie), University of corticospinal, or pyramidal, tract is one of the Michigan Medical Center, and the College of Pharmacy, major pathways by which electrical signals are University of Michigan, (Dr. Guthrie), Ann Arbor, Michigan. Address reprint requests to Sally K. Guthrie, Pharm.D., conducted from the motor cortex to the anterior University of Michigan College of Pharmacy, Ann Arbor, MI motor neurons of the spinal cord. Collateral 48109-1065. pathways split from the corticospinal tract toward 544 PHARMACOTHERAPY Volume 14, Number 5, 1994 the basal ganglia by way of the caudate nucleus through their actions on dopamine pathways in the and putamen, two structures known collectively as basal ganglia, whereas dopamine cell bodies the neostriatum. The basal ganglia are a collection located in the substantia nigra or ventral tegmental of subcortical and midbrain structures made up of areas that project to the limbic system and the the globus pallidus, substantia nigra, neostriatum, cortex (mesolimbic and mesocortical systems) and subthalamic nucleus. The collateral pathways, appear to affect mood and thought proce~ses.~ which travel through the basal ganglia, are Neuroleptic effects on movement are thought to be considered to be separate from the pyramidal tract mediated primarily by another dopamine pathway, and are called the extrapyramidal tracts. the nigrostriatal pathway, which consists of cell The extrapyramidal system modulates and bodies in the substantia nigra that project to the modifies the motor signals sent by the corticospinal neo~triatum.~ tract. Sensory and motor information travels from In addition to dopamine, the glutamatergic y- the cortex to the basal ganglia, where it is integrated, aminobutyric acid (GABA), acetylcholine, and refined, and relayed through the thalamus back to serotonin neurotransmitter systems affect the prefrontal cortex and, ultimately, the spinal cord extrapyramidal movement. Cortical afferent tracts, (Figure l).7 which are primarily glutamatergic, project into the Dopamine is one of several neurotransmitters striatum (putamen) where they terminate on GABA that act on the extrapyramidal system. At least five neurons. The GABA neurons in the putamen then important dopamine pathways have been project to the globus pallidus, as well as the delineated in the human brain.8 Neuroleptics are substantia nigra. Glutamate generally acts as an thought to produce effects on movement primarily excitatory neurotransmitter in the brain, and GABA Figure 1. Summary of basal ganglia circuitry. SN = substantia nigra; STR = neostriatum; GPE = globus pallidus externa, GPI = globus pallidus interna; STN = subthalamic nucleus; Thal = thalamus; ACh = acetylcholine; DA = dopamine; GABA = y- aminobutyric acid; Glu = glutamate; 0 = unknown neurotransmitter; + = excitatory, - = inhibitory. ACUTE NEUROLEPTIC-INDUCED MOVEMENT DISORDERS Tonda and Guthrie 545 is usually inhibitory. The exact role of GABA is not subtypes are not well characterized. The atypical clearly defined, but this neurotransmitter appears neuroleptic agent clozapine causes almost no EPS to maintain normal basal ganglia function through and exhibits a relatively high affinity for D4 a complex system of negative feedback loops. receptor^,'^ but at this time it is not clear if the Glutamatergic input to the striatum is modulated decreased frequency of EPS is related to this by dopamine neurons originating from the affinity. Clozapine also has relatively higher affinity substantia nigra, by acetylcholine interneurons in for muscarinic receptors and has lower occupancy the striatum, and by input from other GABA of D2 receptors in the basal ganglia compared with neurons within the striatum. Dopamine appears to typical antipsychotics.15-17 have an overall inhibitory effect on the thalamic The exact sites of dopamine-serotonin inter- output to the prefrontal cortex that is antagonized actions that are most relevant to motor control are by the acetylcholine interneurons in the ~triatum.~ not known, but it appears that serotonin neurons Although the mechanism of action of neuroleptic projecting from the nucleus raphe dorsalis agents has not been definitively identified, the modulate dopamine pathways in the basal antipsychotic action of the drugs is thought to ganglia.18 Ritanserin, a serotonin type 2 (5-HTz) result from the postsynaptic blockade of dopamine receptor-blocking agent, decreases EPS when given receptors in the mesocortical and mesolimbic to patients receiving neuroleptics without systems.’ Unfortunately, most neuroleptics are concomitant anti-EPS agents.Ig Risperidone, the relatively nonselective with regard to which newly marketed atypical neuroleptic, causes fewer dopamine pathways are affected, and dopamine EPS than the standard neuroleptics and has a high receptors in the striatum are also blocked. This affinity for 5-HT2 receptors.20*21 Clozapine also causes a relative deficiency of dopaminergic activity has relatively high affinity for 5-HTz receptors.12.l5 in the striatum, and a disturbance in the balance It is hypothesized that the low frequency of EPS between striatal dopaminergic and cholinergic associated with these two drugs is due to their 5- systems. Neuroleptic-induced EPS may result HT2-blocking action. This argument is particularly primarily from blockade of dopamine receptors in compelling for risperidone because the drug shows the striatum, but the imbalance between virtually no affinity for muscarinic receptors.2’ acetylcholine and dopamine systems in this area is also an important factor. Many treatment regimens Pathophysiology and Clinical Manifestations of aim to restore this balance by either reducing Drug-Induced EPS acetylcholine or increasing dopamine neuro- transmission in the striatum. In addition to their Table 1 lists the dopamine receptor-blocking dopamine receptor-blocking actions, neuroleptic potency and relative frequency of adverse effects of agents may also block cholinergic receptors, cx- commonly used neuroleptic agents.l0*l1 The adrenergic receptors, and histaminel receptors.”, l1 frequency of drug-induced EPS varies from 4-50% The propensity for a neuroleptic agent to induce depending on the specific The low- EPS depends not only on its dopamine receptor- potency agents are associated with a higher blocking potency but also on its inherent frequency of antiadrenergic (orthostatic hypo- anticholinergic activity. Neuroleptic agents are tension) and anticholinergic (dry mouth, consti- classified as low or high potency based on their pation, blurred vision) effects and a lower frequen- degree of dopamine receptor blockade. The high- cy of EPS, whereas the reverse is true for the high- potency agents possess a greater affinity for the potency drugs. Although higher dosages of dopamine receptor and lower cholinergic neuroleptics are generally associated with a higher (muscarinic) receptor affinity than